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The effects of alcohol and nicotine pretreatment during adolescence on adulthood responsivity to alcohol

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Title:
The effects of alcohol and nicotine pretreatment during adolescence on adulthood responsivity to alcohol
Physical Description:
Book
Language:
English
Creator:
Maldonado, Antoniette M
Publisher:
University of South Florida
Place of Publication:
Tampa, Fla.
Publication Date:

Subjects

Subjects / Keywords:
Addiction
Adolescent
Alcohol-nicotine interactions
Conditioned place preference
Novelty preference
Dissertations, Academic -- Psychology -- Masters -- USF   ( lcsh )
Genre:
bibliography   ( marcgt )
theses   ( marcgt )
non-fiction   ( marcgt )

Notes

Abstract:
ABSTRACT: Adolescence is a period of development that is associated with increased risk taking behaviors and experimenting with drugs of abuse, including alcohol and nicotine. Early onset of use of these agents may be associated with long-term changes in behavior and enhanced sensitivity to the subsequent effects of alcohol in adulthood. The present experiment was designed to assess the long-term behavioral alterations that occur due to adolescent exposure to ethanol and nicotine, either alone or in combination, on adulthood responsivity to the rewarding properties of environmental cues paired with ethanol. It was hypothesized that adolescent rats exposed to the combination of ethanol and nicotine would exhibit enhanced novelty seeking behaviors in adulthood. When assessing the rewarding properties of environmental cues paired with ethanol in adulthood using the CPP paradigm, it was hypothesized that adolescent rats exposed to the combination of a moderate dose of alcohol (0.75 g/kg) and nicotine (0.4 mg/kg) would more readily acquire a CPP in adulthood as compared to animals exposed to either drug alone. However, no changes in novelty seeking behaviors or conditioned place preference in adulthood were observed due to exposure to ethanol and/or nicotine during adolescence .Methodological considerations are discussed. Currently, other experiments are being conducted to assess the effects of nicotine on voluntary ethanol treatment in adolescent and adult male rats.
Thesis:
Thesis (M.A.)--University of South Florida, 2007.
Bibliography:
Includes bibliographical references.
System Details:
System requirements: World Wide Web browser and PDF reader.
System Details:
Mode of access: World Wide Web.
Statement of Responsibility:
by Antoniette M. Maldonado.
General Note:
Title from PDF of title page.
General Note:
Document formatted into pages; contains 58 pages.

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University of South Florida Library
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University of South Florida
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All applicable rights reserved by the source institution and holding location.
Resource Identifier:
aleph - 001935144
oclc - 225866278
usfldc doi - E14-SFE0002284
usfldc handle - e14.2284
System ID:
SFS0026602:00001


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The effects of alcohol and nicotine pretreatment during adolescence on adulthood responsivity to alcohol
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ABSTRACT: Adolescence is a period of development that is associated with increased risk taking behaviors and experimenting with drugs of abuse, including alcohol and nicotine. Early onset of use of these agents may be associated with long-term changes in behavior and enhanced sensitivity to the subsequent effects of alcohol in adulthood. The present experiment was designed to assess the long-term behavioral alterations that occur due to adolescent exposure to ethanol and nicotine, either alone or in combination, on adulthood responsivity to the rewarding properties of environmental cues paired with ethanol. It was hypothesized that adolescent rats exposed to the combination of ethanol and nicotine would exhibit enhanced novelty seeking behaviors in adulthood. When assessing the rewarding properties of environmental cues paired with ethanol in adulthood using the CPP paradigm, it was hypothesized that adolescent rats exposed to the combination of a moderate dose of alcohol (0.75 g/kg) and nicotine (0.4 mg/kg) would more readily acquire a CPP in adulthood as compared to animals exposed to either drug alone. However, no changes in novelty seeking behaviors or conditioned place preference in adulthood were observed due to exposure to ethanol and/or nicotine during adolescence .Methodological considerations are discussed. Currently, other experiments are being conducted to assess the effects of nicotine on voluntary ethanol treatment in adolescent and adult male rats.
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Addiction.
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Conditioned place preference.
Novelty preference.
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PAGE 1

T he E f f e c t s of A l c ohol a nd N i c ot i ne P r e t r e a t m e nt D ur i ng A dol e s c e nc e on A dul t hood R e s pons i vi t y t o A l c ohol by A nt oni e t t e M M a l dona do A t he s i s s ubm i t t e d i n pa r t i a l f ul f i l l m e nt of t he r e qui r e m e nt s f or t he de g r e e of M a s t e r s of A r t s D e pa r t m e nt of P s yc hol ogy C ol l e ge of A r t s a nd S c i e nc e s U ni ve r s i t y of S ou t h F l o r i da M a j or P r of e s s or : C he r yl L K i r s t e i n, P h D M a r k G ol dm a n, P h D T or u S hi m i z u, P h. D D a vi d J D r obe s P h. D D a t e of A ppr ova l : 18 O c t obe r 2007 K e yw or ds : a ddi c t i on, a dol e s c e nt a l c ohol ni c ot i ne i nt e r a c t i ons c ondi t i one d pl a c e pr e f e r e nc e nove l t y pr e f e r e nc e C opyr i ght 2007 A nt oni e t t e M M a l dona do

PAGE 2

D e di c a t i on T o m y m om S yl vi a A nn V a l de z M om you a r e m y ve r y be s t f r i e nd a nd I do not know w ha t I w oul d ha ve done w i t hout a l l o f t he s uppor t you ga ve m e t h r ough e ve r y s i ngl e s t e p of t hi s j ou r ne y. Y ou m a ke s uc h a di f f e r e nc e i n m y l i f e a nd I c a nnot e ve n be gi n t o de s c r i be how gr a t e f ul I a m t o ha ve you s t i l l he r e w i t h m e I t ha nk G od e ve r yda y f o r l e t t i ng m e ke e p you he r e w i t h m e t o e nj oy i t a l l e a c h a nd e ve r y da y.

PAGE 3

A c know l e dge m e nt s C he r yl t ha nk you f o r t he gr e a t m e nt or s hi p t hr ough out t he s e ye a r s K i m t ha nks f or t e a c hi ng m e a l l t he ba s i c s of e ve r yt hi ng I know K i r s t i e t ha nk you f o r be i ng s uc h a de a r f r i e nd t o he l p m e a l o ng t hr ou gh t hi s p r oc e s s a nd f o r a l l you r s uppor t Y our f r i e nds hi p i s i nva l ua bl e t o m e M a r i o t ha nk you f o r m a ki ng t he l a t t e r pa r t of t hi s p r oc e s s m uc h m or e be a r a bl e by ha vi ng you i n m y l i f e t o l i f t m y s pi r i t s w he n i t a l l s e e m e d t oo r ough T ha nk you t o L a ur e n F i nkbe i ne r K e nt A l i pour D a vi d O r t e ga a nd K r ys t a l M c F e e f or a l l o f your e xc e l l e nt t e c hni c a l a s s i s t a n c e

PAGE 4

T a bl e of C ont e nt s L i s t of F i gur e s i i i A bs t r a c t i v C ha pt e r O ne : B a c kgr ound 1 H um a n dr ug us e : E m pha s i s on A dol e s c e nt A l c ohol a nd C i ga r e t t e U s e 1 A ni m a l M ode l of A dol e s c e nc e 3 E f f e c t s of A l c ohol on B e ha vi or 4 A dul t s 4 A dol e s c e nt s 5 E f f e c t s of E t ha nol i n t he B r a i n 5 A dul t s 5 A dol e s c e nt s 7 L ong t e r m N e ur obe ha vi or a l E f f e c t s o f E t ha nol E x pos ur e D ur i ng A dol e s c e nc e 8 E f f e c t s of N i c ot i ne on B e ha vi or 9 A dul t s 9 A dol e s c e nt s 10 E f f e c t s of N i c ot i ne i n t he B r a i n 10 A dul t s 10 A dol e s c e nt s 11 C om bi ne d E f f e c t s of A l c ohol a nd N i c ot i ne on B e ha vi or 12 A dul t s 12 A dol e s c e nt s 13 C om bi ne d E f f e c t s of A l c ohol a nd N i c ot i ne i n t he B r a i n 14 O ve r vi e w of t he P r e s e nt S t udy 15 H ypot he s e s 16 C ha pt e r T w o: E f f e c t s of A l c ohol a nd / or N i c ot i ne P r e t r e a t m e nt D ur i ng A d ol e s c e nc e O n A dul t hood A l c ohol R e l a t e d B e ha vi or s M a t e r i a l s a nd M e t hods S ubj e c t s 18 A ppa r a t us 18 O pe n F i e l d 18 C ondi t i one d P l a c e P r e f e r e nc e A ppa r a t us 19 P r oc e dur e 19 P r e t r e a t m e nt 19 N ove l t y P r e f e r e nc e 20 i

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C ondi t i one d P l a c e P r e f e r e nc e 20 D e s i gn a nd A na l ys e s 21 C ha pt e r T hr e e : R e s ul t s 23 E f f e c t s of E t ha nol a nd/ or N i c ot i ne P r e t r e a t m e nt on N ove l t y R e l a t e d B e ha vi or s i n A dul t hood 23 N ove l t y I nduc e d E xpl o r a t i on 23 N ove l t y P r e f e r e nc e 24 N ove l E nvi r onm e nt I nduc e d E xpl or a t i on 25 E xa m i ni ng t he R e w a r di ng E f f e c t s t o E t ha nol A f t e r A do l e s c e nt T r e a t m e nt of A l c ohol a nd/ o r N i c ot i ne 26 C ha pt e r F i ve : D i s c us s i on 30 C om or bi d U s e of A l c ohol a nd N i c ot i ne i n H um a ns 30 C ondi t i one d P l a c e P r e f e r e nc e P a r a di gm a nd E t ha n ol H i s t or y 30 C om b i ne d E t ha nol a nd N i c ot i ne T r e a t m e nt 33 C onc l us i ons 36 R e f e r e nc e s 38 i i

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L i s t of F i gur e s F i gur e 1A : E t ha nol a nd/ o r N i c ot i ne D u r i ng A dol e s c e nc e D i d N ot 24 A l t e r N ove l t y I nduc e d E x pl or a t i on i n A dul t hood: C hr oni c E t ha nol a nd / or N i c ot i ne F i gur e 1B : E t ha nol a nd/ o r N i c ot i ne D u r i ng A dol e s c e nc e D i d N ot 24 A l t e r N ove l t y I nduc e d E xpl or a t i on i n A dul t hood: R e pe a t e d I nt e r m i t t e nt E t ha nol a nd/ o r N i c ot i ne F i gur e 2A : E t ha nol a nd/ o r N i c ot i ne D u r i ng A dol e s c e nc e D i d N ot 25 A l t e r N ove l t y P r e f e r e nc e i n A dul t hood: C hr oni c E t ha nol a nd/ o r N i c ot i ne F i gur e 2B : E t ha nol a nd/ o r N i c ot i ne D u r i ng A dol e s c e nc e D i d N ot 25 A l t e r N ove l t y P r e f e r e nc e i n A dul t hood: R e pe a t e d I nt e r m i t t e nt E t ha nol a nd/ or N i c ot i ne F i gur e 3A : E t ha nol a nd/ o r N i c ot i ne D u r i ng A dol e s c e nc e D i d N ot 26 A l t e r N ove l E nvi r onm e nt I nduc e d E xpl or a t i on i n A dul t hood: C hr oni c E t ha nol a nd/ o r N i c ot i ne F i gur e 3B : E t ha nol a nd/ o r N i c ot i ne D u r i ng A dol e s c e nc e D i d N ot 26 A l t e r N ove l E nvi r onm e nt I nduc e d E xpl or a t i on i n A dul t hood: R e pe a t e d I nt e r m i t t e nt E t ha nol a nd/ or N i c ot i ne F i gur e 4: C hr oni c E t ha nol a nd / or N i c ot i ne T r e a t m e nt D ur i n g 28 A dol e s c e nc e D i d N ot A l t e r C ondi t i one d P l a c e P r e f e r e nc e i n A dul t hood F i gur e 5: R e pe a t e d I nt e r m i t t e nt E t ha nol a nd/ o r N i c ot i ne T r e a t 29 m e nt D ur i ng A dol e s c e nc e D i d N ot A l t e r C ondi t i o ne d P l a c e P r e f e r e nc e i n A dul t hood i i i

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T he E f f e c t s of A l c ohol a nd N i c ot i ne P r e t r e a t m e nt D ur i ng A dol e s c e nc e on A dul t hood R e s pons i vi t y t o A l c ohol A nt oni e t t e M M a l dona do A B S T R A C T A dol e s c e nc e i s a p e r i od of de ve l opm e nt t h a t i s a s s oc i a t e d w i t h i nc r e a s e d r i s k t a ki ng be ha vi or s a nd e xpe r i m e nt i ng w i t h dr ugs of a bus e i nc l udi ng a l c ohol a nd ni c ot i ne E a r l y ons e t of us e of t he s e a ge nt s m a y be a s s oc i a t e d w i t h l ong t e r m c ha nge s i n be ha vi or a n d e nha nc e d s e n s i t i vi t y t o t he s ubs e que nt e f f e c t s o f a l c ohol i n a dul t hood. T he p r e s e nt e xpe r i m e nt w a s de s i gne d t o a s s e s s t he l ong t e r m be ha vi or a l a l t e r a t i ons t ha t oc c ur du e t o a dol e s c e nt e xpos ur e t o e t ha nol a nd ni c ot i ne e i t he r a l one or i n c om bi na t i on, on a dul t hood r e s pons i vi t y t o t he r e w a r di ng pr ope r t i e s of e nvi r onm e nt a l c ue s pa i r e d w i t h e t ha nol I t w a s hypot he s i z e d t ha t a dol e s c e nt r a t s e xpos e d t o t he c om bi na t i on of e t ha nol a nd n i c ot i ne w oul d e xhi bi t e nha nc e d nove l t y s e e ki ng be ha vi o r s i n a dul t hood. W he n a s s e s s i ng t he r e w a r di ng pr ope r t i e s of e nvi r onm e nt a l c ue s pa i r e d w i t h e t ha nol i n a dul t hood us i ng t he C P P pa r a di gm i t w a s hypot he s i z e d t ha t a dol e s c e nt r a t s e xpos e d t o t he c om bi na t i on o f a m ode r a t e dos e of a l c ohol ( 0. 75 g/ kg) a nd ni c ot i ne ( 0. 4 m g/ kg) w oul d m o r e r e a di l y a c qui r e a C P P i n a dul t hood a s c om pa r e d t o a ni m a l s e xpos e d t o e i t he r dr ug a l one H ow e ve r no c ha nge s i n nove l t y s e e ki ng be ha vi or s or c ondi t i one d pl a c e pr e f e r e nc e i n a dul t h ood w e r e obs e r ve d due t o e xpos ur e t o e t ha nol a nd/ or n i c ot i ne dur i ng a dol e s c e nc e i v

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M e t hodol ogi c a l c ons i de r a t i ons a r e di s c us s e d. C ur r e nt l y, ot he r e xpe r i m e nt s a r e be i ng c onduc t e d t o a s s e s s t he e f f e c t s of ni c ot i ne on vol unt a r y e t ha nol t r e a t m e nt i n a dol e s c e nt a nd a dul t m a l e r a t s v

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C ha pt e r O ne : B a c kgr ound H um an D r ug U s e : E m phas i s on A do l e s c e nt A l c oh ol and C i gar e t t e U s e A l c ohol a nd c i ga r e t t e s a r e t w o of t he m os t w i de l y us e d dr ugs of a bus e ( S A M S H A 2003) a nd t he c o us e a nd a bus e of a l c ohol a nd ni c ot i ne i s w e l l doc um e nt e d i n hum a ns ( B i e n & B ur ge 1990 ; I s t va n & M a t a r a z z o, 1984; M i l l e r & G ol d, 1998) I nt e r e s t i ngl y, i nd i vi dua l s de pe nde nt on c i ga r e t t e s c ons um e a ppr oxi m a t e l y t w i c e a s m uc h a l c ohol a s nons m oke r s ( C a r m ody e t a l 1985) a nd i t ha s be e n e s t i m a t e d t ha t up t o 90 % o f a l c ohol i c s a r e r e gul a r s m oke r s ( B a t e l e t a l 1995; B i e n & B ur ge 1990; D i F r a nz a & G ue r r e r a 1990 ; G r a nt 1998; M i l l e r & G ol d 1998 ) C ons i de r a bl e e vi de nc e i ndi c a t e s t ha t us e of e i t he r of t he s e s ubs t a nc e s i nc r e a s e s a s s oc i a t e d r i s k f or di s e a s e de ve l opm e nt a nd i nde e d, t he c om b i ne d he a l t h r i s ks of a l c ohol a nd s m oki ng a r e e s t i m a t e d t o be a s m uc h a s 50% hi ghe r t ha n t he us e of e i t he r s ubs t a nc e a l one ( B i e n & B ur ge 1990 ) I t i s i m por t a nt t o not e t ha t a dol e s c e nc e i s a c om m on de ve l opm e nt a l pe r i od i n w hi c h i ni t i a t i on of us e of t he s e s ubs t a nc e s oc c ur s S ubs t a nt i a l e vi de nc e s uppor t s t he not i on t ha t a dol e s c e nc e i s a uni que de ve l opm e nt a l pe r i od i n w hi c h i ndi vi dua l s a r e m or e l i ke l y e nga ge i n r i s k t a ki ng be ha vi or s uc h a s e xp e r i m e nt i ng w i t h d r ugs of a bu s e i nc l udi ng a l c ohol a nd c i ga r e t t e s A l c ohol i s not onl y one of t he m os t c om m onl y a bu s e d ps yc hoa c t i ve s ub s t a nc e s but a l s o t he us e of a l c ohol i s qui t e p r e va l e nt i n a dol e s c e nt s ( B a t e s & L a bouvi e 1997; W i ndl e 1990) D ur i ng t he a dol e s c e nt pe r i od, t he r e i s a dr a m a t i c i nc r e a s e i n t he us e of a l c ohol 1

