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Alcohol promotes dopamine release in the human nucleus accumbens

Alcohol Promotes Dopamine Release in the
Human Nucleus Accumbens
1McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montre´al, QC, Canada 2Department of Psychology, McGill University, Montre´al, QC, Canada 3Department of Psychiatry, McGill University, Montre´al, QC, Canada 4Research Unit on Children’s Psychosocial Maladjustment, Universite´ de Montre´al, Montre´al, QC, Canada PET; [11C]raclopride; addiction; personality; impulsivity; heart rate;CNS stimulants Microdialysis experiments in rodents indicate that ethanol promotes dopamine release predominantly in the nucleus accumbens, a phenomenon that is
implicated in the reinforcing effects of drugs of abuse. The aim of the present study was
to test the hypothesis in humans that an oral dose of ethanol would lead to dopamine
release in the ventral striatum, including the nucleus accumbens. Six healthy subjects
underwent two [11C]raclopride PET scans following either alcohol (1 ml/kg) in orange
juice or orange juice alone. Subjective mood changes, heart rate, and blood-alcohol levels
were monitored throughout the procedure. Personality traits were evaluated using the
tridimensional personality questionnaire. PET images were co-registered with MRI and
transformed into stereotaxic space. Statistical parametric maps of [11C]raclopride bind-
ing potential change were generated. There was a significant reduction in [11C]raclo-
pride binding potential bilaterally in the ventral striatum/nucleus accumbens in the
alcohol condition compared to the orange juice condition, indicative of increased extra-
cellular dopamine. Moreover, the magnitude of the change in [11C]raclopride binding
correlated with the alcohol-induced increase in heart rate, which is thought to be a
marker of the psychostimulant effects of the drug, and with the personality dimension
of impulsiveness. The present study is the first report that, in humans, alcohol promotes
dopamine release in the brain, with a preferential effect in the ventral striatum. These
findings support the hypothesis that mesolimbic dopamine activation is a common
property of abused substances, possibly mediating their reinforcing effects. Synapse 49:
226 –231, 2003.

al., 1992; Diana et al., 1992) that are reversed by eth- Addiction is thought to result in large part from the anol administration (Weiss et al., 1996). Alcohol is reinforcing properties of drugs of abuse on brain re- widely abused by humans; however, no studies have ward systems, and in particular on mesolimbic dopa- directly investigated the effect of alcohol consumption mine (Koob et al., 1998; Wise, 1996). Microdialysis on the dopamine system. We now present, for the first studies in rats show that ethanol and other drugs of time in humans, evidence that alcohol consumed orally abuse, such as opiates, nicotine, amphetamine, and promotes dopamine release specifically in the NAc.
cocaine, acutely increase extracellular dopamine levels We measured dopamine release in response to a sin- predominantly in the nucleus accumbens (NAc) (Di gle-dose administration of alcohol using positron emis- Chiara and Imperato, 1988). The role of NAc dopaminein alcohol self-administration is further supported byreports of changes in consumption following alterations Contract grant sponsors: the Canadian Institutes for Health Research and the Fonds de la Recherche en Sante´ du Que´bec.
in mesolimbic dopamine neurotransmission (Rassnick *Correspondence to: Alain Dagher, Montreal Neurological Institute, 3801 Uni- et al., 1993; Samson et al., 1993; Nowak et al., 2000), versity St., Montre´al (QC), Canada, H3A 2B4.
ethanol self-administration into the ventral tegmental Received 31 January 2003; Accepted 4 April 2003 area (Gatto et al., 1994), and alcohol withdrawal-in- duced reductions in both dopamine neuron firing andNAc extracellular dopamine concentration (Rossetti et ALCOHOL PROMOTES DOPAMINE RELEASE IN HUMANS sion tomography (PET) and the dopamine receptor li-gand [11C]raclopride. We used a two-scan methodbased on evidence in primates, including combinedPET microdialysis studies, that the binding of benz-amides such as [11C]raclopride is sensitive and propor-tional to extracellular dopamine concentration in thestriatum (Endres et al., 1997; Ginovart et al., 1997;Hartvig et al., 1997; Laruelle et al., 1997; Laruelle,2000). This approach has been used in humans to mea-sure the dopamine response to psychostimulants (Car-son et al., 1997; Schlaepfer et al., 1997; Volkow et al., Study design. The vertical arrows indicate the time points 2001) and behavioral tasks (Koepp et al., 1998). Three of blood sampling, subjective mood assessments, and physiological recent PET studies have also shown that dopamine release following amphetamine occurs mostly in theventral striatum and that the amount of dopamine lected based on previous behavioral experiments show- released correlates with self-reported behavioral mea- ing that it was intoxicating but without significant sures of euphoria or drug wanting (Drevets et al., 2001; adverse effects in this population. At the end of con- Leyton et al., 2002; Martinez et al., 2003).
