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Sex Differences in Striatal Dopamine Release in Young Adults After Oral Alcohol Challenge: A Positron Emission Tomography Imaging Study With [11C]Raclopride

      Background

      We used a positron emission tomography paradigm with the D2/3 radiotracer [11C]raclopride and an alcohol challenge to examine the magnitude of alcohol-induced dopamine release and compare it between young men and women.

      Methods

      Twenty-one nonalcohol-dependent young social drinkers completed two positron emission tomography scans on separate days following ingestion of a juice mix containing either ethanol (.75 mg/kg body water) or trace ethanol only. The extent of dopamine released after alcohol was estimated by the percentage difference in [11C]raclopride binding potential (ΔBPND) between days.

      Results

      Alcohol administration significantly displaced [11C]raclopride in all striatal subregions, indicating dopamine release, with the largest effect observed in the ventral striatum. Linear mixed model analysis across all striatal subregions of regional ΔBPND with region of interest as repeated measure showed a highly significant effect of sex (p < .001). Ventrostriatal dopamine release in men, but not in women, showed a significant positive correlation to alcohol-induced measures of subjective activation. Furthermore, we found a significant negative correlation between the frequency of maximum alcohol consumption per 24 hours and ventrostriatal ΔBPND (r = .739, p = .009) in men.

      Conclusions

      This study provides definitive evidence that oral alcohol induces dopamine release in nonalcoholic human subjects and shows sex differences in the magnitude of this effect. The ability of alcohol to stimulate dopamine release may contribute to its rewarding effects and, thereby, to its abuse liability in humans. Our report further suggests several biological mechanisms that may mediate the difference in vulnerability for alcoholism between men and women.