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w i t h a s m a ny a s 43% of 8 t h gr a de 65% of 10 t h g r a de a nd 73 % of 12 t h g r a de s t ude nt s r e por t e d us i ng a l c ohol i n t he pa s t ye a r a nd 8% 24 % a nd 32 % r e s pe c t i ve l y, r e po r t e d be i ng dr un k i n t he pa s t m on t h ( J ohns t on e t a l 200 1) A ddi t i ona l l y t he t i m e c our s e f r om c a s ua l us e t o de pe nde nc e on a l c ohol dur i ng a dol e s c e nc e i s a c c e l e r a t e d r e l a t i ve t o a dul t s w ho i ni t i a t e us e a f t e r t he a ge o f 21 ( C l a r k e t a l 19 98) I m po r t a nt l y, i t ha s be e n s ugge s t e d t ha t us e of a l c ohol dur i ng t he a dol e s c e nt de ve l opm e nt a l pe r i od m a y r e nde r i ndi vi dua l s a t m or e r i s k f o r de ve l opi ng de pe nde nc e on a l c ohol ( A nde r s e n e t a l 2003; D e w i t e t a l 2000; H a w ki ns e t a l 1997 ; R os e e t a l 2001) a nd t o a bus e a l c ohol a s a d ul t s ( D unc a n e t a l 1997 ) T he s e da t a s ugge s t t ha t l e ve l of c ons um pt i on of a l c ohol i s hi gh i n a dol e s c e nt s a nd t ha t i ni t i a t i on of us e dur i ng t hi s pe r i od c a n pr oduc e l ong t e r m c ha nge s i n a l c ohol r e l a t e d be ha vi or s A ddi t i ona l l y, t he r a t e s of s m oki ng i ni t i a t i on dur i ng a dol e s c e nc e a r e a l s o e xt r e m e l y hi gh, w i t h a s m a ny a s 50% o f hi gh s c hool s t ude nt s r e por t e d ha vi ng t r i e d c i ga r e t t e s a t l e a s t onc e i n t he i r l i f e t i m e a nd 25 % of t hos e i ndi vi dua l s pr og r e s s i ng t o s us t a i ne d c i ga r e t t e us e i n a dul t hood ( C D C 2001 ) A ppr oxi m a t e l y 80 % o f i ndi vi dua l s w ho s m oke s t a r t e d be f or e t he a ge of 18 ( C D C 200 1) a nd i t ha s be e n s ugge s t e d t ha t t he l e ve l of a ddi c t i on t o ni c ot i ne i s hi ghe r a m ong i ndi vi dua l s w ho i ni t i a t e us e of t hi s s ubs t a nc e a t a n e a r l y a ge ( K a nde l & C he n, 2000; T a oi l i & W ynde r 1991 ) I m por t a nt l y t he r e a ppe a r s t o be a s t r ong c or r e l a t i on be t w e e n a g e of ons e t of s m oki ng a nd l e ve l of de pe nde nc e on a l c ohol a nd t he p r ope ns i t y t o de ve l op a ddi c t i on t o t he s e s ubs t a nc e s l a t e r i n l i f e ( A be l s on e t a l 1977; D i F r a nz a & G ue r r e r a 1 990; G r a nt 1998 ) A l l of t he s e da t a de m ons t r a t e a n i nc r e a s e d vul ne r a bi l i t y o f a dol e s c e nt s t o a l c ohol a nd c i ga r e t t e us e a nd l ong t e r m be ha vi or a l e f f e c t s t ha t m a y a r i s e f r om u s e of one or bot h o f t he s e s ubs t a nc e s 2

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dur i ng t hi s de ve l opm e nt a l pe r i od. A l t ho ugh i t i s i m por t a nt t o not e t ha t s t udyi ng t he e f f e c t s of a dol e s c e nt a l c ohol a nd ni c ot i ne e xpos ur e i s c r i t i c a l i t i s une t hi c a l t o s ys t e m a t i c a l l y e xa m i ne t he e f f e c t s of t he s e s ubs t a nc e s i n hum a n a dol e s c e nt s T he r e f or e i t i s i m por t a nt t o de ve l op a n a dol e s c e nt a ni m a l m ode l t o e na bl e s ys t e m a t i c i nve s t i ga t i on of t he s hor t t e r m a nd l ong t e r m e f f e c t s of a l c ohol a nd ni c ot i ne e xpos ur e dur i ng a dol e s c e nc e on s ubs e que nt a dul t hood r e s pons i vi t y t o t he s e a ge nt s A ni m al M ode l of A dol e s c e nc e A dol e s c e nc e i s a t i m e of c ha ng e t ha t i s m a r ke d by m a ny f a c t or s i nc l udi ng t he ons e t of pube r t y hor m ona l c ha nge s gr ow t h s pur t a nd i nc r e a s e d i nt e r a c t i ons w i t h pe e r s ( f or r e vi e w s e e S pe a r 2000) I n r ode nt s a dol e s c e nc e i s ge ne r a l l y a c c e pt e d t o oc c ur f r om a bout pos t na t a l da y ( P N D ) 28 t o 42 ( S pe a r & B r a k e 1983) a nd l a s t unt i l a ppr oxi m a t e l y P N D 55 ( O j e da & U r ba ns ki 1994) A dol e s c e nt r o de nt s ha ve be e n s how n t o de m ons t r a t e i nc r e a s e d nove l t y s e e ki ng ( S t a ns f i e l d e t a l 2004; S t a ns f i e l d & K i r s t e i n 2006) a nd s oc i a l i nt e r a c t i ons w i t h pe e r s ( P r i m us & K e l l ogg, 1989; f or r e vi e w s e e S pe a r 2000 ) I n a ddi t i on t o be ha vi or a l c ha nge s t he a dol e s c e nt br a i n i s unde r goi ng m a j or c ha nge s dur i ng t hi s de ve l opm e nt a l pe r i od ( f or r e vi e w s e e S pe a r 2 000) F or e xa m pl e dopa m i ne r gi c i nput t o t he pr e f r ont a l c or t e x i s s t i l l de ve l opi ng dur i ng t hi s pe r i od ( K a l s be e k e t a l 1988 ; R os e nbe r g & L e w i s 1994 ) a s a r e a m ygda l a r pr oj e c t i ons t o c or t i c a l a r e a s ( C unni ngha m e t a l 2002 ) L i m i t e d da t a s ugge s t t ha t e xpos ur e t o d r ugs of a bus e dur i ng t hi s t i m e m a y a l t e r nor m a l de ve l opm e nt a l pr oc e s s e s r e nde r i ng t h e br a i n m o r e vul ne r a bl e t o a c qui r i ng s ubs t a nc e us e di s or de r s i n a dul t hood ( f or r e vi e w s e e C ha m be r s e t a l 2003; S m i t h 2003) a nd t he ne e d f o r a n a ni m a l m ode l t o a s s e s s t he e f f e c t s of e t ha nol on de ve l opm e nt ha s 3

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be e n r a i s e d ( W i t t 1994) E f f e c t s of E t hanol on B e hav i or A dul t s E t ha nol ha s be e n s how n t o pr oduc e di f f e r e nt e f f e c t s on be ha vi or i n a dul t a ni m a l s t ha t m a y be r e l a t e d t o t he r e w a r di ng a nd r e i n f or c i n g or a ve r s i ve p r ope r t i e s of e t ha nol A l c ohol ha s bi pha s i c e f f e c t s on be ha vi or ( L e w i s & J une 1990) a nd s om e s t udi e s ha ve yi e l de d m i xe d r e s ul t s us i ng l ow a nd hi gh dos e s of e t ha nol I n a dul t r a t s hi gh dos e s of e t ha nol pr oduc e s e da t i ve / hypnot i c e f f e c t s on be ha vi or s s uc h a s m ot or c oor di na t i on ( W hi t e e t a l 2002) a nd l oc om ot or a c t i vi t y ( e g L i t t l e e t a l 1996) a nd a ppe a r t o be a ve r s i ve i n a c ondi t i one d pl a c e p r e f e r e nc e ( C P P ) p a r a di gm ( va n de r K ooy e t a l 1983 ) I n c ont r a s t l ow dos e s of e t ha nol ha ve be e n s how n t o pr oduc e s t i m ul a t or y e f f e c t s of l oc om ot or a c t i vi t y ( C or r e a e t a l 2003 ) w he n a ni m a l s w e r e s e pa r a t e d i nt o hi gh a nd l ow r e s ponde r s t o nove l t y ( H os ha w & L e w i s 2001) A dul t a ni m a l s ha ve be e n s how n t o de m ons t r a t e e t ha nol i nduc e d C P P ( B oz a r t h, 1990; B i e nkow s ki e t a l 1995; G a uvi n & H ol l ow a y, 1992) how e ve r ot he r s ha ve ha d di f f i c u l t y de m ons t r a t i ng e t ha nol i nduc e d C P P i n a dul t a ni m a l s ( A s i n e t a l 1985) I t i s i m p or t a nt t o not e t ha t t he de ve l opm e nt o f a n e t ha nol i nduc e d C P P i s de pe nde nt on pr e vi ous a l c ohol t r e a t m e nt ( B oz a r t h 1990; B i e nkow s ki e t a l 1995; G a uvi n & H ol l ow a y, 199 2) T hus i t a ppe a r s t ha t i n a dul t a ni m a l s pr i or e xpos ur e t o e t ha nol i s ne c e s s a r y f or t he de ve l opm e nt of a n e t ha nol i nduc e d C P P A l l o f t he s e da t a de m ons t r a t e t he c om pl e xi t y of t he e f f e c t s of a l c ohol on be ha vi or i n a dul t a ni m a l s H i gh a nd l ow dos e s of e t ha nol h a ve di f f e r e nt e f f e c t s on be ha vi or a nd pr i or e xpos ur e t o a l c ohol c a n a l t e r C P P N ove l t y r e l a t e d be ha vi or s a l s o a ppe a r t o be r e l a t e d t o a l c ohol s e f f e c t s on be ha vi or G i ve n t ha t a dol e s c e nt s a ppe a r t o be di f f e r e nt i a l l y 4

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s e ns i t i ve t o t he e f f e c t s of a l c ohol r e l a t i ve t o a dul t s i t i s i m por t a nt t o e xa m i ne t he l ong t e r m be ha vi or a l e f f e c t s of a l c ohol dur i ng t hi s de ve l opm e nt a l pe r i od. A dol e s c e nt s A dol e s c e nt r a t s a r e e s pe c i a l l y s e ns i t i ve t o t he e f f e c t s of a l c ohol on a num be r of be ha vi or a l m e a s ur e s ( f or a r e vi e w s e e S pe a r & V a r l i ns ka ya 2005) A dol e s c e nt s ha ve be e n r e por t e d t o be l e s s s e ns i t i ve t o t he s e da t i ve / hypnot i c a nd m ot or i nc oor di na t i ng e f f e c t s of a l c ohol ( L i t t l e e t a l 1996; S i l ve r i & S pe a r 1998; W hi t e e t a l 2002) t o d e ve l op a n e t ha nol i nduc e d C P P m or e r e a di l y ( P hi l pot B a da ni c h & K i r s t e i n, 2003) a nd t o vol unt a r i l y c ons um e m or e e t ha nol t ha n a dul t s ( D or e m us e t a l 2005) A ddi t i ona l l y a dol e s c e nt r a t s r e a c h pe a k bl ood e t ha nol c onc e nt r a t i ons ( L i t t l e e t a l 1996) a nd de ve l op t ol e r a nc e t o a l c ohol m o r e r a pi dl y t ha n a dul t s ( S i l v e r i & S pe a r 1999) T oge t he r t he s e da t a s ugge s t t ha t a dol e s c e nt s e xpe r i e nc e m or e of t he r e w a r di ng p r ope r t i e s of e t ha nol t ha n a dul t s r e nde r i ng t he m e s pe c i a l l y s e ns i t i ve t o t he e f f e c t s of e t ha nol I m por t a nt l y, t he e f f e c t s of e t ha nol p r e t r e a t m e nt du r i ng a dol e s c e nc e ha ve be e n s how n t o pr oduc e l ong t e r m be ha vi or a l a l t e r a t i ons i n nove l t y pr e f e r e nc e ( S t a ns f i e l d & K i r s t e i n, a c c e pt e d pe ndi ng r e vi s i ons ) a nd l oc om ot o r a c t i vi t y ( M a l don a do & K i r s t e i n, m a nus c r i pt i n pr e p) i n a dul t hood. A l l of t he s e da t a de m ons t r a t e t ha t a dol e s c e nt s a nd a dul t s a r e di f f e r e nt i a l l y s e ns i t i ve t o t he be ha vi or a l e f f e c t s of e t ha nol a nd t h a t e t ha nol c a n pr oduc e l ong t e r m c ha nge s i n nove l t y pr e f e r e nc e a nd e t ha nol r e l a t e d be ha vi or s i n a d ul t hood, w hi c h m a y be m e di a t e d by e t ha nol s e f f e c t s on t he de ve l opi ng br a i n. E f f e c t s of E t hanol i n t he B r ai n A dul t s E t ha nol ha s be e n s how n t o pr oduc e a nu m be r o f ne ur oc he m i c a l a l t e r a t i ons i n t he 5

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a dul t br a i n t ha t m a y be r e l a t e d t o t he r e w a r di ng a n d r e i nf or c i ng a s w e l l a s a ve r s i ve pr ope r t i e s of e t ha nol A m ong ot he r ne ur oc he m i c a l s ys t e m s a f f e c t e d by e t ha nol t he m e s ol i m bi c dopa m i ne ( D A ) s ys t e m ha s be e n i m pl i c a t e d i n t he e f f e c t s of e t ha nol a nd ot he r dr ugs o f a bus e m e di a t i ng t he r e w a r di ng e f f e c t s a s s oc i a t e d w i t h t he s e dr ugs ( K oob, 1992; M ogha dda m & B unne y, 1989; N a ka ha r a e t a l 1989 ; P hi l l i ps e t a l 1992; W i s e & R om pr e 1989) E t ha nol ha s be e n s how n t o i nc r e a s e a c t i vi t y of t he m e s ol i m bi c D A pa t hw a y ( A ppe l e t a l 2004; B l om qvi s t e t a l 199 3; E nge l e t a l 1988 I m pe r a t o & D i C hi a r a 1986; L a r s s on e t a l 2004; M e r e u e t a l 19 84; W e i s s e t a l 1993 ) vi a a c t i va t i on of ve nt r a l t e gm e nt a l a r e a ( V T A ) ne ur ons ( G e s s a e t a l 1985) M os t s t udi e s de m ons t r a t e a dos e r e s pons e r e l a t i ons hi p w i t h l ow t o m ode r a t e dos e s pr oduc i ng a n i nc r e a s e i n D A w hi l e hi ghe r dos e s pr oduc e a de c r e a s e i n a c c um ba l D A a nd D A a c t i vi t y ( W i l l i a m s H e l m s by & P or r i no 1994 ) H ow e ve r s om e s t udi e s ha ve s how n t ha t a dm i ni s t r a t i on o f hi gh dos e s of e t ha nol ( i e 2 3 g / kg) e l e va t e a c c um ba l D A f or up t o 2 hour s ( K ohl e t a l 1998) R a t s w i l l s e l f a dm i ni s t e r e t ha nol di r e c t l y i nt o t he V T A ( G a t t o e t a l 1994 ) a nd pha r m a c ol ogi c a l m a ni pul a t i on of D A ne ur ot r a ns m i s s i on m odi f i e s s e l f a dm i ni s t r a t i on a nd pr e f e r e nc e of a l c ohol ( W e i s s e t a l 1990; S a m s on e t a l 1993; G e o r ge e t a l 1995; P a noc ka e t a l 1995) G onz a l e s a nd c ol l e a gue s ( 2 004) s ugge s t t ha t i ni t i a l i nc r e a s e s i n a c c um ba l D A i n a ni m a l s pr e vi ous l y t r e a t e d w i t h e t ha nol a r e m e di a t e d by c ue s r a t he r t ha n t he a c t ua l pha r m a c ol ogi c a l e f f e c t s o f e t ha nol c on s um pt i on. T a ke n t oge t he r t he s e s t udi e s i m pl y t ha t ne u r oc he m i c a l di f f e r e nc e s w i t hi n t he nu c l e us a c c um be ns s e pt i ( N A c c ) i nf l ue nc e t he r e i n f or c i ng na t u r e of e t ha nol a nd r e s ul t i n a c or r e s pondi ng c ha nge i n be ha vi or a l out put w hi c h m a y be de pe nde nt on c ue s a s s oc i a t e d w i t h pr e vi ous e xpos ur e t o e t ha nol 6

