Delta 9 Thc Atv n Acumbens

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Brain Research, 621 (1993) 65-70 65 1993 Elsevier Science Publishers B.V. All rights reserved 0006-8993/93/$06.00

BRES 19149

Ventral tegmental microinject ion of Ag-tetrahydrocannabinol enhancesventra l tegm enta l som atodend ri ti c dopa m ine l eve l s but not forebra indo pam ine levels: evide nc e for local neural act ion by marijuana's

psychoactive ingredientJ i a n p i n g C h e n a , b R o n e n M a r m u r h , A d d y P u l l e s b , W i ll ia m P a r e d e s b a n d E l i o t L . G a r d n e r a,b

Depar tm en t s o f ~ Neurosc ience and b P sych ia t ry , A lber t E ins t e in Co l lege o f M ed icine, Ne w York , N Y 10461 ( USA )(Accepted 30 March 1993)

Key words: Marijuana; Cannabis; Cannabinoid; Ag-Tetrahydrocannabinol A9-THC); Dopamine; Ventral tegmental area; Nucleus accumbens;Microdialysis; Brain reward; Addiction

Basal extracellular levels of dopamine (DA) and its metabolites in both ventral tegmental area (VTA) and nucleus accumbens (Acb) weresimultaneously monitored by in vivo brain microdialysis in laboratory rats. Microinjection of 12/zg or 24/zg A9-tetrahydrocannabinol ~Ig-THC),the psychoactive ngredient in marijuana and hashish, into the VTA produced a dose-dependent increase in somatodendritic DA levels in VTAbut failed to produce any simultaneous change in extracellular DA in Acb. Direct A9-THCperfusion (5 10 -5 and 2 10 -4 M) into Acb via themicrodialysis probes caused a significant increase in extracellular DA levels in Acb. These findings suggest that (1) ZI9-THC has a facilitatingeffect on somatodendritic DA effiux, and (2) the elevation of Acb DA levels seen in our previous studies with systemic administration of A 9 - T H Cmay result from local actions of A9-THC at or near the DA terminal projections in Acb.

INTRODUCTIONSeveral studies have shown that A9-tetrahydrocan-

nabinol (A9-THC), the major psychoactive principle ofmarijuana, augments functional extracellular dopamine(DA) levels in the brain. Thus, A9-THC inhibitsdop amin e (DA) upta ke 1'14'16 and increases both synthe-sis 2 and release 24 of DA in synapt osomes . Using invivo techniques, we have previously reported that A9-TH C augm ents brain-s timulat ion reward 12, which isknown to critically involve a mesotelencephalic DAsubstrate 9'3t. We have also shown, again using in vivotechniques, that A9-THC enhances potassium-evokedDA effiux in cauda te-pu tamen 2t and basal extracellu-lar D A levels in both nucleus accumbens (Acb) 7 andmedial prefro ntal cortex 8. The exact neur al locus ofactivation of the mesotelencephalic DA system byA9-THC remains unclear, however, since A9-THCwas administered systemically in previous in vivo stud-ie s 7 '8 '12 '21. Two working hypotheses become apparent:(1) A9-THC might act at presynaptic DA terminals,

inhibiting DA re-uptake or inducing DA release; or (2)A9-THC might activate DA neurons in the ventralmesencephalon, the axons of which project to the fore-brain, thereby increasing forebrain DA synthesis andterminal release. To shed light on these two possibili-ties, the present study was designed to examine theeffects of direct administration of Ag-THC into theventral tegmental area (VTA), the DA nuclear cellgroup for the mesolimbic DA projections to Acb, onextracellular DA levels in both the somatodendriticarea in VTA and the terminal area in Acb, monitoredsimultaneously by using two in vivo brain microdialysisprobes in the same rats. Additionally, direct adminis-tration o f A9-THC was also made into the Ac b, andlocal extracellular Acb DA levels were monitored by invivo brain microdialysis.MATERIALS AND METHODS

Male Lewis rats (Charles River) weighing 250-300 g were used.For the first experiment (local VTA A9-THC administration), ratswere implanted under sodium pentobarbital anesthesia (50 mg/kg)

Correspondence: E.L. Gardner, Laboratory of Behavioral Pharmacology,Department of Psychiatry, Forchheimer Building G-49, Albert EinsteinCollege of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Fax: (1) (718) 918-9274.