      Key Words

      Alcohol is one of the most commonly abused substances, and alcoholism is one of the leading causes of disability in the United States (
      • Hasin D.S.
      • Stinson F.S.
      • Ogburn E.
      • Grant B.F.
      Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions.
      ,
      • Keyes K.M.
      • Geier T.
      • Grant B.F.
      • Hasin D.S.
      Influence of a drinking quantity and frequency measure on the prevalence and demographic correlates of DSM-IV alcohol dependence.
      ). In most developed countries, the lifetime risk for alcohol use disorders is 20% in men (twofold higher than in women) (
      • Saxena S.
      Alcohol, Europe and the developing countries.
      ), with a risk of 15% for alcohol abuse and 10% for dependence (
      • Teesson M.
      • Baillie A.
      • Lynskey M.
      • Manor B.
      • Degenhardt L.
      Substance use, dependence and treatment seeking in the United States and Australia: A cross-national comparison.
      ,
      • Schuckit M.A.
      Alcohol-use disorders.
      ). The heaviest drinking in the general population occurs between the ages of 18 and 22 years (
      • Kuperman S.
      • Chan G.
      • Kramer J.R.
      • Bierut L.
      • Bucholz K.K.
      • Fox L.
      • et al.
      Relationship of age of first drink to child behavioral problems and family psychopathology.
      ), and consequently, the highest risk to develop alcohol use disorders is at the beginning of the third decade of life (
      • Clark D.B.
      The natural history of adolescent alcohol use disorders.
      ).
      Little is known about the mechanisms through which alcohol produces its rewarding effects in humans, in part because of the diversity of ethanol targets in the brain (
      • Krystal J.H.
      • Tabakoff B.
      Ethanol abuse, dependence, and withdrawal: Neurobiology and clinical implications.
      ). Principally based on preclinical studies, primarily the ability of alcohol to stimulate dopaminergic (DA) transmission in the ventral striatum has been hypothesized to contribute to its abuse liability in humans. Alcohol administration induces DA release in the dorsal caudate and nucleus accumbens in rats (
      • Di Chiara G.
      • Imperato A.
      Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.
      ). The rewarding and euphoriant properties of alcohol-induced mesolimbic DA stimulation (
      • Samson H.H.
      • Tolliver G.A.
      • Haraguchi M.
      • Hodge C.W.
      Alcohol self-administration: Role of mesolimbic dopamine.
      ,
      • Wise R.
      • Romprè P.
      Brain dopamine and reward.
      ,
      • Le Moal M.
      • Simon H.
      Mesocorticolimbic dopaminergic network: Functional and regulatory roles.
      ) are believed to play a major role in reinforcing its consumption (
      • Wise R.
      • Romprè P.
      Brain dopamine and reward.
      ,
      • Fibiger H.C.
      Drugs and reinforcement mechanisms: A critical review of the catecholamine theory.
      ). However, in rats habituated to alcohol exposure, self-administration of an ethanol solution raised DA levels in the accumbens only during the early phase after onset of drinking, and there was no DA increase after cue presentation, suggesting that while DA may play a significant role, it is not the only or central substrate producing the reinforcement from alcohol (
      • Nurmi M.
      • Sinclair J.D.
      • Kiianmaa K.
      Dopamine release during ethanol drinking in AA rats.
      ).
      Alcohol-preferring rats have been found to have lower extracellular DA levels at baseline than abstainer rats and decreased D2 receptor density (
      • McBride W.J.
      • Chernet E.
      • Dyr W.
      • Lumeng L.
      • Li T.K.
      Densities of dopamine D2 receptors are reduced in CNS regions of alcohol-preferring P rats.
      ), as well as lower DA concentrations in the mesolimbic terminals (
      • Murphy J.M.
      • McBride W.J.
      • Lumeng L.
      • Li T.K.
      Regional brain levels of monoamines in alcohol-preferring and -nonpreferring lines of rats.
      ), and intraperitoneal ethanol induced a twofold greater increase of DA release in the nucleus accumbens measured by microdialysis (
      • Bustamante D.
      • Quintanilla M.E.
      • Tampier L.
      • Gonzalez-Lira V.
      • Israel Y.
      • Herrera-Marschitz M.
      Ethanol induces stronger dopamine release in nucleus accumbens (shell) of alcohol-preferring (bibulous) than in alcohol-avoiding (abstainer) rats.
      ). Greater magnitude of alcohol-induced DA release was also found to be a predictor of degree of alcohol preference in rats in some (
      • Katner S.N.
      • Weiss F.
      Neurochemical characteristics associated with ethanol preference in selected alcohol-preferring and -nonpreferring rats: A quantitative microdialysis study.
      ) but not other studies (
      • Ramachandra V.
      • Phuc S.
      • Franco A.C.
      • Gonzales R.A.
      Ethanol preference is inversely correlated with ethanol-induced dopamine release in 2 substrains of C57BL/6 mice.
      ). These findings may suggest that both a low dopaminergic tone and a strong mesolimbic DA response to ethanol are associated with ethanol-seeking behavior.
      Human studies have evaluated dopamine transmission in the striatum of both chronic alcohol users and healthy control subjects. Dopamine release after amphetamine administration is reduced in the ventral striatum (VST) of detoxified subjects with alcohol dependence (
      • Martinez D.
      • Gil R.
      • Slifstein M.
      • Hwang D.R.
      • Huang Y.
      • Perez A.
      • et al.
      Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum.
      ,
      • Volkow N.D.
      • Wang G.J.
      • Telang F.
      • Fowler J.S.
      • Logan J.
      • Jayne M.
      • et al.
      Profound decreases in dopamine release in striatum in detoxified alcoholics: Possible orbitofrontal involvement.
      ).
      Despite this evidence, the dopaminergic response to alcohol itself has not been extensively studied in humans. Four studies quantifying in vivo alcohol-induced displacement of [11C]raclopride from DA D2/3 receptors have reported mixed findings: two studies suggested that alcohol-induced DA release within the striatum in humans can be measured with [11C]raclopride displacement (
      • Boileau I.
      • Assaad J.M.
      • Pihl R.O.
      • Benkelfat C.
      • Leyton M.
      • Diksic M.
      • et al.
      Alcohol promotes dopamine release in the human nucleus accumbens.
      ,
      • Yoder K.K.
      • Morris E.D.
      • Constantinescu C.C.
      • Cheng T.E.
      • Normandin M.D.
      • O'Connor S.J.
      • Kareken D.A.
      When what you see isn't what you get: Alcohol cues, alcohol administration, prediction error, and human striatal dopamine.
      ), one reported no overall effect on binding but a relationship between subjective effects of alcohol and the magnitude of [11C]raclopride displacement (
      • Yoder K.K.
      • Constantinescu C.C.
      • Kareken D.A.
      • Normandin M.D.
      • Cheng T.E.
      • O'Connor S.J.
      • Morris E.D.
      Heterogeneous effects of alcohol on dopamine release in the striatum: a PET study.
      ), and one found no effect of alcohol on difference in [11C]raclopride binding potential (ΔBPND) (
      • Salonen I.
      • Hietala J.
      • Laihinen A.
      • Lehikonen P.
      • Leino L.
      • Nagren K.
      • et al.
      A PET study on the acute effect of ethanol on striatal D2 dopamine receptors with [11C]raclopride in healthy males.
      ).
      Here, we present a study designed to evaluate the capacity of oral alcohol to stimulate DA release in the human striatum with a larger sample of subjects providing greater statistical power and robustness to the sources of variance reported in prior studies. We hypothesized that sex is an important moderator of alcohol effects on DA release with greater effect to be expected in men.