sumption, subjects were immediately positioned in thescanner and a 12-min transmission scan was acquired MATERIALS AND METHODS
using a 68Ge source for the purpose of attenuation Seven healthy male nonalcoholic moderate drinkers correction. Following the transmission scan, and 15 (brief Michigan Alcoholism Screening Test, Pokorny et min after the end of alcohol consumption, [11C]raclo- al., 1972), age 22 (Ϯ0.6), were recruited from an exis- pride 10 mCi was injected as a bolus into the antecu- tent longitudinal cohort (Tremblay et al., 1994). All bital vein, after which PET dynamic acquisition (63 subjects who participated had experienced the alcohol slices, 26 time frames of 60 min total duration) was dose administered in this study at least twice in a laboratory setting. Data from one of the seven subjects Subjects were scanned on the CTI/Siemens ECAT had to be excluded due to excessive motion during the HRϩ PET camera with lead septa removed, with in- scan. All subjects were free of active or past medical or trinsic resolution 4.8 ϫ 4.8 ϫ 5.6 mm FWHM. Blood psychiatric illness. Subjects fasted and abstained from samples, for plasma alcohol measurements, were with- caffeine or tobacco for a minimum of 4 h before each drawn from the venous cannula before the initiation of test session. Five of the six subjects were nonsmokers drinking, at tracer injection (15 min after finishing and one was a light smoker (1–2 cigarettes per day).
drinking), and every 15 min thereafter. Subjective ef- They were also asked to refrain from taking drugs for 7 fects of alcohol, assessed with the Subjective High As- days and alcohol for 24 h prior to each experimental sessment Scale (SHAS, Judd et al., 1977; Schuckit et day. Before each scanning session, subjects underwent al., 1997), and heart rate were measured prior to alco- screening for drugs of abuse (Triage Panel for Drugs of hol consumption and throughout the procedure. The Abuse, Biosite Diagnostics, San Diego, CA) including SHAS is a visual analog scale that assesses sensations alcohol (Alcosensor III intoxicometer, Thomas Instru- such as feeling high, drunk, and drowsy. In a separate ments, Montreal, QC). All subjects read and signed a session, prior to the first scan, all subjects completed consent form approved by the Research and Ethics the tridimensional personality questionnaire (TPQ; Committee of the Montreal Neurological Institute.
Cloninger et al., 1991). This test assesses three dimen- Subjects participated in two [11C]raclopride PET sions of personality, including novelty seeking (impul- scans after consumption of alcohol in orange juice or sive, excitable, exploratory temperament), which is orange juice alone (Fig. 1). Subjects were only told thought to depend in significant part on activity in the about drink content (alcohol or orange juice alone) at dopamine pathways (Cloninger, 1994). For the purpose the beginning of the session, and they did not come into of anatomical co-registration, subjects also underwent contact with the drink until the time of consumption.
a 1 ϫ 1 ϫ 1 mm anatomical T -weighted MRI of the PET data acquisition was performed at the same time whole brain using a gradient echo pulse sequence of day (between 14:00 and 16:00) on separate days, 1 (TR ϭ 9.7 ms, TE ϭ 4 ms, flip angle ϭ 12°, FOV ϭ 250, week apart, and counterbalanced for order of adminis- tration of alcohol (three out of six received alcohol on PET frames were summed across time, co-registered the first day, randomly chosen). Prior to scanning, a with the corresponding MRI (Woods et al., 1993), and venous catheter was inserted in the subject’s left arm.
transformed into standardized stereotaxic space (Ta- Oral consumption of alcohol (1 ml/kg of 95% USP alco- lairach and Tournoux, 1988) by means of automated hol over 15 min) or alcohol-free mixture started 30 min feature-matching to the MNI template (Collins et al., prior to tracer injection. The dose of alcohol was se- 1994). Voxelwise [11C]raclopride binding potential (BP) change in [11C]raclopride BP inducedby an acute oral dose of alcohol (1 ml/kg) in healthy volunteers (n ϭ 6). Colorclusters superimposed on the averageMRI from all subjects depict a signifi-cant change in BP in the ventralstriatum.