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with two microdialysis probes, one in the VTA and one in the Acb,using standard surgical and stereotaxic techniques. Concent ric micro-dialysis probes were used, having exposed cellulose dialysis mem-branes (Spect rum, MCO 6000) of 1 and 2 mm for VTA and Acb,respectively. A 25 /zl microsyringe with 225 /~m outs ide d iame terneedle was pre-loa ded with A9-THC solution or vehicle and im-planted into the VTA immediately adjacent and lateral to the VTAmicrodialysis probe, with th e microsyringe needle ceme nted parallelto the microdialysis probe such that the n eedle tip was positionedhalfway down t he exposed piece of microdialysis membrane in theVTA (see Fig. 1). The stereotaxic implant coordinates (according tothe atlas of Paxinos and Watson z2) relative to bregma were: A - 5.3,L 1.0, V -7 .7 (from dura) for VTA, and A 2.0, L 1.2, V -8 .0 (fromdura) for Acb. A 3 h recovery time was allowed following implanta-tion surgery before sample collection started. Animals were main-tained un der surgical anesthesia for the duration of microdialysissample collections. For the second experiment (local Acb A9-THCadministration), rats were impl anted with microdialysis probes (2 mmexposed dialysis membra ne) in Acb 20-24 h prior to A9-THC admin-istration at the same stereotaxic coordinates as in the first experi-ment. Animals were allowed to recover from surgery and the experi-ment was carried out on conscious, freely moving rats. The brainperfusate, a modified Ri nger's solution (165 mM NaCI, 3.7 mM KCI,2.5 mM CaClz, pH adjusted to 7.4) was pumped through the probesat a flow rate of 2 /xl/min. Dialysis samples (40/zl) were collectedevery 20 min and immediately assayed for DA and its metabolites3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid(HVA) by high-per formance liquid chromatogra phy with electro-chemical detection. The compounds were separated by reverse-phasechromatography with a Brownlee Velosep RP-18 (3 /~m particles)1003.2 mm column and a mobile phase containing 0.1 Mchloroacetic acid, 0.1 mM EDTA, 0.2 mM sodium octyl sulfate, and6-6.5% methanol, with pH adjusted to 3.0 with 10 N NaOH. The

mobile phase flow rate was 1.0 ml/min. Electrochemical measure-ments were made with a dual glassy carbon electrode (BioanalyticalSystems) coupled to two LC-4C (Bioanalytical Systems) dete ctor s,one for detection of DA and the other for DA metabolites, set at+ 0.7V.Ag-THC (National Institute on Drug Abuse) was evaporated withnitrogen and then dissolved in 10% v/v emulphor, 10% v/v propy-lene glycol and 80% v/ v perfusate. This mixed suspension was thenfurther diluted with the modified Ringer's solution to a final suspen-sion containing 4 ~g //xl or 8 p. g/~ l A9-THC for the first experi-ment. For the second experiment, A9-THC was prepared in the sameway and diluted to 5 10 -5 and 2 10 -4 M as the final adminis-tered concentrations. Vehicle solutions were prepare d by the sameprocedure, but without the addition of A9-THC.For the first experiment, following the 3 h recovery period aftersurgery, sample collection was started and cont inued until 3 consecu-tive stable 20 min samples were collected simultaneously from bothVTA and Acb. Then, microinjection of A9-THC or vehicle into theVTA was made. 3.0 ~.1 of the A9-THC suspension (4 /~g// zl or 8/zg/~zl for a to tal injection of 12 or 24 ~g Ag-THC) were slowlyinjected by hand over a 10 min period. Manual microsyringe injec-tion was used instead of an automated microinjection pump becauseA9-THC binds readily to the plastic tubing of automated microinjec-tion apparatuses. Supplemental sodium pentobarbital (14 mg/kg)was given every hour to maintain a steady state of anesthesiathroughout the experiment, and body temperature was maintained at37C. Possible influences of sodium pentobarbital itself on VTA andAcb DA levels were excluded by control experiments in whichrepeated intraperitoneal administrations of 14 mg/k g sodium pento-barbital were given to rats every hour for 4 consecutive hours withoutany significant changes in extracellular levels of DA and its metabo-lites in either VTA or Acb (data not shown).For the second experiment, after baselines for DA, DOP AC and

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Fig. 1. Reconstruc tion of representat ive implant of microdialysis pr obe and microinjector in ventral te gmental area (VTA), mapped according tothe brain atlas of Paxinos and Wat son 2z. The imper meable stainless- steel portion of the microdialysis probe is shown in solid black. The 1 mmexposed microdialysis tubing, shown in horizontal hatching, exten ded vertically over the entire extent of the VTA. The microinjector needle,shown in diagonal hatching, was cement ed to the stainless-st eel tubing of the microdialysis probe, with nee dle tip pos itioned immediately lateralto and halfway down the vertical ex tent of the expose d microdialysis tubing.