      Methods and Materials

      Study Population

      The study was approved by the Institutional Review Board of the New York State Psychiatric Institute and informed consent was obtained from all subjects. Male and female social drinkers not meeting criteria for alcohol abuse or dependence, aged 21 to 27 years, were included. Subjects were required to have sufficient experience with alcohol to minimize adverse effects associated with the administration of alcohol, based on consumption of at least 10 to 15 standard drinks (standard drinking unit in United States = 14 g alcohol) per week. This was ascertained by self-reported drinking history and Alcohol Time Line Follow Back Interview (
      • Maisto S.A.
      • Sobell L.C.
      • Cooper A.M.
      • Sobell M.B.
      Comparison of two techniques to obtain retrospective reports of drinking behavior from alcohol abusers.
      ), used to estimate drinking patterns and the amount consumed over the past 30 days and past 12 months. In addition, all subjects completed questionnaires assessing their prior experiences with alcohol (
      • Maisto S.A.
      • Sobell L.C.
      • Cooper A.M.
      • Sobell M.B.
      Comparison of two techniques to obtain retrospective reports of drinking behavior from alcohol abusers.
      ). Smoking was not an exclusion criterion.

      Study Design

      Two [11C]raclopride positron emission tomography (PET) scans on two separate days following consumption of either a placebo or an alcohol drink were obtained in counterbalanced order (11 out of 21 received alcohol on the first day, randomly chosen). The placebo consisted of cranberry juice and soda alone, while the alcohol drink in addition contained the equivalent of three standard drinks of 100 proof vodka designed to deliver an average of .75 g alcohol per kilogram body water. The individual amount of alcohol was calculated based on the subject's amount of body water according to the equation: total body water (g/liter) = −2.097 + .1069 (height in cm) + .2466 (weight in kg) (
      • Watson P.E.
      • Watson I.D.
      • Batt R.D.
      Total body water volumes for adult males and females estimated from simple anthropometric measurements.
      ). For men, the volume of the drink amounted to 500 mL, while women received 350 mL. This difference intended to keep the alcohol concentration per drink similar between groups. Participants were blinded to the drink content. We disguised olfactory cues that might have indicated the nature of the drink before consumption by covering the rim of the drink containers with a paper napkin doused in vodka. The alcohol challenge was administered in a nonfasting condition. Subjects were asked to refrain from alcohol the night before, from smoking tobacco for the 2 hours before the PET scan, and from using any recreational drugs after the time of screening. Subjects underwent screening for substances of abuse including alcohol (AlcoMate Pro digital alcohol detector, KHN Solutions, San Francisco, California) on the first day of screening and on scan days. Oral consumption of alcohol or alcohol-free mixture had to be completed within 5 to 10 minutes.