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A dol e s c e nt s R e w a r d m e c ha ni s m s i n t he br a i n, i nc l udi ng a l t e r a t i ons of t he m e s ol i m bi c D A s ys t e m c ont i nue t o unde r go s i gni f i c a nt de ve l opm e nt a l c ha nge s dur i ng a dol e s c e nc e ( L i dow e t a l 1991; N a ka no e t a l 1996; S e e m a n e t a l 1987; S pe a r 2000; T e i c he r e t a l 1995 ) H ow e ve r r e l a t i ve l y l i t t l e i n f or m a t i on i s a va i l a bl e r e l a t e d t o c ha nge s i nduc e d by e t ha nol i n t he de ve l opi ng a dol e s c e nt br a i n a nd how t he s e c ha nge s m a y be a s s oc i a t e d w i t h t he di f f e r e nt i a l s e n s i t i vi t y o f a dol e s c e nt s t o e t ha nol F ol l ow i ng r e pe a t e d t r e a t m e nt w i t h e t ha nol pe r i a dol e s c e nt a ni m a l s ( pos t na t a l da y ( P N D ) 25) ha ve be e n s how n t o e xhi bi t a s hi f t t o t he l e f t i n t he t e m por a l pe a k of s t i m ul a t e d D A r e l a t i ve t o t he e f f e c t s o f a c ut e l y a dm i ni s t e r e d e t ha nol ( P hi l po t & K i r s t e i n, 1998) A ddi t i ona l l y, a dol e s c e nt ( P N D 45) r a t s ha ve be e n s how n t o ha ve gr e a t e r ba s a l D A l e ve l s a nd l a c k of c ha nge i n D O P A C / D A t ur nove r r a t i o r e l a t i ve t o younge r a nd ol de r a ni m a l s ( P hi l pot & K i r s t e i n 2004) T hi s uni que ne u r oc he m i c a l pr of i l e i n a dol e s c e nt a ni m a l s m a y be i ndi c a t i ve o f a l a c k of t ol e r a nc e t o t he r e w a r di ng e f f e c t s of et hanol T he s e s pe c i f i c a ge r e l a t e d ne ur oc he m i c a l pa t t e r ns r e l a t e d t o m e s ol i m bi c D A m a y be i m pl i c a t e d i n t he r e w a r di ng e f f e c t s of e t ha nol t ha t i s uni que t o a dol e s c e nt s A l t hough a dol e s c e nt s a r e l e s s s e ns i t i ve be ha vi or a l l y t o m a ny of t he e f f e c t s of et ha nol w he n f oc us i ng on br a i n a l t e r a t i ons a dol e s c e nt s a ppe a r m or e s e ns i t i ve t o c or t i c a l a nd hi ppoc a m pa l ne ur ot oxi c a l t e r a t i ons i nduc e d by e t ha nol S w a r t z w e l de r a nd c ol l e a gue s obs e r ve d t ha t a dol e s c e nt s s uf f e r e d f r om m or e e t ha nol i nduc e d di s r upt i ons of hi ppoc a m pa l pl a s t i c i t y a nd m e m or y ( S w a r t z w e l de r e t a l 1995a b ) I n a hi ppoc a m pa l de pe nde nt t a s k, a dol e s c e nt s a l s o a ppe a r t o be m or e i m pa i r e d i n t he M or r i s w a t e r m a z e t o 1. 0 or 2. 0 g/ kg e t ha nol ( M a r kw e i s e e t a l 1998 ) a n d l a r ge r i m pa i r m e nt s i n w or ki ng 7

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m e m or y w e r e obs e r ve d i n a dol e s c e nt a ni m a l s e xpos e d t o r e pe a t e d 5. 0 g/ kg e t ha nol e ve r y 48 hour s ( W hi t e e t a l 2000 ) C r e w s a nd c ol l e a gu e s ha ve a l s o s e e n gr e a t e r e t ha nol i nduc e d ne ur ot oxi c i t y i n a dol e s c e nt a ni m a l s ( C r e w s e t a l 2000, 2006) S pe c i f i c a l l y a dol e s c e nt s de m ons t r a t e d m or e f r ont a l da m a ge f ol l ow i ng a bi nge m ode l of e t ha nol a dm i ni s t r a t i on ove r a pe r i od o f f our da ys t o 9 10 g / kg/ da y ( C r e w s e t a l 2000) a nd i nhi bi t i on of ne ur oge ne s i s i n hi ppoc a m pa l a nd f or e br a i n r e gi ons f o l l ow i ng a c ut e et hanol a dm i ni s t r a t i on ove r a r a nge o f e t ha nol dos e s r a ngi ng f r om 1. 0 5. 0 g/ kg ( C r e w s e t a l 2006) A l l of t he s e da t a i ndi c a t e t ha t a dol e s c e nt a ni m a l s a r e uni que l y s e ns i t i ve t o t he e f f e c t s of e t ha nol i n t he b r a i n, w i t h i nc r e a s e d D A r e l a t e d a c t i vi t y a nd gr e a t e r hi ppoc a m pa l a nd c or t i c a l da m a ge i nduc e d by e t ha nol T he s e a l t e r a t i ons oc c ur r e d dur i ng a dol e s c e nc e a nd r e s ul t e d i n l ong t e r m ne ur oa da pt a t i ons w hi c h a ppe a r s t o c a us e l ong t e r m c ha nge s i n et hanol a s s oc i a t e d be ha vi or s L ong t e r m N e ur obe hav i or al E f f e c t s of E t hanol E x pos ur e D ur i ng A dol e s c e nc e A dol e s c e nt s ha ve be e n s how n t o be uni que l y s e ns i t i ve t o t he e f f e c t s of e t ha nol w i t h l e s s s e ns i t i vi t y e xpr e s s e d be ha vi or a l l y, but g r e a t e r ne ur ot oxi c e f f e c t s obs e r ve d i n t he br a i n. W he n a ni m a l s w e r e e xpos e d t o e t ha nol dur i ng pr e w e a ni ng ( H a ya s hi & T a dokor o 1985) o r pos t w e a ni ng ( H o e t a l 1989) l a t e r i nc r e a s e s i n pr e f e r e nc e f or e t ha nol w e r e obs e r ve d. H ow e ve r ot he r s ha ve r e por t e d no c ha ng e i n pr e f e r e nc e f or e t ha nol l a t e r i n l i f e w he n pr e e xpos ur e oc c ur r e d dur i ng a dol e s c e nc e ( K a ki ha na & M c C l e a n, 1963; P a r i s e l l a & P r i t ha m 1964; T ol l i ve r & S a m s on, 1991) E xpos u r e t o e t ha nol dur i ng a dol e s c e nc e ha s be e n s how n t o i nduc e i m pa i r m e nt s i n a t t e nt i on a nd m e m or y ( S l a w e c ki e t a l 2004) a nd f e a r c ondi t i oni ng ( B e r gs t r om e t a l 2006 ) i n a dul t h ood. A ddi t i ona l l y, a dol e s c e nt e t ha nol e xpos ur e pr oduc e d e nha nc e d a nxi e t y a nd de pr e s s i ve l i ke be ha vi or s ( S l a w e c ki e t a l 8

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2004) a nd l ong t e r m t ol e r a nc e i n a dul t hood ( S i l ve r s e t a l 2003) E xpos ur e t o e t ha nol dur i ng a dol e s c e nc e i m pa i r e d s pa t i a l m e m or y ( S i r c a r & S i r c a r 2005) a nd a l t e r e d hi ppoc a m pa l m e di a t e d ne ur ophys i ol ogi c a l f unc t i o n ( S l a w e c ki e t a l 2001) i n a dul t ho od. F ur t he r m or e a dol e s c e nt e t ha nol dr i nk i ng ha s be e n s how n t o a l t e r s t i m ul a t e d e t ha nol i nduc e d D A e f f l ux i n a dul t hood i n a l c ohol pr e f e r r i ng ( P ) r a t s ( S a hr e t a l 2004 ) A l l o f t he s e da t a s ugge s t t ha t i nde e d, a dol e s c e nt e t ha nol e xpos ur e pr oduc e s l ong t e r m be ha vi or a l a nd ne ur oc he m i c a l a l t e r a t i ons i n a nxi e t y a nd de pr e s s i ve l i ke be ha vi or s a nd a da pt a t i ons of hi ppoc a m pa l a nd D A s ys t e m s H o w e ve r l ong t e r m a l t e r a t i ons t o t he r e w a r di ng e f f e c t s of e t ha nol a nd i m por t a nt l y t he l ong t e r m e f f e c t s of ot he r dr ugs s uc h a s ni c ot i ne on e t ha nol r e l a t e d be ha vi or s ha ve not be e n s ys t e m a t i c a l l y i nve s t i ga t e d. N i c ot i ne E f f e c t s on B e hav i or A dul t s N i c ot i ne i s be l i e ve d t o be t he m a j or ps yc hoa c t i ve s ubs t a nc e i n c i ga r e t t e s t ha t dr i ve s a ddi c t i on. A ni m a l m ode l s us i ng ni c ot i ne ha ve s how n t ha t a d ul t a ni m a l s de ve l ope d di f f e r e nt be ha vi or a l r e s pons e s t o ni c ot i ne R e pe a t e d e xpos ur e t o ni c ot i ne i n a dul t r a t s ha s be e n s how n t o r e s ul t i n be ha vi or a l s e ns i t i z a t i on ( B e nw e l l & B a l f ou r 1992; C l a r ke & K um a s r 1983; J a nhune n e t a l 2005; W a l t e r & K us c hi ns ky, 1989) w hi c h ha s be e n s ugge s t e d t o be c ue de pe nde nt ( S c hr oe de r e t a l 2 001) A ddi t i ona l l y, a dul t r a t s ha ve a l s o be e n s how n t o s e l f a dm i ni s t e r ni c ot i ne ( C or r i ga l l 1992; D onne y e t a l 1995, S hoa i b e t a l 1997 ) N i c ot i ne ha s be e n s how n t o b e r e w a r di ng i n a dul t a ni m a l s us i ng a C P P pa r a di gm w i t h s e ve r a l r e por t s s uppor t i ng t he a bi l i t y of ni c ot i ne t o e s t a bl i s h a C P P a t dos e s r a ngi ng f r om 0. 1 2 0 m g/ kg ( s c ) w i t h m a xi m a l c ondi t i oni ng a t t he m ode s t dos e s r a ngi ng f r om 0. 1 t o 1 4 m g/ kg/ s c ( F uda l a e t a l 198 5 ; J a nhune n e t a l 2005; L e 9

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F ol l & G ol dbe r g, 2005) A l l o f t he s e da t a de m ons t r a t e t ha t a dul t a ni m a l s r e s pond t o ni c ot i ne i n a m a nne r t ha t l e a ds t o i nc r e a s e d r e w a r d a s s oc i a t e d w i t h r e pe a t e d dr ug e xpos ur e G i ve n t ha t a dol e s c e nt s a nd a dul t s a r e di f f e r e nt i a l l y r e s pons i ve t o ni c ot i ne i t i s i m por t a nt t o f oc us on t hi s c r i t i c a l de ve l opm e nt a l pe r i od w he n us e of c i ga r e t t e s i n hum a ns i s hi gh. A dol e s c e nt s T o da t e onl y a l i m i t e d num be r o f s t udi e s ha ve i nv e s t i ga t e d be ha vi or a l di f f e r e nc e s of ni c ot i ne be t w e e n a d ol e s c e nt a nd a dul t a ni m a l s A dol e s c e nt a ni m a l s ha ve be e n s how n t o s e l f a dm i ni s t e r hi ghe r l e ve l s of ni c ot i ne ( L e vi n e t a l 2003) a nd e xhi bi t f e w e r s om a t i c s i gns of w i t hdr a w a l t ha n a dul t s ( O D e l l e t a l 200 6) A ge r e l a t e d di f f e r e nc e s i n t he a nxi ol yt i c a nd r e w a r di ng e f f e c t s of ni c ot i ne i n a dol e s c e nt s r e l a t i ve t o a dul t s ha ve be e n i nve s t i ga t e d, w i t h a dol e s c e nt s e xhi bi t i ng gr e a t e r a nxi ol yt i c e f f e c t s ( T or e l l a e t a l 2004 ; V a s t ol a e t a l 2002 ) a nd r e w a r d ( S hr a m e t a l 2006 ; V a s t ol a e t a l 2002) t o a m ode r a t e do s e of ni c ot i ne a s c om pa r e d t o a dul t s H ow e ve r a n a bs e nc e of dr ug c ue c ondi t i on i ng ha s a l s o be e n de m ons t r a t e d i n pe r i a dol e s c e nt a ni m a l s ( S c hoc he t e t a l 2004 ) R e pe a t e d a dm i ni s t r a t i on of ni c ot i ne dur i ng a dol e s c e nc e ha s be e n s how n t o i nc r e a s e s e l f a dm i ni s t r a t i on i n a dul t hood ( A dr i a ni e t a l 2003) T he s e da t a s ugge s t t ha t a dol e s c e nt s a r e m or e s e ns i t i ve t o t he r e w a r di ng e f f e c t s a nd l e s s s e ns i t i ve t o t he a ve r s i ve e f f e c t s of ni c ot i ne a s c om pa r e d t o a dul t a ni m a l s w hi c h m a y be m e di a t e d by a ge r e l a t e d ne ur oc he m i c a l di f f e r e nc e s i n r e s pons i vi t y t o ni c ot i ne i n t he b r a i n. N i c ot i ne E f f e c t s i n t he B r ai n A dul t s B e ha vi or a l l y, ni c ot i ne ha s be e n s how n t o a l t e r r e s pons i vi t y i n a dul t a ni m a l s a nd 10

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t he s e di f f e r e nc e s a r e l i ke l y m e di a t e d by ne ur oc he m i c a l s ys t e m s i nc l ud i ng t he D A s ys t e m ( S i nge r e t a l 1982 ) T he c e nt r a l e f f e c t s of n i c ot i n e a r e m e di a t e d vi a n i c ot i ni c a c e t yl c hol i ne r e c e pt or s ( nA C hR s ) ( S t ol e r m a n 199 1) w hi c h a r e l oc a t e d w i t h i n t he m e s ol i m bi c D A s ys t e m i n bot h t he V T A a nd N A c c ( C l a r ke e t a l 1985; S c hw a r t z e t a l 1984; S ode r pa l m e t a l 2000 ) H ow e ve r t he D A e nha nc i ng e f f e c t s of ni c ot i ne a ppe a r t o be m e di a t e d pr i m a r i l y by a c t i va t i on of t he s e r e c e pt or s i n t he V T A ( C or r i ga l l e t a l 1994 ; N i s e l l e t a l 1994) W he n ni c ot i ne i s a dm i ni s t e r e d i nt o t he V T A ( F e r r a r i e t a l 2002; I m pe r a t o e t a l 1986) s pe c i f i c a l l y, t he pos t e r i o r p or t i on of t he V T A ( I ke m ot o e t a l 2006) i nc r e a s e s i n D A a r e obs e r ve d i n t he N A c c ( B e nw e l l & B a l f our 1992; E r i c s on e t a l 2003 N i s s e l l e t a l 1994) M a ny s t udi e s ha ve de m ons t r a t e d t ha t ni c ot i ne w i l l i nc r e a s e a c c um ba l D A how e ve r i t ha s a l s o be e n s how n t ha t r e pe a t e d a dm i ni s t r a t i on of ni c ot i ne r e duc e s s ubs e que nt ni c ot i ne i nduc e d i nc r e a s e s of D A i n a dul t a ni m a l s ( V e z i na e t a l 1992 B e nw e l l & B a l f our 1992 I m pe r a t o e t a l 19 86 B e nw e l l e t a l 1993) T oge t he r t he s e s t udi e s de m ons t r a t e t ha t ni c ot i ne i s a bl e t o i nduc e D A r e l e a s e i n t he N A c c w hi c h a ppe a r s t o be m e di a t e d, a t l e a s t pa r t i a l l y, by ni c ot i ni c r e c e pt or s i n t he V T A A dol e s c e nt s I n a dul t s i t i s w e l l doc um e nt e d t ha t n i c ot i ne i s a bl e t o i nduc e D A r e l e a s e i n t he nuc l e us a c c um be ns vi a a c t i va t i on of nA C hR s i n t h e V T A H ow e ve r t he s e e f f e c t s ha ve not be e n w e l l doc um e nt e d i n a dol e s c e nt a ni m a l s A r e c e nt s t udy ha s de m ons t r a t e d t ha t a dol e s c e nt a nd a dul t r a t s a r e di f f e r e nt i a l l y a f f e c t e d by a c ut e a nd r e pe a t e d ni c ot i ne i n t e r m s of ni c ot i ne s t i m ul a t e d a c c um ba l D A r e l e a s e S pe c i f i c a l l y i t w a s obs e r ve d t ha t a dul t a ni m a l s e xhi bi t a n e l e va t i on i n D A w he n a c u t e l y a dm i ni s t e r e d ni c ot i ne but t hi s pa t t e r n w a s not e vi de nt i n a dol e s c e nt a ni m a l s H ow e ve r a f t e r r e pe a t e d ni c ot i ne 11