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H V A w e r e e s t a b li s h ed p e r f u s a te c o n t a in i n g A 9 - T H C ( 5 x 1 0 - 5 o r2 l 0 - 4 M ) w a s p e f f u s e d t h r o u g h t h e d i a ly s i s p r o b e s f o r 2 0 m i n a n dt h e n s w i t c h e d b a c k t o n o r m a l p e r f u s a t e . S i x m o r e s a m p l e s w e r e t h e nc o l l e c t e d .

M e a n l e v el s o f D A , D O P A C , a n d H V A o f th e t h r e e p r e- in j e c ti o ns a m p l e s w e r e u s e d a s b a s e l i n e s a n d a n a l y s is w a s p e r f o r m e d o np e r c e n t c h a n g e s a f t e r d r u g o r v e h i c l e i n j e c t i o n s. D a t a w e r e a n a l y z e db y t w o - w a y a n al y si s o f va r i an c e ( A N O V A ) f o r r e p e a t e d m e a s u re s ,f o l lo w e d b y p o s t - h o c D u n n e t t a n d T u k e y - K r a m e r t e s ts o f i n di v id u a lc o m p a r i s o n s 1 7. S t a n d a r d h i s t o l o g y w a s u s e d t o v e r i f y d i a l y si s p r o b el o c a t i o n s a f te r t h e c o m p l e t i o n o f e x p e r i m e n t s .

RESULTSFor the f i r s t exper iment (anes thet i zed rats ; local

A 9 - TH C a d m i n i s t r a t i o n i n t o V TA ) , b a s a l D A a n dmetabol i te l eve l s (uncorrected for probe recovery rate )preced ing drug o r ve h ic le in jec t ion w ere 46 .5 4- 3 .9f m o l / 4 0 # 1 / 2 0 m i n D A ( n = 1 3 ), 1 .2 6 + 0 .1 3 p m o l / 4 0/~1/20 min D O PA C (n --- 13), and 2 .31 -1- 0 .20 pm ol /4 0

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Fig. 4. Effect s of local perfusi on of A9-THC (5 10 _5 or 2 10 4 M)or vehicle into nucleus accumbens (Acb) on extracellular levels ofdopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and ho-movanillic acid (HVA) in Acb. Values are expressed as mean per-centages ( + SEM, n = 3 for each group) of pre- perfusi on basal levels.** Statistical significance of individual Dunn ett comparisons withpre-injec tion basal level (P < 0.01). ## Statistical significance of indi-vidual Tukey-K ram er comparisons between individual A9-THC datapoints and vehicle da ta points (P < 0.01). @ Statistical significance ofindividual Tuke y-Kram er comparisons betwee n individual high doseand low dose A9-THC data points (P < 0.05). There were no statisti-cally significant changes in extracellular levels of DOP AC or HV A inAcb aft er admini stration of A9-THC into Acb.

jection basal DA levels. A9-THC also produced adose-dependent increase in the extracellular levels ofDOPAC in VTA, but no significant change in extracel-lular HVA levels in VTA (Fig. 2). In contrast, microin-jection of A9-THC into the VTA did not significantlyalter extracellular levels of DA, DOPAC or HVA inAcb (Fig. 3). Local Acb perfusion of vehicle did notalter extracellular DA, DOPAC, or HVA levels in Acb(Fig. 4), however, local per fusion of A9-THC into Acbcaused a dose-dependent increase in extracellular DAlevels in Acb (A9-THC effect, F2,6 = 6.35, P < 0.05;time effect, F5,10 = 8.80, P < 0.0001; drug x time inter-action effect, F]0,30 -- 2.97, P < 0.001) without signifi-cantly altering DOPAC or HVA levels in Acb (Fig. 4).

DISCUSSIONThe present findings of A9-THC-induced augmenta-

tion of extracellular DA overflow in VTA appear to bein fundamental agreement with previous reports fromother groups that A9-THC augments extracellular DAneurotransmitter levels in both in vitro and in vivopreparations 1'24'27, and in close agreement with ourown previous in vivo findings that A9-THC augmentsboth potassium-evoked and basal extracellular DAoverflow in forebrain DA loci 7'8"21, although the pre-sent s tudy is the first to explore A9-THC's effects in theventral mesencephalic DA nuclear groups.