      PET Data Acquisition

      Five minutes after the drink, [11C]raclopride was delivered as a bolus plus constant infusion (
      • Martinez D.
      • Slifstein M.
      • Broft A.
      • Mawlawi O.
      • Hwang D.R.
      • Huang Y.
      • et al.
      Imaging human mesolimbic dopamine transmission with positron emission tomography Part II: Amphetamine-induced dopamine release in the functional subdivisions of the striatum.
      ,
      • Mawlawi O.
      • Martinez D.
      • Slifstein M.
      • Broft A.
      • Chatterjee R.
      • Hwang D.R.
      • et al.
      Imaging human mesolimbic dopamine transmission with positron emission tomography I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum.
      ). Emission data were collected using an ECAT EXACT HR+ scanner (Siemens Medical Systems, Knoxville, Tennessee) starting 40 minutes into the constant infusion. Blood samples for plasma alcohol levels were drawn at 25, 40, 55, and 70 minutes after the drink (Figure S1 in Supplement 1). Subjective effects of alcohol were assessed with the Biphasic Alcohol Effects Scale for rating subjective activation (elation, feeling up, energy, excitement, stimulation, vigor, talkativeness) and sedation (difficulty concentrating, feeling down, heavy head, inactive, sedated, slowed thoughts, sluggishness) on scales from 1 to 10 (
      • Martin C.S.
      • Earleywine M.
      • Musty R.E.
      • Perrine M.W.
      • Swift R.M.
      Development and validation of the biphasic alcohol Effects Scale.
      ), given at baseline and every 30 minutes after drink administration for 90 minutes. Subjects underwent structural magnetic resonance imaging (MRI) (GE Signa 1.5 or 3 Tesla scanner, General Electric Healthcare, Waukesha, Wisconsin) on a separate day for co-registration and regions of interest (ROI) analysis.

      PET Data Analysis

      Image analysis was performed as described previously (
      • Mawlawi O.
      • Martinez D.
      • Slifstein M.
      • Broft A.
      • Chatterjee R.
      • Hwang D.R.
      • et al.
      Imaging human mesolimbic dopamine transmission with positron emission tomography I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum.
      ). Positron emission tomography data were co-registered to the structural MRI images using maximization of mutual information as implemented in the SPM2 software environment (Wellcome Trust Centre for Neuroimaging, London, United Kingdom) (
      • Ashburner J.
      Computational anatomy with the SPM software.
      ). Regions of interest were drawn on each individual's MRI and applied to the co-registered PET images. Regions of interest included precommissural caudate and putamen (preDCA, preDPU), postcommissural caudate and putamen (postCA, postPU), and ventral striatum (
      • Martinez D.
      • Slifstein M.
      • Broft A.
      • Mawlawi O.
      • Hwang D.R.
      • Huang Y.
      • et al.
      Imaging human mesolimbic dopamine transmission with positron emission tomography Part II: Amphetamine-induced dopamine release in the functional subdivisions of the striatum.
      ). Cerebellum was used as a reference region to measure free and nonspecifically bound [11C]raclopride activity, as the concentration of D2 receptors in the cerebellum is negligible (
      • Hall H.
      • Sedvall G.
      • Magnusson O.
      • Kopp J.
      • Halldin C.
      • Farde L.
      Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain.
      ). Equilibrium analysis was used to derive the specific to nondisplaceable equilibrium partition coefficient BPND (unitless) as (ROI activity/cerebellum activity − 1) during steady state (
      • Martinez D.
      • Gil R.
      • Slifstein M.
      • Hwang D.R.
      • Huang Y.
      • Perez A.
      • et al.
      Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum.
      ).
      The primary outcome measure for the study was the percentage change in BPND between conditions, calculated as:
      ΔBPND=[(BPNDalcohol/BPNDplacebo)1]×100%.


      This expresses the relative reduction in DA D2/3 receptor availability for [11C]raclopride binding after alcohol-induced DA release.