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t r e a t m e nt t he i nc r e a s e i n D A di s a ppe a r e d ( i e t ol e r a nc e ) i n a dul t a ni m a l s ( B a da ni c h & K i r s t e i n, 2004) S i m i l a r l y, i t ha s be e n s how n t ha t a f t e r r e pe a t e d ni c ot i ne t r e a t m e nt f or s e ve n da ys a dul t r a t s de m on s t r a t e d a n i nc r e a s e i n nA C hR bi ndi ng, but t hi s e f f e c t w a s a bs e nt i n a dol e s c e nt r a t s ( C ol l i ns e t a l 2 004) T h e s e da t a s ugge s t t ha t a dol e s c e nt a nd a dul t a ni m a l s a r e di f f e r e nt i a l l y r e s pons i ve t o a c ut e a nd r e pe a t e d ni c ot i ne t r e a t m e nt w he n e xa m i ni ng D A r e l a t e d a c t i va t i on O ve r a l l a dol e s c e nc e a ppe a r s t o be a pe r i od of vul ne r a bi l i t y t o t he di f f e r e nt be ha vi o r a l a nd ne ur oc he m i c a l e f f e c t s of e t ha nol a nd ni c ot i ne a l t hough da t a f oc us i ng on t he c om bi ne d e f f e c t s of t he s e t w o s ubs t a nc e s i s s pa r s e T he r e f o r e i nve s t i ga t i ons f oc us i ng on t he i nt e r a c t i ve e f f e c t s of e t ha nol a nd ni c ot i ne a r e ne e de d t o e l uc i da t e t he l e ve l o f vul ne r a bi l i t y of a dol e s c e nt s t o t he c om m onl y c om bi ne d us e of e t ha nol a nd ni c ot i ne C om bi ne d E f f e c t s of E t hanol and N i c ot i ne on B e ha v i or A dul t s N i c o t i ne ha s be e n s how n t o ha ve i nt e r a c t i ve e f f e c t s w i t h e t ha nol i n a dul t a ni m a l s T he s e e f f e c t s ha ve be e n obs e r ve d w he n bot h dr ugs a r e c o a dm i ni s t e r e d o r w he n a ni m a l s a r e pr e t r e a t e d w i t h one dr ug a nd c ha l l e nge d w i t h a not he r N i c ot i ne t r e a t m e nt ha s be e n s how n t o i nc r e a s e e t ha nol i nt a ke a nd p r e f e r e nc e ( B l om qvi s t e t a l 1996 C l a r k e t a l 2001, L e e t a l 2000, L ope z M or e no e t a l 2004; P ot hof f e t a l 1983 S m i t h e t a l 1999 ) a nd i nc r e a s e e t ha nol r e i ns t a t e m e nt ( L e e t a l 2003) i n a dul t a ni m a l s H ow e ve r t he s e e f f e c t s a ppe a r t o be dos e de pe nde nt w i t h l ow e r dos e s of ni c ot i ne i nc r e a s i ng e t ha nol c ons um pt i on a nd hi ghe r dos e s s uppr e s s i ng c ons um pt i on a f t e r a c ut e ni c ot i ne t r e a t m e nt ( G a uvi n e t a l 1993) T he s e da t a s ugge s t a c om pl e x i nt e r a c t i on of ni c ot i ne on e t ha nol i nt a ke 12

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N i c ot i ne ha s be e n s how n t o pr oduc e e f f e c t s on ot h e r e t ha nol r e l a t e d be ha vi or s a s w e l l P r e t r e a t m e nt of ni c ot i ne bl oc ke d a n e t ha nol i nduc e d c ondi t i one d t a s t e a ve r s i on ( K uni n e t a l 1999) N i c ot i ne ha s be e n s how n t o e nha nc e e t ha nol di s c r i m i na t i on ( S i gns & S c he c t e r 1986) but t o i m pa i r pe r f or m a nc e on w or ki ng m e m or y a nd a t t e nt i on t a s k pe r f or m a nc e ( B i z a r r o e t a l 2003; R e z va ni & L e vi n, 2002) H ow e ve r e t ha nol ha s be e n s how n t o ha ve no e f f e c t on n i c ot i ne di s c r i m i na t i on ( L e F ol l & G ol db e r g 2006 ) F ur t he r m or e ni c ot i ne ha s be e n s how n t o i nc r e a s e t he r a t e of t ol e r a nc e t o e t ha nol ( H j e r e s e n, 1989) a nd c r os s t ol e r a nc e ha s be e n obs e r ve d be t w e e n t he s e t w o s ubs t a nc e s ( C ol l i ns e t a l 1988 ) ; a n e f f e c t t ha t ha s a l s o be e n o bs e r ve d i n a dol e s c e nt a ni m a l s ( L ope z e t a l 2001) L ow dos e s of ni c ot i ne ha ve be e n s how n t o e nha nc e t he m ot o r s t i m ul a t o r y e f f e c t s of e t ha nol i n m i c e ( B l om qvi s t e t a l 1992) a nd r a t s ( S c ha e f e r & M i c ha e l 1992 ) a nd a n a ddi t i ve i nc r e a s e i n i nt r a c r a ni a l s e l f s t i m ul a t i on w a s obs e r ve d r e l a t i ve t o a dm i ni s t r a t i on of e i t he r d r ug a l one ( S c ha e f e r & M i c ha e l 1992) A l l of t he s e da t a s ugge s t t ha t t he r e a r e i nt e r a c t i ve e f f e c t s be t w e e n e t ha nol a nd ni c ot i ne on be ha vi o r i n a dul t a ni m a l s a nd t hi s dr ug c om bi na t i on s houl d be s ys t e m a t i c a l l y e xa m i ne d i n a dol e s c e nt a ni m a l s A dol e s c e nt s T o da t e t he r e i s a l i m i t e d a m ount o f da t a on t he be ha vi or a l a nd ne ur oc he m i c a l e f f e c t s of t he c o a dm i ni s t r a t i on o f e t ha nol a nd ni c o t i ne N e ur oc he m i c a l a l t e r a t i ons due t o t he c o a dm i ni s t r a t i on o f t he s e s ubs t a nc e s a pp e a r t o be c om pl e x. O f pa r t i c ul a r i m por t a nc e i s t ha t ni c ot i ne a dm i ni s t r a t i on dur i ng a dol e s c e nc e vi a s ubc ut a ne ous i nj e c t i ons pr oduc e d l ong t e r m i nc r e a s e s of e t ha nol i nt a ke i nt o a dul t hoo d ( T s ui e t a l 2001 L e 2002) H ow e ve r i t ha s a l s o be e n s ugge s t e d t ha t c hr oni c c ont i nuous ni c ot i ne i nf us i on, vi a 13

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s ubc ut a ne ous i m pl a nt a t i on of ni c ot i ne pe l l e t s dur i ng a dol e s c e nc e doe s not i nc r e a s e e t ha nol i nt a ke i n a dul t hood ( S m i t h e t a l 2002) T he r e s ul t s f r om t he s e s t udi e s de m ons t r a t e t ha t t he de l i ve r y m e t hod o f a dol e s c e nt ni c ot i ne ( s c o r pe l l e t ) c a n di f f e r e nt i a l l y a f f e c t e t ha nol r e l a t e d be ha vi o r s i n a dul t hood. T he s e da t a a r e c ons i s t e nt w i t h t he a dul t da t a s ugge s t i ng t ha t c ont i nuous a dm i ni s t r a t i on of ni c ot i ne doe s not pr oduc e a l t e r a t i ons i n e t ha nol c ons um pt i o n, w he r e a s r e pe a t e d s ubc ut a ne ous a dm i ni s t r a t i on, doe s i nde e d i nc r e a s e vol unt a r y e t ha nol c ons um pt i on. W he n a ni m a l s w e r e gi ve n a c hoi c e t o c ons um e e t ha nol ni c ot i ne a nd w a t e r i n a l i m i t e d a c c e s s pa r a di gm t he r e w e r e no i nt e r a c t i ve e f f e c t s on i n t a ke w he n bot h e t ha nol a nd ni c ot i ne w e r e o f f e r e d. T ha t i s t o s a y t ha t t he r e w a s not a n a ddi t i ve e f f e c t on e t ha nol i nt a ke w he n ni c ot i ne w a s a l s o of f e r e d i n young a nd ol de r r a t s ( M a r s ha l l e t a l 2002) W he n ni c ot i ne a nd a l c ohol w e r e s ys t e m i c a l l y a dm i ni s t e r e d i n c om bi na t i on, but not e i t he r dr ug a l one uni que a ge r e l a t e d be ha vi or a l out c om e s w e r e obs e r ve d, w i t h a dol e s c e nt s e xpos e d t o t he c om bi na t i on o f t he s e t w o dr ugs s how i ng gr e a t e r hype r t he r m i a r e l a t i ve t o t he i r a dul t c ount e r pa r t s ( R e z va ni & L e vi n 2004) T he s e da t a i m p l y uni qu e a nd pos s i bl y a ddi t i ve e f f e c t s o f ni c ot i ne a nd e t ha nol i n a dol e s c e nt r a t s i n be ha vi or a nd br a i n m e c ha ni s m s m a y m e di a t e t he s e e f f e c t s C om bi ne d E f f e c t s of E t hanol and N i c ot i ne i n t he B r ai n I t i s w e l l doc um e nt e d t ha t ni c ot i ne ( vi a nA C hR s i n t he V T A ) a s w e l l a s e t ha nol c a us e s a c t i va t i on of t he D A s ys t e m E t ha nol ha s be e n s how n t o pr oduc e s t i m ul a t or y e f f e c t s on di f f e r e nt nA C hR s ubt ype s i n t he V T A ( J e r l ha g e t a l 2006 ; S ol de r pa l m e t a l 2000) A ddi t i ona l l y e t ha nol ( G e s s a 1985) a nd ni c ot i ne ( C a l a br e s i e t a l 1989 ) f a c i l i t a t e s D A r e l e a s e i n t he N A c c ( L e e t a l 2001 ) vi a a c t i va t i on o f t he V T A i n a dul t r a t s 14

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( B l om qvi s t e t a l 1996 ) A n a ddi t i ve e f f e c t of l oc a l l y a dm i ni s t e r e d ni c ot i ne i n t o t he V T A on e t ha nol i nduc e d D A r e l e a s e i n t he N A c c w a s obs e r ve d w i t h a m ode r a t e dos e of ni c ot i ne ( T i z a bi e t a l 2002 ) F ur t he r m o r e a s yne r gi s t i c e f f e c t o f e t ha nol a nd ni c ot i ne on s pont a ne ous f i r i ng of t he V T A ha s be e n obs e r ve d ( C l a r k & L i t t l e 2004) M e c a m yl a m i ne a nonc om pe t i t i ve nA C hR a nt a goni s t a dm i ni s t e r e d i n t he V T A but no t N A c c b l oc ke d e t ha nol i nduc e d a c c um ba l D A i nc r e a s e s a nd r e duc e d e t ha nol pr e f e r e nc e a nd i nt a ke ( B l om qvi s t e t a l 1997; E r i c s on e t a l 1998) A l l of t hi s e vi de nc e s uppor t s t he no t i on t ha t e t ha nol s a c t i ons a r e a t l e a s t pa r t i a l l y m e di a t e d by i t s a c t i on on ni c ot i ni c r e c e pt or s e s pe c i a l l y t hos e i n t he V T A ( S ode r pa l m e t a l 200 0) a nd pr ovi de s e vi de nc e t ha t t he s e t w o s ubs t a nc e s w or k t oge t he r a t t he ne ur oc he m i c a l l e ve l t o m odul a t e e t ha nol i nduc e d D A r e l e a s e i n t he N A c c O v e r v i e w of t he P r e s e nt S t udy B l om qvi s t a nd c ol l e a gue s ha ve s pe c ul a t e d t ha t ni c ot i ne a bus e e s pe c i a l l y dur i ng a dol e s c e nc e m a y r e nde r i ndi vi dua l s m o r e s e ns i t i ve t o de ve l opi ng a l c ohol de pe nde nc e i n a dul t hood ( B l om qvi s t e t a l 1996) F ur t he r m or e a dol e s c e nt s not onl y a ppe a r t o be m or e s e ns i t i ve t o t he e f f e c t s of a l c ohol or ni c ot i ne but a l s o e s pe c i a l l y s e ns i t i ve t o t he i nt e r a c t i ve e f f e c t s of t hi s dr ug c om bi na t i on. T he r e f or e t he goa l o f t he pr e s e nt e xpe r i m e nt w a s t o a s s e s s t he l ong t e r m e f f e c t s of e t ha nol ni c ot i ne or t he c om bi na t i on of e t ha nol a nd ni c ot i ne du r i ng a dol e s c e nc e on a dul t h ood nove l t y pr e f e r e nc e a nd e t ha nol r e l a t e d be ha vi or s A ddi t i ona l l y g i ve n t ha t hu m a n a dol e s c e nt s do not us ua l l y c ons um e a l c ohol e ve r yda y, a r e pe a t e d i nt e r m i t t e nt e t ha nol e xpos ur e dos i ng r e gi m e n w a s a l s o us e d t o m i m i c a dol e s c e nt hum a n a l c ohol c ons um pt i on a nd a s s e s s i f t hi s pr oduc e d di f f e r e nt r e s ul t s f r om c hr on i c e xpos ur e t o e t ha nol F ur t he r m or e gi ve n t ha t a C P P ha s be e n 15

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de m ons t r a t e d a t m ode r a t e but not l ow e r or h i ghe r dos e s of ni c ot i ne a m ode r a t e dos e of 0. 4 m g/ kg ni c ot i ne w a s us e d i n t he pr e s e nt e xpe r i m e nt S pe c i f i c a l l y, a dol e s c e nt a ni m a l s w e r e c hr oni c a l l y or r e pe a t e d i nt e r m i t t e nt l y a dm i ni s t e r e d e i t he r dr ug a l one ( e t ha nol or ni c ot i ne or s a l i ne ) or i n c om bi na t i on ( e t ha nol a nd ni c ot i ne ) dur i ng a dol e s c e nc e ( P N D 30 47) F or t he r e pe a t e d i nt e r m i t t e nt e xpos ur e a dol e s c e nt a ni m a l s w e r e a dm i ni s t e r e d ni c ot i ne or s a l i ne e ve r yda y a nd e xpos e d t o e t ha nol on P N D 30 33, P N D 37 40, a nd P N D 44 47. S ubs e que nt l y, i n a dul t hood f o l l ow i ng a w a s hout pe r i od, nove l t y pr e f e r e nc e ( P N D 64 67 ) a nd c ondi t i one d pl a c e pr e f e r e nc e t o e t ha nol ( P N D 68 73) w a s a s s e s s e d. P r e l i m i na r y da t a f r o m our l a bor a t or y i ndi c a t e t ha t c hr oni c e xpos ur e t o a m ode r a t e dos e of e t ha nol dur i ng a dol e s c e nc e a l t e r s nove l t y r e l a t e d b e ha vi or s i n a dul t hood ( F i gur e 1; S t a ns f i e l d a nd K i r s t e i n, 2007) H y pot he s e s T he ove r a l l goa l of t he p r opos e d e xpe r i m e nt s w a s t o a s s e s s t he l ong t e r m be ha vi or a l a l t e r a t i ons t ha t oc c ur due t o a dol e s c e nt e xpos ur e of e t ha nol a nd ni c ot i ne e i t he r a l one or i n c om bi na t i on, on a dul t hood r e s pons i vi t y t o t he r e w a r di ng p r ope r t i e s of e nvi r onm e nt a l c ue s pa i r e d w i t h e t ha nol G i ve n t ha t i n hum a ns a dol e s c e nt e xpos ur e t o t hi s dr ug c om bi na t i on a ppe a r s t o f a c i l i t a t e t he de ve l opm e nt of a l c ohol de pe nde nc e i n a dul t hood, i t w a s hypot he s i z e d t ha t a dol e s c e nt a ni m a l s e xpos e d t o t he c om bi na t i on o f e t ha nol a nd ni c ot i ne w oul d be m or e vul ne r a bl e t o de ve l opi ng a l t e r a t i ons i n e t ha nol r e l a t e d be ha vi or s i n a dul t hood I t ha s a l r e a dy be e n e s t a bl i s he d t ha t a dol e s c e nt e t ha nol e xpos ur e e nha nc e d nove l t y r e l a t e d be ha vi or s i n a d ul t hood ( S t a ns f i e l d & K i r s t e i n, 2007 ) G i ve n t ha t a dol e s c e nt a ni m a l s a r e m or e s e ns i t i ve t o t he a nxi ol yt i c e f f e c t s of ni c ot i ne i t i s hypot he s i z e d t ha t a dol e s c e nt r a t s e xpos e d t o ni c ot i ne a l one dur i ng a dol e s c e nc e w ou l d 16