Very few studies have reported on either basal ordrug-influenced extracellular DA levels in the DA nu-clear groups of the ventral mesencephalon, and it isdifficult to compare the presently observed basal extra-cellular levels of DA and its metabolites in VTA tovalues reported by others, due to differences in micro-dialysis probe recovery rates and experimental condi-tions. For example, the basal values we observed in thepresent study are almost 3-times the basal extracellularDA levels in VTA reported by Bradberry and Roth 5.One cause for this difference might well be the highercalcium concentration (2.5 mM) in the present per-fusate, making the present 'basal' DA levels to somedegree calcium-evoked levels. It should be also notedthat the microdialysis probe placement used in thepresent study was 1.0 mm distant within the VTA fromthe site sampled by Bradberry and Roth 5.

A9-THC is the principal psychoactive constituent ofmarijuana, the most widely used illicit habit-formingdrug in the world 19. That habit-forming drugs act aseither direct or indirect DA agonists on a portion ofthe mesotelencephalic DA systems involved in the neu-ral mediation of reward and reinforcement, and derivetheir euphorigenic properties and abuse potentialtherefrom, is at present the most compelling hypothesisof the neurobiology of drug abuse 9J8'28'30,31. Many linesof evidence support this hypothesis. First, virtually allhabit-forming drugs augment electrical brain-stimula-tion reward in brain loci associated with the mesotelen-cephalic DA system9. Second, most indirect DA ago-nists are euphorigenic (and have consequent habit-for-ming potential) while most DA antagonists are dys-phorigenic 29'31 (direct DA agonists, while self-adminis-tered by rodents, dogs, and monkeys, appear to havelow habit-forming potential in humans, perhaps be-cause in humans they additionally activate other brainsystems mediating nausea, emesis, and other subjec-tively unpleasant effects). Third, virtually all habit-for-ming drugs augment extracellular DA synaptic levels inthe mesotelencephalic DA system9. Fourth, animals


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w i l l v o lu n t a r i l y s e l f - a d min i s t e r h a b i t - f o r min g d r u g s i n tom e s o t e l e n c e p h a l i c D A b r a i n l o ci , b u t f o r t h e m o s t p a r tno t in to o th er br ain loci 4'13,15'23,31. Fif th, les ion s orp h a r m a c o l o g ic a l b l o c k a d e o f t h e m e s o t e l e n c e p h a l i c D As y s t e m d r a ma t i c a l l y i n h ib i t t h e r e in f o r c e me n t d e r i v e df r o m v o lu n t a r y s y s t e mic (e . g. i n t r a v e n o u s ) s e l f -a d min i s -tra tio n of ha bi t-fo rm ing dr ug s 4,2'25'26,32.

W i th in t h i s c o n t e x t o f t h e D A n e u r a l s u b s t r a t e s o fr e in f o r c e m e n t a n d r e w a r d a c t i v a t e d b y h a b i t - f o r min gd r u g s , i t i s c l e a r t h a t h a b i t - f o r min g d r u g s o f d i f f e r e n tc l a s s e s a c t i v a t e t h e me s o t e l e n c e p h a l i c D A r e w a r d c i r -c u i t r y b y v a r y in g a n d d i f f e r e n t me c h a n i s m s . T h u s , a m-p h e t a m i n e s a p p e a r t o r e l e a s e D A f r o m p r e s y n a p t i cs y n th e s i s p o o l s , c o c a in e t o b lo c k p r e s y n a p t i c r e - u p t a k eo f D A , a n d o p i a t e s t o a u g m e n t s y n a p ti c re l e a s e o f D Ab y in c r e a s in g n e u r o n a l f i ri n g o f p r e s y n a p t i c D A n e u -r o n s 9. T h e q u e s t i o n s o b v io u s ly a r i s e - a t w h ic h n e u r a ll o c u s a n d b y w h ic h n e u r a l m e c h a n i s m w i th in t h em e s o t e l e n c e p h a l i c D A s y s t e m d o e s A 9 - T H C a c t ?