was calculated using a simplified reference tissue session with orange juice that was greater than 2 SD method (Lammertsma et al., 1996; Gunn et al., 1997) to from the sample mean, magnitude of heart rate generate statistical parametric images of the change in change was analyzed with the nonparametric Wil- binding (Aston et al., 2000). BP values for each subject coxon matched pairs test. Maximum change in SHAS were extracted from regions of interest (ROI) manu- rating from baseline taken on the same day (⌬max ally drawn on the co-registered MRI on the left and [SHAS]) was used to evaluate the subjective effects right caudate (drawn on transverse slices at Ta- of alcohol and control drinks. A t-test for paired lairach-space z coordinate from ϩ2 to ϩ15 mm), pu- samples was used to determine the difference be- tamen (ϩ2 to ϩ10 mm), ventral putamen (– 8 to – 4 mm), NAc (– 8 to – 4 mm), and cerebellum, which was [SHAS] for the control. Stepwise linear regression used as the reference region. BP values extracted analysis was used to examine whether percent from ROI during alcohol and control scans were an- change in ROI BP could be predicted by changes in alyzed using a three-way ANOVA for dependent sam- heart rate, change in SHAS scores, or TPQ person- ples [Treatment ϫ ROI ϫ hemisphere]. Sphericity was assessed with the Mauchly test and, when indi-cated, corrections were made with Greenhouse-Gei- sser adjustments. When appropriate, least signifi- Screening for drugs of abuse was positive for only one cant difference t-tests, Bonferroni corrected, were subject (THC and trace cocaine prior to both scan con- applied to determine the significance of regional dif- ditions). Therefore, two different analyses were carried ferences in BP between the alcohol and orange juice out, one excluding the data from this subject. In both conditions. Heart rate during the ascending part of cases, receptor parametric mapping identified signifi- the blood alcohol curve was compared to a baseline cant reductions in [11C]raclopride BP in bilateral ven- taken just prior to the study session. Since one sub- tral striatum in the alcohol compared to the alcohol- ject exhibited a change in heart rate during the test free condition (Fig. 2). In the statistically generated ALCOHOL PROMOTES DOPAMINE RELEASE IN HUMANS DISCUSSION
The observed reduction in [11C]raclopride BP con- fined to the ventral part of the striatum is indicative ofdopamine release specifically in the NAc and ventralputamen in response to alcohol in humans. The ventralspecificity of the effect is consistent with three other[11C]raclopride PET studies, in which amphetaminewas found to preferentially induce dopamine release inthe ventral striatum in humans (Drevets et al., 2001;Leyton et al., 2002; Martinez et al., 2003). In animals,in vivo microdialysis studies have also shown a propen-sity for alcohol to induce dopamine release in the ven-tral striatum. Di Chiara and Imperato (1988) found Mean [11C]raclopride BP in the alcohol and control (orange that ethanol at rewarding doses had an almost 10-fold juice) conditions. The data are extracted from manually drawn ROI on greater effect on dopamine release in the NAc than in each subject’s MRI. Bonferroni corrected pairwise comparisons: †Dif- the dorsal caudate. Moreover, low doses of ethanol ference between alcohol and control, P Ͻ 0.001. Error bars representthe SEM.
produce a dose-dependent increase in the firing rate ofA10 dopamine neurons in the ventral tegmental area, t-map, [11C]raclopride BP values were 16.8 Ϯ 16.3% which project to the ventral striatum (Gessa et al., lower on the test day with alcohol, compared to orange 1985). Activation of A9 dopamine neurons, which juice (t(5) ϭ 2.54, P ϭ 0.05).
project to the dorsal striatum, only occurs at 5-fold Analyses of [11C]raclopride BP values in the a priori defined ROI supported the receptor parametric map- While a direct pharmacological effect of alcohol could ping analyses (Fig. 3). A treatment ϫ ROI ϫ hemi- account for our findings, it is possible that conditioned sphere ANOVA yielded a main effect of ROI (F(3,15) ϭ cues and anticipation also played a role in enhancing 42.55, P Ͻ 0.001, Greenhouse-Geisser corrected) and a dopamine release. In humans, exposure to the odor of treatment ϫ ROI interaction (F(3,15) ϭ 3.21, P ϭ 0.05).
alcohol leads to autonomic nervous system activity Bonferroni-corrected pairwise comparisons confirmed (Stormark et al., 1995), and alcohol-related cues have that alcohol significantly reduced BP in the NAc (P ϭ been shown to cause dopamine release in rats previ- 0.003) and ventral putamen (P ϭ 0.001) but not in the ously trained to self-administer alcohol (Katner and caudate (P ϭ 0.98) or putamen (P ϭ 0.84). The percent Weiss, 1999). The subjects in our study only learned change in [11C]raclopride BP also varied with ROI whether they would receive alcohol or not when they (F(3,15) ϭ 13,50, P ϭ 0.001). In both the nucleus ac- arrived at the lab and they were kept away from the cumbens (15.0 Ϯ 15.9%) and the ventral putamen drinks until the start of consumption, thus limiting the (13.7 Ϯ 16.4%), the percent decreases in [11C]raclopride potential influence of anticipation in this experiment.