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e xhi bi t gr e a t e r nove l e nvi r onm e nt i nduc e d be ha vi o r a l a c t i va t i on. F u r t he r m or e a dol e s c e nt a ni m a l s e xpos e d t o t he c om bi na t i on of e t ha nol a nd ni c ot i ne w oul d e xhi bi t gr e a t e r nove l t y s e e ki ng be ha vi or s a s c om pa r e d t o a ni m a l s e xpos e d t o e i t he r dr ug a l one O ve r a l l i t w a s e xpe c t e d t ha t a ni m a l s e xpos e d t o t h e c om bi na t i on of e t ha nol a nd n i c ot i ne w oul d e xhi bi t t he hi ghe s t be ha vi or a l r e s pons i vi t y t o t he r e w a r di ng pr ope r t i e s of e nvi r onm e nt a l c ue s pa i r e d w i t h e t ha nol i n a dul t ho od. W he n a s s e s s i ng t he r e w a r di ng pr ope r t i e s of e t ha nol i n a dul t hood us i ng t he C P P p a r a di gm i t w a s hypot he s i z e d t ha t a dol e s c e nt s a ni m a l s e xpo s e d t o t he c om bi na t i on o f a m ode r a t e dos e o f a l c ohol ( 0. 75 g/ kg) a nd ni c ot i ne ( 0 4 m g/ kg ) w oul d m or e r e a di l y a c qui r e a C P P i n a dul t hood a s c om pa r e d t o a ni m a l s e xpos e d t o e i t he r dr ug a l one T hus a ni m a l s e xpos e d t o bot h e t ha nol a nd ni c ot i ne du r i ng a dol e s c e nc e w oul d e xhi bi t t he g r e a t e s t l e ve l of r e s pons i vi t y t o a l c ohol i n a dul t hood. 17

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C ha pt e r T w o: E f f e c t s of E t ha nol a nd/ or N i c ot i ne P r e t r e a t m e nt D ur i ng A dol e s c e nc e on A dul t hood E t ha nol R e l a t e d B e ha vi or s M at e r i al s and M e t hods Subj e c t s T w o hundr e d a nd f o r t y t w o m a l e S p r a gue D a w l e y r a t s de r i ve d f r om e s t a bl i s he d br e e di ng pa i r s a t t he U ni ve r s i t y o f S out h F l o r i da T a m pa ( H a r l a n l a bor a t or i e s I N ) w e r e us e d i n t he pr e s e nt s t udy. L i t t e r s w e r e s e xe d a nd c ul l e d t o 10 pups pe r l i t t e r on pos t na t a l da y ( P N D ) 1 w i t h t he da t e of bi r t h de s i gna t e d a s P N D 0. P ups w e r e hous e d w i t h t he i r r e s pe c t i ve da m s unt i l P N D 21 w he n t he y w e r e w e a ne d a nd hous e d i n gr ou ps of t h r e e / f our w i t h s a m e s e x l i t t e r m a t e s T he c ol ony r oom w a s m a i nt a i ne d i n a hum i di t y a nd t e m pe r a t ur e c ont r ol l e d v i va r i um on a 12: 12 hour l i ght / da r k c yc l e w i t h l i ght s on f r om 0700 hour s t o 1900 hour s A ni m a l s w e r e a l l ow e d a d l i bi t um a c c e s s t o f ood a nd w a t e r i n t he hom e c a ge E a c h a ni m a l w a s t e s t e d a c r os s de ve l opm e nt be gi nni ng on P N D 30 a nd e ndi ng on P N D 75 N o m o r e t ha n one m a l e pup p e r l i t t e r w a s us e d i n a ny gi ve n c ondi t i on. I n a l l r e s pe c t s m a i nt e na nc e a nd t r e a t m e nt of t he a ni m a l s w a s w i t hi n t he gui de l i ne s f or a ni m a l c a r e by t he N a t i ona l I ns t i t ut e s of H e a l t h. A ppar at us O pe n f i e l d. T he a ppa r a t us c ons i s t e d of a n ope n c i r c ul a r f i e l d w i t h a b l a c k pl a s t i c f l oor ( D = 96 5 c m ) a nd a n opa que pl a s t i c c i r c ul a r ba r r i e r ( H = 45 7 c m ) i n w hi c h a ni m a l s w e r e a l l ow e d f r e e a c c e s s t o m ove a bout A c a m e r a w a s s us pe nde d a bove t he ope n f i e l d a nd m ove m e nt ( c m ) of t he a ni m a l w a s di gi t a l l y r e c or de d. T hi s s i gna l w a s t r a c ke d, 18

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qua nt i f i e d, a nd a na l yz e d us i ng a n E t hovi s i on vi de o t r a c ki ng s ys t e m ( N ol dus I nf or m a t i on T e c hnol ogy, U t r e c ht N e t he r l a nds ) A l l be ha vi or a l t e s t i ng oc c ur r e d unde r di m l y l i t c ondi t i ons a nd oc c ur r e d be t w e e n 1000 a nd 1400 h r C ondi t i one d P l ac e P r e f e r e nc e A ppar at us T he c ondi t i on i ng a ppa r a t us c ons i s t e d of a s i ngl e bl a c k P l e xi gl a s ( R ohm a nd H a a s C om p a ny, P hi l a de l phi a P e nns yl va ni a ) r unw a y t ha t c oul d be s e pa r a t e d by a r e m ova bl e P l e xi gl a s w a l l i nt o t w o e qua l s i z e d c om pa r t m e nt s ( 21 x 24. 5 x 20 5 c m ) c ont a i ni ng di s t i nc t vi s ua l a nd t a c t i l e c ue s O ne c om pa r t m e nt c ons i s t e d of ve r t i c a l l y s t r i pe d w a l l s ( 1 i n c h t hi c k) w i t h a w i r e m e s h f l oor T he ot he r c om pa r t m e nt c ons i s t e d of h or i z ont a l l y s t r i pe d w a l l s ( 1 i nc h t hi c k) w i t h a gr e y s a ndpa pe r f l oor ( 100 gr i t ) P r oc e dur e P r e t r e at m e nt A ni m a l s w e r e r a ndom l y a s s i gne d t o one of f ou r p r e t r e a t m e nt c ondi t i ons ba s e d on dr ug c om bi na t i ons o f e t ha nol ( E t O H ) ni c ot i ne ( N I C ) a nd s a l i ne ( S A L ) a dm i ni s t e r e d. T he f our pr e t r e a t m e nt c ondi t i ons us e d w e r e : S A L / S A L N I C / S A L S A L / E t O H a nd N I C / E t O H A l l a ni m a l s w e r e pr e t r e a t e d w i t h S A L ( 0 9 % N a C l ; s ubc ut a ne ous ( s c ) or i nt r a pe r i t one a l ( i p) ) N I C ( 0 0 or 0 4 m g / kg/ s c ; e xpr e s s e d a s t he s a l t ) or E t O H ( 17% v/ v; 0. 0 or 0. 75 g/ kg/ i p ) f r om P N D 30 t o 47. R a t s t ha t w e r e c hr oni c a l l y a dm i ni s t e r e d e t ha nol w e r e e xpos e d t o bot h a s c ( ni c ot i ne or s a l i ne ) a nd i p ( e t ha nol or s a l i ne ) e ve r yda y f r om P N D 30 47 R a t s t ha t w e r e r e pe a t e d i nt e r m i t t e nt l y a dm i ni s t e r e d e t ha nol w e r e e xpos e d t o a s c ( ni c ot i n e or s a l i ne ) e ve r yda y f r o m P N D 30 47 a nd w e r e a dm i ni s t e r e d a n i p i nj e c t i on ( e t ha nol o r s a l i ne ) on P N D 30 33 P N D 3 7 40, a nd P N D 44 47. D u r i ng P r e t r e a t m e nt ( P N D 30 47 ) a n i m a l s w e r e t r a ns por t e d t o t he l a b w e i ghe d a nd a dm i ni s t e r e d t he i r r e s pe c t i ve i nj e c t i o ns A l l a ni m a l s r e c e i ve d t w o i nj e c t i ons 19

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i n t he hom e c a ge ( or one s c i nj e c t i on on P N D 34 3 6 a nd P N D 41 43 i f t he y unde r w e nt r e pe a t e d i nt e r m i t t e nt e xpos u r e t o e t ha nol ) T he f i r s t i nj e c t i on w a s a s c i nj e c t i on ( s a l i ne or 0. 4 m g/ kg ni c ot i ne ) I m m e di a t e l y f ol l ow i ng t he f i r s t i nj e c t i on, a ni m a l s r e c e i ve d a n i p i nj e c t i on ( s a l i ne or 0. 75 g/ kg/ i p E t O H ) F ol l ow i ng dr ug a dm i n i s t r a t i on a ni m a l s w e r e i m m e di a t e l y r e t u r ne d t o t he c ol ony. F r om P N D 48 63 a ni m a l s r e m a i ne d undi s t ur be d i n t he c ol ony, e xc e pt f or r e gul a r c a ge m a i nt e na nc e N ov e l t y P r e f e r e nc e F r om P N D 64 66 a l l a ni m a l s w e r e s ubj e c t e d t o a nove l t y pr e f e r e nc e pr obe ( S t a ns f i e l d e t a l 2004; S t a ns f i e l d & K i r s t e i n, 2006) B e gi nni ng on t he m or ni ng of P N D 64 a ni m a l s w e r e t r a ns por t e d t o t he l a b ( 0900 1000 ) a nd pl a c e d on t he nove l ope n f i e l d a s de s c r i be d a bove a nd be ha vi or r e c or de d f or 5 m i n. I m m e di a t e l y f ol l ow i ng t he f i ve m i nut e ha bi t ua t i on t r i a l a ni m a l s w e r e r e t ur ne d t o t he c ol ony O n t he a f t e r noon on P N D 64 ( 1400 1500) a ni m a l s w e r e a ga i n t r a ns por t e d t o t he l a b a nd pl a c e d on t he ope n f i e l d f o r a f i ve m i nu t e ha bi t ua t i on t r i a l a nd t he n i m m e di a t e l y r e t ur ne d t o t he c ol ony. T hi s pr oc e s s w a s r e pe a t e d on P N D 65 67 f or a t ot a l of 8 ha bi t ua t i on t r i a l s I m m e di a t e l y f ol l ow i ng t he e i ght h ha bi t ua t i on t r i a l a ni m a l s w e r e r e t u r ne d t o t he i r hom e c a ge f or one m i nut e a nd t he n r e t ur ne d t o t he ope n f i e l d w he r e a nove l obj e c t ( 7 c m i n he i ght ) w a s pl a c e d i n t he c e nt e r of t he o pe n f i e l d T i m e s pe nt ne a r t he nove l obj e c t ( s e c ) f r e que nc y of a pp r oa c he s t o t he nove l obj e c t l a t e nc y t o a ppr oa c h ( s e c ) t he nove l obj e c t w e r e r e c or de d f o r t he ni nt h t r i a l T ot a l D i s t a nc e M ove d ( c m ) w a s r e c or de d f or a l l t r i a l s C ondi t i one d P l ac e P r e f e r e nc e ( C P P ) T he C P P p r oc e dur e i s a bi a s e d pr oc e dur e w hi c h oc c ur r e d ove r s i x da ys i n t hr e e pha s e s T he f i r s t pha s e i s p r e c ondi t i oni ng ba s e l i ne ( P N D 68) t he s e c ond pha s e i s c ondi t i oni n g ( P N D 69 72) a nd t he f i na l pha s e i s pos t c ondi t i oni ng t e s t ( P N D 73 ) D u r i ng ba s e l i ne a ni m a l s w e r e pr e s e nt e d i n t he c e nt e r 20

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of t he C P P a ppa r a t us w i t h t he c e nt e r w a l l r e m ove d t o a l l ow f r e e a c c e s s t o bot h c ha m be r s f or 15 m i nut e s T i m e ( s e c ) s pe nt i n e a c h c ha m be r w a s r e c or de d by t he E t hoV i s i on vi de o t r a c ki ng s ys t e m T he c ha m be r t ha t t he a ni m a l s pe nt t he l e a s t a m ount o f t i m e i n ( l e a s t pr e f e r r e d) w a s a s s i gne d a s t he dr ug pa i r e d c ha m be r a nd f or pha s e t w o a ni m a l s w e r e c ondi t i one d w i t h a l c ohol t o t hi s c ha m be r C ont r ol a ni m a l s r e c e i ve d s a l i ne i nj e c t i ons on bot h s i de s of t he a ppa r a t us P ha s e t w o ( c ondi t i oni ng) oc c ur r e d ove r f our da ys P N D 69 72. E a c h m o r ni ng ( 1000 1100 h r ) a ni m a l s w e r e t r a ns por t e d t o t he l a b w e i ghe d, a dm i ni s t e r e d s a l i ne a nd i m m e di a t e l y c onf i ne d t o t he i ni t i a l l y p r e f e r r e d c ha m be r f o r 5 m i nut e s I m m e di a t e l y f o l l ow i ng t he 5 m i nut e c ondi t i oni ng s e s s i on, a ni m a l s w e r e r e t ur ne d t o t he i r ho m e c a ge a nd r e t u r ne d t o t he c ol ony. A ppr oxi m a t e l y f our hour s l a t e r ( 1400 1500 hr ) a ni m a l s w e r e a ga i n t r a ns por t e d t o t he l a b, w e i ghe d a dm i ni s t e r e d t he i r r e s pe c t i ve s a l i ne or e t ha nol i nj e c t i on a nd i m m e di a t e l y c onf i ne d t o t he i ni t i a l l y l e a s t pr e f e r r e d c ha m be r f or 5 m i nut e s I m m e di a t e l y f ol l ow i ng t he 5 m i nu t e c ondi t i oni ng s e s s i on, a ni m a l s w e r e r e t u r ne d t o t he hom e c a ge a nd r e t ur ne d t o t he c ol ony. T h i s pr oc e dur e w a s r e pe a t e d ove r a pe r i od o f f our da ys T he a ppa r a t us w a s c l e a ne d w i t h Q ua t r i c i de ( P ha r m a c a l R e s e a r c h L a bor a t o r i e s I nc o r por a t e d) a nd E t O H ( 70% ) pr i o r t o e a c h t r i a l t o r e m ove l i nge r i ng odo r s D ur i ng pha s e t hr e e P N D 73 a ni m a l s w e r e t r a ns por t e d t o t he l a b, w e i ghe d, a nd i nt r oduc e d t o t he C P P a ppa r a t us w i t h t he c e nt e r w a l l r e m ove d t o a l l ow f r e e a c c e s s t o bot h c ha m be r s f or 15 m i nut e s a nd T i m e ( s e c ) s pe nt i n e a c h c ha m be r w a s di gi t a l l y r e c or de d a nd qua nt i f i e d vi a t he E t hoV i s i on vi de o t r a c ki ng s ys t e m T hi s p r oc e dur e i s i d e nt i c a l t o t ha t of pha s e one w i t h a ni m a l s i n a dr ug f r e e s t a t e D e s i gn and A nal y s e s T he pr e s e nt e xpe r i m e nt a l de s i gn i s a t w o w a y be t w e e n s ubj e c t s de s i gn A N O V A 21

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f or P r e t r e a t m e nt ( 4; S A L / S A L N I C / S A L S A L / E t O H N I C / E t O H ) a nd P os t t r e a t m e nt ( 2; S A L E t O H ) D a t a w e r e a na l yz e d s e pa r a t e l y f o r e a c h dos i ng r e gi m e n ( c h r oni c vs r e pe a t e d I nt e r m i t t e nt e xpos ur e t o e t ha nol ) T he r e f or e a ni m a l s t ha t w e r e a s s i gne d t o a S A L P r e t r e a t m e nt a nd S A L P os t t r e a t m e nt s e r ve d a s c ont r ol s be c a us e t he s e a ni m a l s ne ve r r e c e i ve d E t O H F ur t he r m or e f or a ny P r e t r e a t m e nt c ondi t i on ( S A L / S A L N I C / S A L S A L / E t O H N I C / E t O H ) a f t e r t he w a s h out pe r i od i n a dul t hood ha l f of t he a ni m a l s w e r e s ubs e que nt l y be a dm i ni s t e r e d S A L a nd t he ot he r ha l f w a s a dm i ni s t e r e d E t O H i n t he c ondi t i one d p l a c e pr e f e r e nc e pa r a di g m T he l e ve l f or s i gni f i c a nc e w a s s e t a t 0. 05 f o r a l l a na l ys e s D a t a f or nove l t y pr e f e r e nc e w e r e a na l yz e d us i ng a one w a y be t w e e n s ubj e c t s A N O V A f or a nd P r e t r e a t m e nt ( S A L N I C E t O H N I C / E t O H ) F r e que nc y t o a ppr oa c h t he nove l obj e c t t i m e s pe nt w i t h t he nove l obj e c t a nd t ot a l di s t a nc e m ove d on t r i a l one w e r e us e d a s de pe nde nt m e a s ur e s t o a s s e s s t he e f f e c t s of pr e t r e a t m e nt dur i ng a dol e s c e nc e on a dul t hood nove l t y be ha vi or s D a t a f or C P P w e r e a na l yz e d us i ng a t w o f a c t or be t w e e n s ubj e c t de s i gn A N O V A w i t h P r e t r e a t m e nt ( S A L / S A L N I C / S A L S A L / E t O H N I C / E t O H ) a nd P os t T r e a t m e nt ( S A L E t O H ) a s f a c t or s D i f f e r e nc e s c or e s ( t e s t ba s e l i ne ) of t i m e ( s e c ) s pe nt i n t he l e a s t pr e f e r r e d c ha m be r w e r e us e d a s t he de pe nde n t m e a s ur e A C P P w a s de f i ne d a s a n E t O H pos t t r e a t e d a ni m a l s pe ndi ng s i gni f i c a nt l y m or e t i m e on t he i ni t i a l l y l e a s t pr e f e r r e d s i de a t t e s t r e l a t i ve S A L pos t t r e a t e d a ni m a l s 22