W hi le we 7'8'21 and o the r s 27 have prev iou s ly r e po r tedth a t A g - T H C a u g me n t s e x t r a c e l lu l a r D A l e v e l s i nme s o t e l e n c e p h a l i c D A p r o j e c t i o n l o c i , w i th p a r t i c u l a rs e n s i t i v i t y i n t h e me s o l imb ic D A f ib e r s p r o j e c t i n g t oth e A c b 7 's , t h e s p e c i f ic n e u r o a n a to m ic a l l o c u s o f a c t i o nw i t h i n t h e m e s o l i m b i c D A s y s t e m h a s r e m a i n e d o b -s c u r e . F e w d e f in i t i v e c o n c lu s io n s c a n b e ma d e w h e nA 9 - T H C i s g iv e n s y s te mic a ll y . T h e r e f o r e , i n t h e p r e s e n ts t u d y , d i r e c t a p p l i c a t i o n o f A 9 - T H C in to t h e s o ma to -d e n d r i ti c r e g i o n o f t h e D A n e u r o n s i n V T A w a s m a d e .N o t e w o r t h i l y , s u c h a p p l i c a t i o n a u g m e n t e d s o m a t o d e n -d r i t i c D A l e v e l s i n V T A b u t f a i l e d t o a u g me n t a x o nt e rm i n a l D A l ev e ls o f t h e s a m e n e u r a l p o p u l a t i o n i nA c b . W i th r e s p e c t t o t h e l a c k o f e f f e c t i n A c b , tw op o s s ib i l i t i e s e x i s t : ( 1 ) t h a t A 9 - T H C a u g me n t s n e u r o n a lf ir in g o f D A n e u r o n s b u t t h a t t h e A 9 - T H C d o s es u s e din th e p r e s e n t s t u d y w e r e n o t s u f f i c i e n t t o p r o d u c es u c h a u g m e n t a t i o n a n d r e s u l t i n g a u g m e n t e d t e r m i n a lr e l e a s e o f D A in A c b ; o r ( 2 ) t h a t A 9 - T H C a c t s l o c a l l yo n D A n e r v e m e m b r a n e s t o e i t h e r r e l e a s e D A o rp r e v e n t D A r e - u p t a k e w i th in j u s t t h e l o c a l a r e a o fA 9 - T H C d i f f u s io n . W e f a v o r t h e l a t t e r i n t e r p r e t a t i o nf o r ma n y r e a s o n s . F i r s t , t h e p r e s e n t A 9 - T H C d o s e sw e r e s u f fi c ie n t ly la r g e t o p r o d u c e e n o r m o u s a u g m e n t a -t i o n o f s o ma to d e n d r i t i c e x t r a c e l l u l a r D A o v e r f l o w ( t oa p p r o x ima te ly 4 0 0 % o f p r e - d r u g b a s e l i n e b y 1 2 /~ gA 9 - T H C a n d t o a p p r o x ima te ly 1 , 3 0 0 % o f p r e - d r u gbase l ine by 24 / .Lg Ag-TH C - see F ig . 2 ) . I f sucha u g m e n t a t i o n o f s o m a t o d e n d r i t i c e x t ra c e ll u l ar D Ao v e r f l o w w e r e i n a n y w a y c o r r e l a t e d w i t h a u g m e n t e dn e u r o n a l f i r i n g , i n c r e a s e d e x t r a c e l l u l a r D A o v e r f l o wf r o m A c b t e r min a l s s h o u ld h a v e b e e n e v id e n t . S e c o n d ,a s n o t e d a b o v e , i n v i t r o s t u d i e s h a v e s h o w n th a t A9-T H C i n h i b i t s t h e r e - u p t a k e o f D A 1 '14 '16 , sugges t ing a