BP were greater than those seen in either the putamen The dorsal and ventral striatum can be separated (5.2 Ϯ 17.5%) or caudate nucleus (4.0 Ϯ 16.4%) (P Ͻ functionally and anatomically (Moore and Bloom, 1978; Heimer et al., 1982; Haber et al., 2000). Their dopa- The blood alcohol level reached a mean peak of 18.10 mine innervations originate in different cell groups in (Ϯ1.4) mmol/L (0.0833 gm %) at 30 min after drinking.
the midbrain and their cortical connections likely ac- During the expected ascending phase of the blood alco- count for their different functional roles. The ventral hol curve (15–30 min post drink) alcohol consumption striatum, including the NAc and ventral putamen, be- resulted in small but consistent increases in heart rate long to the “limbic” cortico-striatal loop that includes (5.47 Ϯ 6 beats/min; t(5) ϭ 1.85, P ϭ 0.12; 6/6 subjects the amygdala, hippocampus, orbito-frontal cortex, and higher during alcohol test, Wilcoxon matched pairs cingulate cortex, structures involved in emotional be- test, z ϭ 2.20; P ϭ 0.028) and self-reported feelings of havior and reward processing. There is much evidence “high” and “drunkenness” (paired t-test, ⌬ for specific involvement of ventral striatal, or mesolim- [SHAS] orange juice, P Ͻ 0.01). A bic, dopamine in the reinforcing effects of addictive stepwise linear regression showed that impulsiveness, drugs (Wise, 1996; Koob et al., 1998). It is thought to one of the subscales on the novelty-seeking dimension mediate associative learning, whereby drug-related of the TPQ, and heart rate increase recorded at 30 min cues acquire incentive value (Di Chiara et al., 1999).
(i.e., during the ascending phase of the blood alcohol Conditioned place preference, a laboratory test of con- curve) were the only predictors of BP change in the ditioned incentive learning, is abolished by lesions or ventral striatum (r ϭ 0.985; P ϭ 0.005). Neither the dopamine blockade of the ventral but not dorsal stria- subjective intoxication measures nor the peak blood tum (Everitt et al., 1991; Hiroi and White, 1991). Our alcohol level correlated with the change in [11C]raclo- finding of dopamine release confined to the ventral striatum after oral ingestion of an intoxicating dose of alcohol may therefore account at least in part for its tiple neurotransmitter systems. In particular, the SHAS mostly reflects the sedative effects of alcohol Ethanol most likely acts on dopamine neurons indi- (Conrod et al., 2001), which are probably not mediated rectly (Yim et al., 1998). It potentiates GABA-A recep- tor function (Weiner et al., 1994) to cause inhibition of In conclusion, we showed that alcohol consumed by GABAergic interneurons in the substantia nigra re- mouth in intoxicating doses promotes dopamine re- ticulata (Mereu and Gessa, 1985), which leads to dis- lease in the ventral striatum. The observed relation- inhibition and increased burst firing of dopamine neu- ship between the magnitude of change in [11C]raclo- rons (Grace and Bunney, 1985). As stated above, A10 pride BP, personality, and heart rate increase suggests neurons projecting to the ventral striatum appear to be that the paradigm we have developed could be used to more sensitive to these systemic effects of ethanol than investigate the factors that lead to vulnerability for A9 dopamine neurons projecting to the dorsal striatum (Gessa et al., 1985). Opioid peptides may also be in-volved in the dopamine releasing actions of ethanol REFERENCES
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A velha lei no novo testamento

UM ESTUDO SUPLEMENTAR A VELHA LEI NO NOVO TESTAMENTO OWEN D. OLBRICHT “Agora, com efeito, obteve Jesus ministério tan- digo: até que o céu e a terra passem, nem um i ou to mais excelente, quanto é ele também Mediador um til jamais passará da Lei, até que tudo se de superior aliança instituída com base em supe- riores promessas. Porque, se aquela primeira Essa passage

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darunavir 400mg tablets (Prezista®) SMC No. (707/11) Janssen 08 July 2011 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in Scotland. The advice is summarised as follows: ADVICE : following a full submission darunavir (Prezista®) 400mg is accepted f

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