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C ha pt e r T hr e e : R e s ul t s E f f e c t s of E t hanol and/ or N i c ot i ne P r e t r e at m e nt on N ov e l t y R e l at e d B e hav i or s i n A dul t hood N ov e l t y I nduc e d E x pl or at i on A dul t a ni m a l s t ha t w e r e pr e vi ous l y t r e a t e d w i t h e i t he r s a l i ne e t ha nol a l one ni c ot i ne a l one or e t ha nol c om bi ne d w i t h ni c ot i ne w e r e a s s e s s e d on a num be r of be ha vi or a l m e a s ur e s r e l a t e d t o nove l t y s e e ki ng. O ne of t he m e a s ur e s t ha t a r e a s s e s s e d i n t hi s pa r a di gm i s nove l t y i nduc e d e xpl or a t i on W i t h t hi s m e a s ur e t he num be r o f t i m e s a n a ni m a l a ppr oa c he s t he nove l obj e c t on t he f i na l t r i a l w a s a s s e s s e d. A s i ndi c a t e d i n F i gu r e 1A t he r e w e r e no s i gni f i c a nt di f f e r e nc e s a m ong a ny of t he gr oups i n t he num be r of t i m e s a dul t a ni m a l s t ha t w e r e c h r oni c a l l y e xpos e d t o e t h a nol a l one ni c ot i ne a l one o r t he c om bi na t i on of e t ha nol a nd ni c ot i ne dur i ng a dol e s c e nc e a ppr oa c he d t he nove l obj e c t ( F ( 3, 113 ) = 96 p > 0. 05 ) S i m i l a r l y a s d e pi c t e d i n F i gur e 1B i n a ni m a l s t ha t w e r e r e pe a t e d i nt e r m i t t e nt l y e xpos e d t o s a l i ne e t ha nol a l one ni c ot i ne a l one o r e t ha nol c om bi ne d w i t h ni c ot i ne du r i ng a dol e s c e nc e ; t he r e w e r e no s i gni f i c a nt di f f e r e nc e s a m ong a ny of t he gr oups ( F ( 3 110 ) = 1. 14 p > 0 05) T h e r e f or e t he s e da t a do not r e pl i c a t e r e c e nt f i ndi ngs t ha t i ndi c a t e t ha t t r e a t m e nt w i t h a m ode r a t e dos e of e t ha nol dur i ng a dol e s c e nc e i nc r e a s e s nove l t y i nduc e d e xpl or a t i on i n a dul t r a t s ( S t a ns f i e l d & K i r s t e i n, 2007) 23

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F i gur e 1: E t ha nol a nd / or N i c ot i ne T r e a t m e nt D ur i n g A dol e s c e nc e D i d N ot A l t e r N ove l t y I nduc e d E xpl or a t i on i n A dul t hood. T he r e w e r e no l ong t e r m c ha nge s i n nove l t y i nduc e d e xpl or a t i on due t o e i t he r c h r oni c ( P a ne l A ) or r e pe a t e d i nt e r m i t t e nt ( P a ne l B ) e xpos ur e t o e t ha nol a nd/ or ni c ot i ne dur i ng a dol e s c e nc e P a ne l A : S a l i ne n= 30; E t ha nol n= 27; N i c ot i ne n= 24; E t ha nol / N i c ot i ne n= 33. P a ne l B : S a l i ne n= 26; E t ha nol n= 27; N i c ot i ne n= 32; E t ha nol / N i c ot i ne n= 27 N ov e l t y P r e f e r e nc e N ove l t y pr e f e r e nc e i s a not he r be ha vi or t ha t w a s a s s e s s e d i n t he be ha vi or a l pa r a di gm i ndi c a t e d a bove N ove l t y pr e f e r e nc e i s d e f i ne d a s t i m e ( s e c onds ) s pe nt ne a r a nd a r ound t he nove l obj e c t on t he f i na l t r i a l A s i ndi c a t e d i n F i gur e 2A t he r e w e r e no s i gni f i c a nt di f f e r e nc e s a m ong a ny of t he gr oups t h a t w e r e c hr oni c a l l y t r e a t e d w i t h s a l i ne e t ha nol a l one ni c ot i ne a l one o r e t ha nol c om bi ne d w i t h ni c ot i ne dur i ng a dol e s c e nc e i n t he a m ount of t i m e s pe nt w i t h t he nove l obj e c t on t he f i na l t r i a l ( F ( 3, 113) = 1. 87 p > 0. 05) S i m i l a r l y a s de pi c t e d i n F i gu r e 2B t he r e w e r e no s i gni f i c a nt d i f f e r e nc e s a m ong 24

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a ny of t he gr oups t ha t w e r e r e pe a t e d i nt e r m i t t e nt l y e xpos e d t o s a l i ne e t ha nol a l one ni c ot i ne a l one o r e t ha nol c om bi ne d w i t h n i c ot i ne dur i ng a dol e s c e nc e ( F ( 3 110 ) = 69 p > 0. 05) F i gur e 2: E t ha n ol a nd/ o r N i c ot i ne T r e a t m e nt D ur i ng A dol e s c e nc e D i d N ot A l t e r N ove l t y P r e f e r e nc e i n A dul t hood. T he r e w e r e no l ong t e r m c ha nge s i n nove l t y p r e f e r e nc e due t o e i t he r c hr oni c ( P a ne l A ) or r e pe a t e d i nt e r m i t t e nt ( P a ne l B ) e xpos ur e t o e t ha nol a nd/ or ni c ot i ne dur i ng a dol e s c e nc e P a ne l A : S a l i ne n= 3 0; E t ha nol n= 27; N i c ot i ne n= 24; E t ha nol / N i c ot i ne n= 33. P a ne l B : S a l i ne n= 26; E t ha nol n= 27; N i c ot i ne n= 32; E t ha nol / N i c ot i ne n= 27. N ov e l E nv i r onm e nt I nduc e d E x pl or at i on N ove l e nvi r onm e nt i nduc e d e xpl o r a t i on i s a m e a s ur e t ha t i s c om m on l y us e d t o a s s e s s nove l t y r e l a t e d be ha vi or s a s m e a s ur e d by t h e t ot a l a m ount of di s t a nc e t r a ve l e d on t he f i r s t t r i a l w he n a ni m a l s w e r e e xpos e d t o a nove l e nvi r onm e nt A s de pi c t e d i n F i gu r e 3A t he r e w e r e no s i gni f i c a nt di f f e r e nc e s i n t he di s t a nc e t r a ve l e d on t he f i r s t t r i a l a m ong 25

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a m ong a ni m a l s t ha t w e r e r e pe a t e d i nt e r m i t t e nt l y t r e a t e d w i t h s a l i ne e t ha nol a l one o f t he gr oups t ha t w e r e e xpos e d t o s a l i ne e t ha nol a l one ni c ot i ne a l one o r e t ha nol c om bi ne d w i t h ni c ot i ne dur i ng a dol e s c e nc e ( F ( 3 121 ) = 1. 7 4, p > 0. 05 ) S i m i l a r l y ni c ot i ne a l one or e t ha nol c om bi ne d w i t h ni c ot i ne t he r e w e r e no s i gni f i c a nt di f f e r e nc e s i n t he di s t a nc e t r a ve l e d upon e xpos ur e t o a nove l e nvi r onm e nt ( F ( 3, 114 ) = 1. 41 p > 0. 0 5) F i gur e 3: E t ha nol a nd / o r N i c ot i ne T r e a t m e nt D ur i ng A dol e s c e nc e D i d N ot A l t e r N ove l E nvi r onm e nt I nduc e d E xp l or a t i on. T he r e w e r e no l ong t e r m c ha nge s i n nove l e nvi r onm e nt i nduc e d e xpl or a t i on due t o e i t he r c hr oni c ( P a ne l A ) or r e pe a t e d i nt e r m i t t e nt ( P a ne l B ) e xpos ur e t o e t ha nol a nd/ o r ni c ot i ne dur i ng a dol e s c e nc e P a ne l A : S a l i ne n= 30; E t ha nol n= 27; N i c ot i ne n= 24; E t ha nol / N i c ot i ne n = 33. P a ne l B : S a l i ne n= 26 ; E t ha nol n= 27; N i c ot i ne n= 32; E t ha nol / N i c ot i ne n= 27. E x am i ni ng t he R e w ar di ng E f f e c t s t o E t hanol A f t e r A dol e s c e nt T r e at m e nt of A l c ohol and/ or N i c ot i ne U s i ng t he C P P pa r a di gm c ha nge s i n t he r e w a r di ng pr ope r t i e s of e nvi r onm e nt a l 26

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c ue s a s s o c i a t e d w i t h e t ha nol w e r e a s s e s s e d a f t e r a dol e s c e nt t r e a t m e nt w i t h s a l i ne e t ha nol a l one ni c ot i ne a l one o r t he c om bi na t i on o f e t ha n ol a nd ni c ot i ne du r i ng a dol e s c e nc e A s de pi c t e d i n F i gur e 4, a m ong a ni m a l s t ha t w e r e c hr oni c a l l y t r e a t e d dur i ng a dol e s c e nc e w i t h s a l i ne e t ha nol a l one ni c ot i ne a l one or e t ha nol a nd ni c ot i ne t he r e w a s a n ove r a l l pa t t e r n of de c r e a s e d t i m e s pe nt i n t he c ha m be r pa i r e d w i t h e t ha nol r e l a t i ve t o a ni m a l s t ha t w e r e t r e a t e d w i t h s a l i ne i n bot h c ha m be r s r e ga r d l e s s of pr e t r e a t m e nt a s s uppor t e d by a s i gni f i c a nt m a i n e f f e c t f or P os t t r e a t m e nt ( F ( 1, 112 ) = 6 89, p < 0. 01 ) T he m a i n e f f e c t f or P r e t r e a t m e nt ( F ( 3, 112) = 38 p > 0 05) a nd t h e P r e t r e a t m e nt by P os t t r e a t m e nt i nt e r a c t i on ( F ( 3 112) = 89, p > 0. 05 ) f a i l e d t o r e a c h s i gni f i c a nc e A s i l l us t r a t e d i n F i gur e 5, a m ong a ni m a l s t ha t w e r e r e pe a t e d i nt e r m i t t e nt l y t r e a t e d w i t h s a l i ne e t ha nol a l one ni c ot i ne a l one or e t ha nol c om bi ne d w i t h ni c ot i ne t he r e w e r e no s i gni f i c a nt di f f e r e nc e s a m ong a ny o f t he g r oupe d i n t he a m ou nt of t i m e s pe nt i n t he c ha m be r pa i r e d w i t h e t ha nol a s c om pa r e d t o a ni m a l s t ha t w e r e a d m i ni s t e r e d s a l i ne i n bot h c ha m be r s a s i ndi c a t e d by a nons i gn f i c a nt m a i n e f f e c t f or P r e t r e a t m e nt ( F ( 3, 109) = 96, p > 0 05) P os t t r e a t m e nt ( F ( 1, 109) = 98, p > 0. 05) or P r e t r e a t m e nt by P os t t r e a t m e nt i nt e r a c t i on ( F ( 3, 109 ) = 38 p > 0. 05 ) 27

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F i gur e 4: C hr oni c E t ha nol a nd/ or N i c ot i ne T r e a t m e nt D ur i ng A dol e s c e nc e D i d N ot A l t e r C ondi t i one d P l a c e P r e f e r e nc e i n A dul t hood T he r e w e r e no l o ng t e r m c ha nge s i n c ondi t i one d pl a c e pr e f e r e nc e t o e t ha nol i n a dul t ho od f ol l ow i ng c hr oni c e xpos ur e t o e t ha nol a nd/ or ni c ot i ne dur i ng a dol e s c e nc e P r e t r e a t m e nt P os t t r e a t m e nt : S a l i ne S a l i ne n= 15; S a l i ne E t ha nol n= 14; E t ha nol S a l i ne n= 15 ; E t ha nol E t ha nol n= 14; N i c ot i ne S a l i ne n= 14; N i c ot i ne E t ha nol n= 15; E t ha nol / N i c ot i ne S a l i ne n= 17; E t ha nol / N i c ot i ne E t ha nol n= 16 28

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F i gur e 5: R e pe a t e d I nt e r m i t t e nt E t ha nol a n d/ o r N i c ot i ne T r e a t m e nt D u r i ng A dol e s c e nc e D i d N ot A l t e r C ondi t i one d P l a c e P r e f e r e nc e i n A d ul t hood. T he r e w e r e no l ong t e r m c ha nge s i n c ondi t i one d pl a c e pr e f e r e nc e t o e t ha nol i n a dul t hood f ol l ow i ng r e pe a t e d i nt e r m i t t e nt e xpos ur e t o e t ha nol a nd/ o r ni c ot i ne du r i ng a dol e s c e nc e P r e t r e a t m e nt P os t t r e a t m e nt : S a l i ne S a l i ne n= 15; S a l i ne E t ha nol n= 14; E t ha nol S a l i ne n= 16; E t ha nol E t ha nol n= 14; N i c ot i ne S a l i ne n= 16; N i c ot i ne E t ha nol n= 16; E t ha nol / N i c ot i ne S a l i ne n= 15; E t ha nol / N i c ot i ne E t ha nol n= 13 29

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C ha pt e r F our : D i s c us s i on C om or bi d us e of A l c ohol and N i c ot i ne i n H um ans I n hum a ns t he r e a ppe a r s t o be a dos e de pe nde nt i n c r e a s e i n t he l e ve l of t oba c c o us e a nd a l c ohol c ons um pt i on ( F a l k e t a l 2006) A ddi t i ona l l y, c o us e o f a l c ohol a nd t oba c c o i s hi ghe s t a m ong young pe opl e a ge d 18 2 4 a nd t he r a t e s of c o us e de c l i ne w i t h a ge ( F a l k e t a l 2006) H um a n m a l e s t ha t s m oke d ni c ot i ne c ont a i ni ng c i ga r e t t e s c ons um e d m or e a l c ohol t ha n t he i r non ni c ot i ne c o nt a i ni ng c i ga r e t t e c ount e r pa r t s ( B a r r e t t e t a l 2006) A ddi t i ona l l y, hum a ns t ha t c ons um e d e t ha nol r e por t e d i nc r e a s e d s a t i s f a c t i on r a t i ngs of ni c ot i ne c ont a i ni ng c i ga r e t t e s r e l a t i ve t o de ni c ot i ni z e d c i ga r e t t e s ( R os e e t a l 2002) T oge t he r t he s e da t a s uppor t t he not i on t ha t a l c ohol a nd t oba c c o a r e c om m onl y u s e d i n hum a ns a nd t ha t t he r e i s gr e a t e r pos i t i ve e f f e c t s a s s oc i a t e d w i t h t he c om bi ne d us e of t he s e dr ugs C ondi t i one d P l ac e P r e f e r e nc e P ar adi gm and E t ha nol H i s t or y T he C P P pa r a di g m i s a c om m onl y us e d be ha vi or a l m ode l de s i gne d t o a s s e s s t he r e w a r di ng e f f e c t s a s s oc i a t e d w i t h e nvi r onm e nt a l c ue s pa i r e d w i t h dr ug a dm i ni s t r a t i on I t i s be l i e ve d t ha t e nvi r onm e nt a l c ue s pa i r e d w i t h dr u g a dm i ni s t r a t i on a r e de e m e d m or e r e w a r di ng i f a ni m a l s s pe nt m or e t i m e i n t he e nvi r o nm e nt pa i r e d w i t h dr ug a dm i ni s t r a t i on f ol l ow i ng a nu m be r o f c ondi t i oni ng t r i a l s I f a ni m a l s s pe nd l e s s t i m e i n t he e nvi r onm e nt pa i r e d w i t h d r ug a dm i ni s t r a t i on t he n t he a ni m a l s a r e be l i e ve d t o de ve l op a n a ve r s i on t o t hos e dr ug a s s oc i a t e d c ue s T he e vi de nc e t o e s t a bl i s h a C P P w i t h e t ha nol i s m i xe d 3 0