69lo c a l i z e d s y n a p t i c a c t i o n r a th e r t h a n a g e n e r a l i z e d a c -t i o n o n n e u r o n a l f i ri n g p a t te r n s . T h i r d , p r e v io u s i n v iv ob r a in e l e c t r o c h e m is t r y s tu d i e s s h o w th a t A 9 -T H C p r o -d u c e s a u g m e n t e d v o l t a m m e t r i c s i g n a l s c o r r e s p o n d i n gto e x t r a c e l l u l a r D A th a t a r e i d e n t i c a l t o t h e a u g me n te dv o l t a mm e t r i c s i g n al s p r o d u c e d b y n o mi f e n s in e , a w e ll -c h a r a c t e r i z e d D A r e - u p t a k e b lo c k e r 21. F o u r th , p r e v i -o u s i n v iv o mic r o d i a ly s i s s t u d i e s f r o m th i s l a b o r a to r yd e mo n s t r a t e a n a d d i t i v e o r e v e n s y n e r g i s t i c e f f e c t o ne x t ra c e ll u l ar D A o v e r fl o w in A c b b e t w e e n A 9 - T H Ca n d h a l o p e r i d o l- i n d u c e d a u g m e n t a t io n o f p re s y n a p t icaxona l f i r ing 1, which i s congr uen t w i th za9-THC ac t ing( p e r h a p s i n d i r e c t l y ) a s a D A r e - u p t a k e b lo c k e r . F i f t h ,d i r e c t l o ca l A 9 -T H C a d min i s t r a t i o n i n to t h e A c b c a u s e da s ign i f ican t inc rease in ex t race l lu la r DA leve ls in Acbin the present s tudy . S ix th , a s no ted above , systemicA 9 - T H C a d min i s t r a t i o n p r o d u c e s s i g n i f i c a n t a u g me n ta -t i o n o f e x t r a c e l l u l a r D A o v e r f l o w in A c b 7. O f c o u r s e ,t h e p r e s e n t d a t a w o u l d a l s o b e c o m p a t i b l e w i t h acomb ined a c t i o n b y A 9 - T H C o n both s o m a t o d e n d r i t i cD A r e l e a s e o r r e - u p t a k e b l o c k a d e and a u g m e n t a t i o no f n e u r o n a l f i r i n g , w i th t h e l a t t e r e f f e c t c o u n t e r a c t e db y a ct iv a t io n o f s o m a t o d e n d r i ti c D A a u t o r e c e p t o r sw h ic h i n h ib it D A n e u r o n a l f ir in g 6.

I n s u mma r y , t h e p r e s e n t f i n d in g s a p p e a r t o b e c o m-pa t ib le wi th the hypothes is tha t z I9-THC ac ts loca l lyw i th in D A - r e l e a s in g r e g io n s o f t h e me s o t e l e n c e p h a l i cD A s y s t e m t o a u g m e n t s y n a p t i c D A l e v e l s . T o t h ee x t e n t t h a t s u c h a c t i o n s a r e l o c a l i z e d w i th in s u b p o r -t i on s o f t h e m e s o t e l e n c e p h a li c D A s y s te m m e d i a t i n gr e w a r d a n d r e i n f o r c e m e n t , s u c h a c t i o n s w o u l d a p p e a rto c o n t r i b u t e t o ma r i j u a n a ' s e u p h o r ig e n i c a c t i o n s a n di t s abuse l iab i l i ty .

Acknowledgements. T h i s s tu d y w as s u p p o r t e d b y N I D A G r a n tD A 0 3 6 2 2 a n d N I H G r a n t R R 0 5 3 9 7 f r om t h e U S P u b li c H e a l t hS e r v ic e , N S F G r a n t B N S - 86 -0 9 35 1 f r o m t h e U S N a t i o n a l S c i e n c eF o u n d a t i o n , t h e A a r o n D i a m o n d F o u n d a t i o n , a n d t h e N e w Y o r kS t a t e O f f i c e o f A l c o h o l is m a n d S u b s t a n c e A b u s e S e r v i c e s. R . M . i s int h e M e d i c a l S c i e n t i s t T r a i n i n g P r o g r a m , A l b e r t E i n s t e i n C o l l e g e o fM e d i c i n e . A . P . i s a n e x c h a n g e s t u d e n t f r o m t h e F a c u l t y o f M e d i c i n e ,U n i v e r s i t y o f U t r e c h t , T h e N e t h e r l a n d s . J . C . w a s p a r t ia l l y s u p p o r t e db y f u n d s f r o m t h e S u e G o l d i n g G r a d u a t e D i v i s i o n o f M e d i c a l S c i -e n c e s , A l b e r t E i n s t e i n C o l l e g e o f M e d i c i n e . T h e d a t a i n t h i s p a p e ra r e f r om a t hes i s subm i t t ed by J .C . i n pa r t i a l f u l f i l lmen t o f t her e q u i r e m e n t s f o r t h e d e g r e e o f D o c t o r o f P h i l o s o p h y i n N e u r o -s c i e n c e fr o m t h e S u e G o l d i n g G r a d u a t e D i v i s io n o f M e d i c a l S ci -e n c e s , A l b e r t E i n s t e i n C o l l e g e o f M e d i c i n e , Y e s h i v a U n i v e r si t y .

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