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S om e ha ve r e por t e d e s t a bl i s hm e nt of a c ondi t i one d pl a c e pr e f e r e nc e B i e nkow s ki e t a l 1995 ( B i e nkow s ki e t a l 1995; B oz a r t h, 1990; G a u vi n & H ol l ow a y, 1991) w he r e a s ot he r s ha ve r e por t e d c ondi t i one d pl a c e a ve r s i ons w i t h e t ha nol ( A s i n e t a l 1985; C un ni ngha m e t a l 1993; S c he c ht e r 1992) a nd ot he r s ha ve r e por t e d no c ha nge i n pr e f e r e nc e f or t he e nvi r o nm e nt pa i r e d w i t h e t ha nol ( C i c c oc i oppo e t a l 1999; D a vi e s a nd P a r ke r 1990; S c he c ht e r 1992; S t e w a r t e t a l 1996 ) a c r os s a r a nge o f dos e s H ow e ve r i t a ppe a r s t ha t us ua l l y a dos e of a pp r oxi m a t e l y 1 0 g / kg e t ha nol i s ne e de d t o e s t a bl i s h a C P P w i t h e t ha nol ( B oz a r t h, 1990) H ow e ve r m a n y ot he r s ha ve not be e n a bl e t o e s t a bl i s h a c ondi t i one d pl a c e pr e f e r e nc e w i t h e t ha nol T he di s c r e pa nc y i n t he r e s ul t s a p pe a r s t o be due t o a num be r of f a c t or s i nc l udi ng dos e r out e o f a dm i ni s t r a t i on l e ngt h of c ondi t i oni ng t r i a l num be r o f c ondi t i oni ng t r i a l s a nd p r e vi ous hi s t or y w i t h e t ha nol I t a ppe a r s t ha t a ni m a l s t ha t ha ve a hi s t or y w i t h e t h a nol m or e e a s i l y e s t a bl i s h a c ondi t i one d pl a c e pr e f e r e nc e f o r e t ha nol ( B i e nkow s ki e t a l 1995; B oz a r t h 1990; G a uvi n & H ol l ow a y, 1991 ) H ow e ve r ot he r s ha ve f a i l e d t o obs e r ve a C P P i n a ni m a l s t ha t ha d a hi s t or y of e t ha nol e xpos ur e ( D a vi e s & P a r ke r 199 0) B oz a r t h ( 1990 ) w a s a bl e t o e s t a bl i s h a c ondi t i one d pl a c e pr e f e r e nc e w i t h a m o de r a t e 1. 0 g / kg/ i p e t ha nol dos e a f t e r 15 c ondi t i oni ng t r i a l s t ha t l a s t e d 30 m i nu t e s e a c h. B i e nkow s ki a nd c ol l e a gue s obs e r ve d a n e t ha nol i nduc e d C P P i n a ni m a l s t ha t w e r e c h r oni c a l l y pr e t r e a t e d w i t h 0. 5 g/ kg e t ha nol f o r 20 da ys pr i or t o c ondi t i on i ng ( B i e nkow s ki e t a l 1 995) R a t s i n t he B oz a r t h ( 1990) e xpe r i m e nt ha d m or e a nd l onge r dr ug c ondi t i oni ng t r i a l s a nd w e r e not c ondi t i one d t o t he a l t e r na t e c ha m be r w i t h s a l i ne T he pr e s e nt e xpe r i m e nt c ondi t i one d r a t s w i t h f ou r c ondi t i oni ng t r i a l s pa i r e d w i t h e t ha nol a nd f our c o ndi t i oni ng t r i a l s pa i r e d w i t h s a l i ne t ha t l a s t e d f i ve m i nut e s e a c h. A ni m a l s i n t he B i e nkow s ki e t a l ( 1995) e xpe r i m e nt 31

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i m m e di a t e l y unde r w e nt c ondi t i oni ng f ol l ow i ng pr e e xpos ur e A ni m a l s us e d i n t he pr e s e nt e xpe r i m e nt unde r w e nt a w a s hout pe r i od f r om e t ha nol unt i l t he y m a t ur e d i nt o young a dul t hood. T he r e f or e di f f e r e nt r e s ul t s m a y ha ve b e e n obs e r ve d f or a ni m a l s i n t he p r e s e nt e xpe r i m e nt i f a ni m a l s ha d unde r gone c ondi t i oni ng i m m e di a t e l y f o l l ow i ng pr e t r e a t m e nt r a t he r t ha n w a i t i ng f o r t he t w o w e e k w a s hout pe r i od t o a l l ow a ni m a l s t o m a t u r e t o a dul t hood. I t i s pos s i bl e t ha t t he pr e s e nt e xpe r i m e nt di d not i nc l ude a s uf f i c i e nt num be r of c ondi t i oni ng t r i a l s a nd t ha t i f a ni m a l s i n t he pr e s e nt e x pe r i m e nt w e r e c ondi t i one d w i t h l onge r a nd a g r e a t e r num be r of dr ug pa i r e d c ondi t i oni ng t r i a l s t ha t a C P P f or e t ha nol m a y ha ve be e n obs e r ve d. A m ong a ni m a l s t ha t di d not ha ve a pr e vi ous hi s t or y w i t h e t ha nol r out e of a dm i ni s t r a t i on a ppe a r s t o be a n i m por t a nt f a c t or i n t he a bi l i t y t o e s t a bl i s h a c ondi t i one d pl a c e pr e f e r e nc e w i t h e t ha nol W he n r a t s w e r e a d m i ni s t e r e d e t ha nol i nt r a pe r i t one a l l y ( i p) t he r e w a s e i t he r a n a ve r s i on ( C unni ngha m e t a l 1993 ; S c he c ht e r 1992) or no c ha nge i n pr e f e r e nc e f o r t he e nvi r on m e nt pa i r e d w i t h e t ha nol ( A s i n e t a l 1985 ) U s i ng t he C P P pa r a di gm t he r e w a s no s i gni f i c a nt di f f e r e nc e i n pr e f e r e nc e f or t he c ha m be r pa i r e d w i t h e t ha nol t ha t w a s a dm i ni s t e r e d i nt r a pe r i t one a l l y ( i p) us i ng a ni m a l s t ha t w e r e s e l e c t i ve l y br e d t o pr e f e r a l c ohol ( P r a t s ) o r not t o pr e f e r a l c ohol ( N P r a t s ; S c he c ht e r 1992) I nde e d, bot h P a nd N P r a t s f ound t he e nvi r onm e nt pa i r e d w i t h a m ode r a t e dos e of e t ha nol ( 1. 0 g/ kg/ i p) a ve r s i ve ( S c he c ht e r 1992) H ow e ve r N P r a t s s how e d a de pr e s s i on i n l oc om ot or a c t i vi t y, a n e f f e c t t ha t w a s not obs e r ve d i n P r a t s ( S c he c ht e r 1992 ) A ddi t i ona l l y, i n a not he r l i ne of ge ne t i c a l l y s e l e c t e d a l c ohol pr e f e r r i ng r a t s t he M a r c hi gi a n S a r di ni a n a l c ohol p r e f e r r i ng ( m s P ) r a t s w he n a m ode r a t e dos e of e t ha nol ( 0. 70 g/ kg / i p) w a s a dm i ni s t e r e d i p, s i m i l a r t o t ha t us e d i n t he pr e s e nt s t udy ( 0. 75 g/ kg/ i p) 32

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no c ha nge i n pr e f e r e nc e w a s obs e r ve d f or t he c ha m be r pa i r e d w i t h e t ha nol ( C i c c oc i oppo e t a l 1999) T he a bs e nc e of a C P P w a s obs e r ve d i n m s P r a t s a dm i ni s t e r e d e t ha nol i p r e ga r dl e s s of a pr e vi ous hi s t or y of a l c ohol c ons um pt i on or gr e a t e r num be r of pa i r i ngs o f e t ha nol w i t h t he e nvi r onm e nt ( C i c c oc i oppo e t a l 1999) A ddi t i ona l l y t he r e w a s no e vi de nc e of e t ha nol i nduc e d pl a c e p r e f e r e nc e i n P or N P r a t s a dm i ni s t e r e d 0 5 g/ kg/ i p e t ha nol a nd c ondi t i one d pl a c e a ve r s i ons w e r e obs e r ve d a t hi ghe r 1. 0 or 1. 5 g/ kg/ i p e t ha nol dos e s ( S t e w a r t e t a l 1996) T he s e da t a s u gge s t t ha t i n out br e d s t r a i ns o f r a t s or i n r a t s t ha t a r e s e l e c t i ve l y br e d t o pr e f e r a l c ohol t h e r e w a s no e s t a bl i s hm e nt o f C P P w he n e t ha nol w a s a dm i ni s t e r e d i p. H ow e ve r i n a ni m a l s w i t h a l ong hi s t or y of vol unt a r y o r a l c ons um pt i on, a c ondi t i one d pl a c e pr e f e r e nc e w a s o bs e r ve d w he n a ni m a l s w e r e c onf i ne d t o one c om pa r t m e nt a nd a l l ow e d vol unt a r y a c c e s s t o e t ha nol ( G a uvi n & H ol l ow a y, 1991) T he r e f or e i t a ppe a r s t ha t w he n e t ha nol i s a dm i ni s t e r e d i p, t he r e i s no e s t a bl i s hm e nt of C P P i n a ni m a l s t ha t do not ha ve p r i or e xpe r i e nc e w i t h e t ha nol I n t he pr e s e nt e xpe r i m e nt e t ha nol w a s a dm i ni s t e r e d i p a nd no c ha nge i n pr e f e r e nc e f or t h e e nvi r onm e nt pa i r e d w i t h e t ha nol w a s obs e r ve d, r e g a r dl e s s of dos i ng r e gi m e n o r pr e t r e a t m e nt hi s t or y I t i s pos s i bl e t ha t a C P P m a y ha ve be e n e s t a bl i s he d i n t he a ni m a l s of t he p r e s e nt i f a di f f e r e nt r out e of a dm i ni s t r a t i on ha d be e n us e d i n t he p r e s e nt e xp e r i m e nt be c a us e t he y ha d a l ong pr i or hi s t or y w i t h e t ha nol a nd/ or ni c ot i ne du r i ng a dol e s c e nc e C om bi ne d E t hanol and N i c ot i ne T r e at m e nt R e c e nt w or k i ndi c a t e s t ha t hum a ns t ha t a r e e xpos e d t o bot h a l c ohol a nd t oba c c o dur i ng a dol e s c e nc e e xhi bi t c ha r a c t e r i s t i c s t ha t a r e a s s oc i a t e d w i t h e nha nc e d r i s k t a ki ng be ha vi or s ( S c hm i d e t a l 2007) T he s e r i s k t a ki ng be ha vi or a l c ha r a c t e r i s t i c s m a y be 33

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a s s oc i a t e d w i t h e nha nc e d s ubs t a nc e a bus e pr obl e m s dur i ng a dol e s c e nc e a nd l a t e r i s l i f e C onc ur r e nt a dol e s c e nt us e of a l c ohol a nd t oba c c o w a s a s s o c i a t e d w i t h a n e a r l i e r a ge of ons e t of dr i nki ng a nd g r e a t e r a nd he a vi e r dr i nki ng e pi s ode s r e l a t i ve t o c ons um pt i on of a l c ohol a l one ( S c hm i d e t a l 2007) A ddi t i ona l l y, c onc ur r e nt a l c ohol a nd t oba c c o us i ng a dol e s c e nt s e xpr e s s e d gr e a t e r pos i t i ve e f f e c t e xpe c t a nc i e s f or a l c ohol us i ng t he A l c ohol E xpe c t a nc y Q ue s t i onna i r e ( B r ow n e t a l 1987; S c hm i d e t a l 2007) P r e vi ous l y i t ha s be e n de m ons t r a t e d i n r a t s t ha t a dol e s c e nt t r e a t m e nt w i t h a m ode r a t e dos e of e t ha nol ( 1 0 g/ kg/ i p) e nha nc e d nove l t y i nduc e d e xpl or a t i on i n a dul t hood ( S t a ns f i e l d & K i r s t e i n, 2007) I n t he p r e s e nt e xpe r i m e nt i t w a s hypot he s i z e d t ha t a dol e s c e nt e xpos ur e t o e t ha nol a l one or e t ha nol i n c om bi na t i on w i t h ni c ot i ne w oul d r e pl i c a t e t he s e f i ndi ngs H ow e ve r t he r e w a s no c ha nge i n a ny nove l t y r e l a t e d be ha vi or s i n a dul t hood ( S e e F i gur e s 1 3) obs e r ve d due t o a dol e s c e nt pr e t r e a t m e nt w i t h e t ha nol a nd/ or ni c ot i ne T hi s c oul d ha ve be e n due t o t he f a c t t ha t a l l a dol e s c e nt s w e r e a dm i ni s t e r e d t w o i nj e c t i ons one a dm i ni s t e r e d i p ( e t ha nol or s a l i ne ) a nd one a dm i ni s t e r e d s ubc ut a ne ous l y ( s c ; ni c ot i ne or s a l i ne ) T he a dde d s t r e s s of t he s e c ond i nj e c t i on m a y ha ve da m pe ne d t he e f f e c t pr e vi ous l y obs e r ve d of hi ghe r nove l t y i nduc e d e xp l or a t i on due t o a dol e s c e nt e xpos ur e t o a m ode r a t e d os e of a l c ohol A l t e r na t i ve l y a s l i ght l y l ow e r e t ha nol dos e of 0 75 g / kg/ i p w a s us e d i n t he pr e s e nt e xpe r i m e nt a s c om pa r e d t o t he 1. 0 g/ kg / i p us e d i n t he pr e vi ous s t udy ( S t a ns f i e l d & K i r s t e i n, 2007 ) T hi s s l i ght l y l ow e r dos e m a y not ha ve be e n s uf f i c i e nt t o a l t e r a dul t hood nove l t y r e l a t e d be ha vi or s U s i ng m i c e t he r e w a s no a ddi t i ve e f f e c t of e t ha nol t o e nha nc e C P P f or ni c ot i ne a s c om pa r e d t o a ni m a l s t ha t w e r e a dm i ni s t e r e d ni c ot i ne a l one ( K or kos z e t a l 2006) S i m i l a r l y, i n a ni m a l s t ha t ha d a l ong e xpos ur e t o a l c ohol c ons um pt i on a nd l a t e r t e s t e d f or 34

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e l e va t i ons i n l oc om ot or a c t i vi t y t o ni c ot i ne no e nh a nc e m e nt of pr i o r e t ha nol h i s t or y on ni c ot i ne i nduc e d l oc om ot or a c t i vi t y w a s obs e r ve d ( D a r br a e t a l 2004) A dol e s c e nt na ve a l c ohol pr e f e r r i ng ( P ) r a t s s how e nha nc e d ni c ot i ne s e l f a dm i ni s t r a t i on a nd ni c ot i ne r e i ns t a t e m e nt r e l a t i ve t o t he i r a l c ohol non pr e f e r r i ng ( N P ) c ount e r pa r t s ( L e e t a l 2006) P r e vi ous w or k s ugge s t s t ha t w i t hdr a w a l f r o m e t ha nol a nd ni c ot i ne pr oduc e s gr e a t e r a ve r s i on t o t he ope n a r m s of a n e l e va t e d pl us m a z e r e l a t i ve t o w i t hd r a w a l f r om e i t he r dr ug a l one ( O na i vi e t a l 1989 ) T ol e r a nc e f r om e t ha nol a nd c r os s t ol e r a nc e f r om ni c ot i ne a l one o r ni c ot i ne c om bi ne d w i t h e t ha nol w e r e obs e r ve d i n r e s pons e t o e t ha nol a s m e a s ur e d by e t ha nol i nduc e d hypot he r m i a a nd l oc om ot or a c t i vi t y ( C ol l i ns e t a l 1996) T oge t he r t he s e da t a i ndi c a t e t ha t t he r e i s a n i nt e r a c t i ve e f f e c t of e t ha nol a nd ni c ot i ne on be ha vi or H ow e ve r t he s e s t udi e s i ndi c a t e t ha t e t h a nol ha s e f f e c t s on s ubs e que nt ni c ot i ne i ndu c e d be ha vi or s T he p r e s e nt e xpe r i m e nt a s s e s s e d c ha nge s i nduc e d by pr i or e t ha nol a nd/ or ni c ot i ne e xpos ur e on s ubs e que nt e t ha nol i nduc e d c ondi t i one d pl a c e pr e f e r e nc e W he n s i m i l a r e f f e c t s w e r e e xa m i ne d c r os s t ol e r a nc e w a s obs e r ve d due t o e xpos ur e t o a l c oho l a nd/ o r ni c ot i ne on s ubs e que nt e t ha nol i nduc e d hypot he r m i a a nd l oc om ot or a c t i vi t y ( C ol l i ns e t a l 1996) F unk a nd c ol l e a gue s s ugge s t t ha t r e duc e d s e ns i t i vi t y t o a l c ohol m a y r e s ul t f r o m c hr oni c e xpo s ur e t o ni c ot i ne o r vi c e ve r s a ( F unk e t a l 2006 ) T he r e f or e i f r e duc e d s e ns i t i vi t y t o a l c o hol w a s e s t a bl i s he d due t o a dol e s c e nt e xpos ur e t o ni c ot i ne a l one o r ni c ot i ne c om bi ne d w i t h a l c ohol t he n a C P P w oul d no t be e xpe c t e d f or a l c ohol i n a dul t hood T hi s s pe c ul a t i o n i s qui t e pl a us i bl e gi ve n t ha t w e d i d not o bs e r ve a C P P or c ondi t i one d pl a c e a ve r s i on t o e t ha nol i n a dul t hood, i n a ny g r oup. W he n e t ha nol a nd ni c ot i ne w e r e a dm i ni s t e r e d e i t h e r a l one or i n c om bi na t i on dur i ng a dol e s c e nc e i n m i c e t he r e w e r e no l ong l a s t i ng e f f e c t s on c ogni t i ve pe r f o r m a nc e 35

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i n m a l e r a t s ( A br e u V i l l a c a e t a l 2007) H ow e ve r t he r e w a s a n i m pr ove m e nt i n c ogni t i ve pe r f or m a nc e i n f e m a l e s i n a dul t hood a f t e r a dol e s c e nt c o e xpos ur e t o e t ha nol a nd ni c ot i ne ( A br e u V i l l a c a e t a l 2007 ) T he r e f o r e t he r e s ul t s obt a i ne d i n t he pr e s e nt e xpe r i m e nt i n m a l e r a t s of no e nha nc e m e nt of a l c o hol i nduc e d C P P i n a dul t hood a f t e r a dol e s c e nt e xpos ur e t o e t ha nol a nd ni c ot i ne a dm i n i s t r a t i on a l one or i n c om bi na t i on a r e c ons i s t e nt w i t h t he r e s ul t s obt a i ne d by A b r e u V i l l a c a a nd c ol l e a gue s ( 2007) C onc l us i o ns A l t hough e nha nc e d C P P i n a dul t hood w a s not obs e r ve d due t o a dol e s c e nt e xpos ur e t o e t ha nol a nd/ o r ni c ot i ne i n t he pr e s e nt e xpe r i m e nt ni c ot i ne w a s a bl e t o i nc r e a s e e t ha nol c ons um pt i on i n r ode nt s ( C l a r k e t a l 2001 ; L a r s s on & E nge l 2004; L e e t a l 2000 ; S m i t h e t a l 1999) I n a ni m a l s t ha t w e r e c hr oni c a l l y e xpos e d t o n i c ot i ne a nd l a t e r t e s t e d f or vol unt a r y e t ha nol c ons um pt i on, ni c ot i ne e nha nc e d s ubs e que nt vol unt a r y e t ha nol i nt a ke a f t e r a w a s hout pe r i od ( B l om qvi s t e t a l 1996) T he r e f or e pr i o r ni c ot i ne a dm i ni s t r a t i on i s a bl e t o i nc r e a s e vol unt a r y e t ha nol c ons um pt i on a f t e r a w a s hout pe r i od B l om qvi s t a nd c ol l e a gue s ( 1996) di d not e xa m i ne i f ni c ot i ne c om bi ne d w i t h e t ha nol pr e t r e a t m e nt w oul d l a t e r e nha nc e vol unt a r y e t ha no l i nt a ke r e l a t i ve t o a dm i ni s t r a t i on of e t ha nol a l one T he r e f o r e i f w e ha d e xa m i ne d vol u nt a r y e t ha nol i nt a ke i n a dul t hood t o m e a s ur e t he r e i nf or c i ng pr ope r t i e s of e t ha nol w e m a y ha ve obs e r ve d e nha nc e d i nt a ke i n a dul t hood, a s m a ny e xpe r i m e nt s ha ve r e por t e d e nha nc e d e t ha nol i nt a ke i n a n i m a l s a dm i ni s t e r e d ni c ot i ne ( B l om qvi s t e t a l 1996; C l a r k e t a l 2001; L a r s s on & E nge l 2004; L e e t a l 2000; S m i t h e t a l 1999 ) N i c ot i ne e xpos ur e dur i ng a dol e s c e nc e w a s a bl e t o i nc r e a s e t he r e i nf or c i ng pr ope r t i e s of c oc a i ne i n a dul t hood a s m e a s ur e d us i ng ope r a nt r e s pondi ng ( M c Q uow n e t 36

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a l 2007 ) A s i m i l a r e f f e c t w a s e xpe c t e d f or e t ha n ol i n t ha t a dol e s c e nt a ni m a l s t ha t w e r e e xpos e d t o ni c ot i ne w e r e e xpe c t e d t o s how a C P P i n a dul t hood t o e t ha nol A ddi t i ona l l y i t w a s e xpe c t e d t ha t a ni m a l s t ha t w e r e e xpos e d t o t he c om bi na t i on of e t ha nol a nd n i c ot i ne dur i ng a dol e s c e nc e w e r e e xpe c t e d t o s how a n e nha nc e d C P P r e l a t i ve t o a l l o t he r g r oups G i ve n t ha t t he e vi de nc e f o r e s t a bl i s hm e nt of a n e t h a nol i nduc e d c ondi t i one d pl a c e pr e f e r e nc e i s m i xe d a nd t ha t i p a dm i ni s t r a t i on o f e t ha nol a ppe a r s t o pr oduc e e i t he r a n a ve r s i on or no c ha nge i n pr e f e r e nc e f or t he e nvi r o nm e nt pa i r e d w i t h e t ha nol t hi s pa r a di gm a nd r ou t e of e t ha nol a dm i ni s t r a t i on m a y not ha ve be e n t he m os t a ppr opr i a t e pa r a di gm t o us e t o a s s e s s t he r e w a r di ng pr ope r t i e s of e t ha nol i n a dul t hood. D a t a f r om a not he r s e t of e xpe r i m e nt s c onduc t e d t o a s s e s s t he e f f e c t s of ni c ot i ne on vol unt a r y e t ha nol i nt a ke i n a dol e s c e nt a nd a dul t m a l e r a t s i n di c a t e t ha t a dol e s c e nt s t ha t w e r e e xpos e d t o ni c ot i ne s how e d e nh a nc e d vol unt a r y e t ha nol i nt a ke r e l a t i ve t o t he i r s a l i ne c ount e r pa r t s T hi s e f f e c t w a s not obs e r ve d f o r s i m i l a r l y t r e a t e d a dul t m a l e s ( M a l dona do & K i r s t e i n, m a nus c r i pt i n pr e p) H ow e ve r t he l on g t e r m e f f e c t s of ni c ot i ne on vol un t a r y e t ha nol i nt a ke w e r e n ot e xa m i ne d i n t ha t s e t of e xp e r i m e nt s T oge t he r t he s e e xpe r i m e nt s i ndi c a t e t ha t ni c ot i ne doe s i nc r e a s e vol unt a r y e t ha nol i nt a ke i n a dol e s c e nt but not a dul t m a l e r a t s T he r e f o r e t he a dol e s c e nt pe r i od i s one w he r e t he r e a r e e nha nc e d i nt e r a c t i ve e f f e c t s of ni c ot i ne a nd a l c ohol H ow e ve r gi ve n t he m i xe d l i t e r a t ur e on e t ha nol i nduc e d C P P pe r ha ps ot he r be ha vi or a l pa r a di gm s s houl d b e ut i l i z e d t o a s s e s s t he l ong t e r m i nt e r a c t i ve e f f e c t s of t hi s dr ug c om bi na t i on w he n a dm i ni s t e r e d dur i ng a dol e s c e nc e C ur r e nt l y e xpe r i m e nt s a r e be i ng c onduc t e d t o a s s e s s i f ni c ot i ne e xpos ur e dur i ng a dol e s c e nc e or a dul t hood i nc r e a s e s s ubs e qu e nt vol unt a r y e t ha nol i nt a ke i n m a l e r a t s a f t e r a w a s hout pe r i od. 37

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R e f e r e nc e s A be l s on H F i s hbur ne R M & C i s i n I 1977 N a t i o na l S ur ve y o f D r ug A bus e s 1977. N a t i ona l I ns t i t ut e on D r ug A bus e R oc kvi l l e M D A br e u V i l l a c a Y M e de i r os A H L i m a C S F a r i a F P F i l gue i r a s C C & M a nha e s A C 2007. C om bi ne d e xpos ur e t o ni c ot i ne a nd e t ha nol i n a dol e s c e nt m i c e di f f e r e nt i a l l y a f f e c t s m e m or y a nd l e a r ni ng du r i ng e xpos ur e a nd w i t hdr a w a l B e ha v B r a i n R e s 181, 136 146. A dr i a ni W S pi j ke r S D e r oc he G a m one t V L a vi ol a G L e M oa l M S m i t A B & P i a z z a P V 2003. E vi de nc e f or e nha nc e d ne ur obe ha vi or a l vul ne r a bi l i t y t o ni c ot i ne dur i ng pe r i a dol e s c e nc e i n r a t s J N e ur os c i 23, 4712 4716 A nde r s e n A D ue O H ol s t e i n B E & I ve r s e n L 20 02. T r a c ki ng dr i nki ng be ha vi our f r o m a ge 15 19 ye a r s A ddi c t i on 98 1505 1511 A nt hony J C & P e t r oni s K R 1995 E a r l y ons e t dr u g us e a nd r i s k o f l a t e r dr ug pr obl e m s D r ug A l c ohol D e pe nd 40 ( 1) : 9 15. A ppe l S B M c B r i de W J D i a na M D i a m ond I B onc i A & B r odi e M S 2004. E t ha nol e f f e c t s on dopa m i ne r gi c r e w a r d" ne ur ons i n t he v e nt r a l t e gm e nt a l a r e a a nd t he m e s ol i m bi c pa t hw a y. A l c ohol i s m C l i ni c a l a nd E x pe r i m e nt a l R e s e a r c h 28: 1768 1778 A s i n K E W i r t s ha f t e r D & T a ba kof f B 1985 F a i l ur e t o e s t a bl i s h a c ondi t i one d pl a c e pr e f e r e nc e w i t h e t ha nol i n r a t s P ha r m a c ol ogy B i o c he m i s t r y a nd B e ha vi or 22 ( 2) : 169 173. B a da ni c h K A & K i r s t e i n C L 2004. N i c ot i ne a dm i ni s t r a t i on a l t e r s a c c um ba l dop a m i ne 38

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i n t he a dul t but not i n t he a dol e s c e nt r a t A nn N Y A c a d S c i 1021 410 417. B a r r e t t S P T i c ha ue r M L e yon M & P i hl R O 20 06. N i c ot i ne i nc r e a s e s a l c ohol s e l f a dm i ni s t r a t i on i n non de pe nde nt m a l e s m oke r s D r ug A l c ohol D e pe nd, 81, 197 204 B a t e l P P e s s i one F M a i t r e C & R ue f f B 1995. R e l a t i ons hi p be t w e e n a l c ohol a nd t oba c c o de pe nde nc i e s a m ong a l c ohol i c s w ho s m oke A ddi c t i on 90 977 980. B a t e s M E & L a bouvi e E W 1997 A dol e s c e nt r i s k f a c t or s a nd t he pr e di c t i on of pe r s i s t e nt a l c ohol a nd dr ug us e i nt o a dul t hood A l c ohol C l i n. E xp. R e s 21: 944 950 B e nw e l l M E & B a l f our D J 1992. T he e f f e c t s of a c ut e a nd r e pe a t e d ni c ot i ne t r e a t m e nt on nuc l e us a c c um be ns dopa m i ne a nd l oc om ot or a c t i vi t y. B r J P ha r m a c ol 105, 849 856. B e nw e l l M E B a l f our D J & L uc c hi H M 1993. I n f l ue nc e of t e t r odot oxi n a nd c a l c i um on c ha nge s i n e xt r a c e l l ul a r dopa m i ne l e ve l s e voke d b y s ys t e m i c ni c ot i ne P s yc hopha r m a c ol ogy, 112, 467 474. B e r gs t r om H C M c D ona l d C G & S m i t h R F 2006. A l c ohol e xpos ur e du r i ng a dol e s c e nc e i m pa i r s a udi t or y f e a r c ondi t i on i ng i n a dul t L ong E va ns r a t s P hys i ol B e ha v, 88, 466 472. B i e nkow s ki P K uc a P & K os t ow s ki W 1995. C ondi t i one d pl a c e pr e f e r e nc e a f t e r pr ol onge d pr e e xpos ur e t o e t ha nol P ol J P ha r m a c ol 47( 2) : 189 191 B i z a r r o L P a t e l S & S t ol e r m a n I P 2003 C om pr e he ns i ve de f i c i t s i n pe r f o r m a nc e of a n a t t e nt i ona l t a l k pr oduc e d by c o a dm i ni s t e r i ng a l c o hol a nd ni c ot i ne t o r a t s D r ug a nd A l c ohol D e pe nd, 72, 287 295 B l om qvi s t O E nge l J A N i s s br a ndt H & S ode r pa l m B 1993. T he m e s ol i m bi c dop a m i ne a c t i va t i ng pr ope r t i e s o f e t ha nol a r e a nt a goni z e d by m e c a m yl a m i ne E u r J 39

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P ha r m a c ol 249 207 213. B l om qvi s t O E r i c s on M E nge l J A & S ode r pa l m B 1997 A c c um ba l dopa m i ne ove r f l ow of e t ha nol : L oc a l i z a t i on of t he a nt a goni z i ng e f f e c t o f m e c a m yl a m i ne E ur J P ha r m a c ol 334 149 156. B l om qvi s t O E r i c s on M J ohns on D H E nge l J A & S ode r pa l m B 1996 V ol unt a r y e t ha nol i nt a ke i n t he r a t : e f f e c t s of ni c ot i ni c a c e t yl c hol i ne r e c e pt or bl oc ka de o r s ubc hr oni c ni c ot i ne t r e a t m e nt E ur J P ha r m a c ol 3 14, 257 267 B l om qvi s t O S ode r pa l m B & E nge l J A 1992. E t ha nol i nduc e d l oc om ot or a c t i vi t y: i nvol ve m e nt of c e nt r a l ni c ot i ni c a c e t yl c hol i ne r e c e pt or s ? B r a i n R e s B ul l 29, 173 178. B oz a r t h, M A 1990. E vi de nc e f or t he r e w a r di ng e f f e c t s of e t ha nol us i ng t he c ond i t i one d pl a c e pr e f e r e nc e m e t hod. P ha r m a c ol B i oc he m B e h a v, 35( 2 ) : 485 487 B r ow n S A C hr i s t i a ns e n B A & G ol dm a n M S 198 7. T he a l c ohol e xpe c t a nc y que s t i onna i r e : a m i ns t r um e nt f or t he a s s e s s m e nt of a dol e s c e nt a nd a dul t a l c ohol e xpe c t a nc i e s J S t ud A l c ohol 48, 483 491 C a l a br e s i P L a c e y M G & N or t h R A 1989. N i c ot i ne e xc i t a t i on of r a t ve nt r a l t e gm e nt a l ne ur ons i n vi t r o s t udi e d by i nt r a c e l l ul a r r e c or di ng. B r i t i s h J our na l o f P ha r m a c ol ogy, 98, 135 140 C a r m ondy T P B r i s c he t t o C S M a t a r a z z o J D O D onne l R P & C onne r W E 1985. C onc ur r e nt us e of c i ga r e t t e s a l c ohol a nd c of f e e i n he a l t hy, c om m un i t y l i vi ng m e n a nd w om e n. H e a l t h P s yc hol 4, 323 335. C D C 2002. T oba c c o I nf o r m a t i on a nd P r e ve nt i on S our c e s ( T I P S ) N a t i ona l C e nt e r f or C hr oni c D i s e a s e P r e ve nt i on a n d H e a l t h P r om ot i on 40

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C e nt e r f or D i s e a s e C ont r ol a nd P r e ve nt i on. 2001 T he yout h r i s k be ha vi o r s ur ve y: T r e nds i n c i ga r e t t e s m oki ng a m ong h i gh s c hool s t u de nt s W a s hi ngt on, D C C ha m be r s R A T a yl or J R P ot e nz a M N 2003 D e ve l opm e nt a l ne ur oc i r c ui t r y of m ot i va t i on i n a dol e s c e nc e : a c r i t i c a l pe r i od o f a ddi c t i on vul ne r a bi l i t y A m J P s yc hi a t r y. 160, 1041 52 C i c c oc i oppo R P a noc ka I F r ol di R Q ui r a da m o E & M a s s i M 1999. E t ha nol i nduc e s c ondi t i one d pl a c e pr e f e r e nc e i n ge ne t i c a l l y s e l e c t e d a l c ohol pr e f e r r i ng r a t s P s yc hopha r m a c ol 141, 235 241. C l a r k D B K i r i s c i L & T a r t e r R E 1998 A dol e s c e nt ve r s us a dul t ons e t a nd t he de ve l opm e nt of s ubs t a nc e us e di s or de r s i n m a l e s D r ug A l c ohol D e pe nd, 49, 115 121. C l a r k A L i ngr e n S B r ooks S P W a t s on W P & L i t t l e H J 2001 C hr oni c i n f us i on of ni c ot i ne c a n i nc r e a s e ope r a nt s e l f a dm i ni s t r a t i on o f a l c ohol N e ur opha r m a c ol 41 108 117. C l a r k A & L i t t l e H J 2004. I n t e r a c t i ons be t w e e n l ow c onc e nt r a t i ons of e t ha nol a nd ni c ot i ne on f i r i ng r a t e of ve nt r a l t e gm e nt a l dopa m i ne ne ur ons D r ug A l c ohol D e pe nd, 75, 199 206 C l a r ke P B & K um a r R 1983 T he e f f e c t s of n i c ot i ne on l oc om ot or a c t i vi t y i n non t ol e r a nt a nd t ol e r a nt r a t s B r J P ha r m a c ol 78 329 337. C l a r ke P B S c hw a r t z R D P a ul S M P e r t C B & P e r t A 1985 N i c ot i ni c bi ndi ng i n r a t br a i n: a ut or a di ogr a phi c c om pa r i s on of 3 H a c e t yl c h ol i ne 3 H ni c ot i ne a nd 1 2 5 I a l pha bunga r ot oxi n. J N e ur os c i 5, 1307 1315. C ol l i ns A C B ur c h J B de F i e br e C M & M a r ks M J 1988 T ol e r a nc e t o a nd c r os s 41

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