      Statistical Analysis

      Comparisons between drink conditions were performed with paired t tests; comparisons between groups were performed with two-group t tests at the ROI level. A linear mixed model across all striatal subregions with regional ΔBPND as the dependent variable and region of interest as repeated measure was performed to test for a global effect of sex on ΔBPND. Correlation analysis between PET measures and other variables (ΔBPND for all ROIs vs. measures of drinking history and subjective response to alcohol) were performed. Data were inspected for normality. Pearson product-moment coefficients were computed for normally distributed data and the Spearman rank correlation coefficient was applied to nonnormally distributed data. A two-tailed probability value of p < .05 was chosen as statistically significant. The false discovery rate method (
      • Benjamini Y.
      • Hochberg Y.
      Controlling the false discovery rate—a practical and powerful approach to multiple testing.
      ) was applied to the correlations between drinking history and VST DA release to correct for multiple comparisons.

      Results

      Subjects

      Twenty-one subjects, ages 24 ± 1.7 (mean ± SD) years, including 11 males and 10 females completed the study (Table 1).
      Table 1Demographics and Scan Parameters
      DemographicsMen (n = 11)Women (n = 10)t Test (p)
      Age (Years)24.4 ± 1.823.0 ± 1.5.07
      Smokers (<10 Cigarettes/Day)31
      Ethnicity (C, AA, H, As)6,2,2,17,0,1,2
      Family History of EtOH23
      PET Parameters (All, n = 21)Placebo DrinkAlcoholt Test (p)
      ID (mCi)7.99 ± 1.097.80 ± 1.53.65
      IM (μg)3.34 ± 1.932.99 ± 1.33.35
      SA (Ci/mmol)1787 ± 10901726 ± 1031.84
      VND (mL/cm3).43 ± .08.45 ± .1.32
      fp (unitless)4.2 ± 1.6%4.1 ± 0.7%.68
      Sample composition and scan parameters. Injected dose, injected mass, specific activity, distribution volume of the reference region, and plasma free faction are shown.
      AA, African American; As, Asian; C, Caucasian; EtOH, ethanol; fp, plasma free faction; H, Hispanic; ID, injected dose; IM, injected mass; PET, positron emission tomography; SA, specific activity; VND, distribution volume of the reference region.

      Drinking History

      Table 2 shows drinking history over the last 12 months before enrollment. Regular drinking (i.e., number of drinks per average drinking session), as well as binge drinking (defined as more than five drinks in 2 hours for men and more than four drinks for women [
      National Institute of Alcohol Abuse and Alcoholism
      Council Approves Definition of Binge Drinking.
      ]) were similar in both groups. The measure M, maximum number of drinks per 24 hours (
      • Begleiter H.
      • Hesselbrock V.
      • Porjesz B.
      • Li T.-K.
      • Schucki M.A.
      • Edenberg H.J.
      • Rice J.P.
      The collaborative study on the genetics of alcoholism.
      ), a quantitative trait expected to be related to alcohol tolerance (
      • Schuckit M.A.
      • Tipp J.E.
      • Reich T.
      • Hesselbrock V.M.
      • Bucholz K.K.
      The histories of withdrawal convulsions and delirium tremens in 1648 alcohol dependent subjects.
      ), showed slightly different patterns. Men had a higher magnitude of M during the past 12 months and when considering lifetime drinking history. Women, on the other hand, consumed M more frequently and with greater variability.
      Table 2Drinking History: Pattern of Drinking Behavior for Men and Women Over the Past 12 Months Before Enrollment
      Men (n = 11)Women (n = 10)Sex Difference p
      Age of Onset Regular Alcohol Consumption (Years)18.6 ± 1.618.6 ± 1.4.96
      Duration Regular Alcohol Consumption (Years)5.5 ± 2.74.2 ± 1.5.22
      Average Number of Drinking Days/Week (Past 12 Months)2.8 ± 1.03.8 ± 1.0.05
      Average Number Drinks/Week (Past 12 Months)14.9 ± 5.917.6 ± 14.4.57
      Average Number Drinks/Regular Drinking Occasion5.5 ± 2.14.5 ± 2.5.32
      Number of Drinking Binges (Past 12 Months)23.5 ± 28.812.5 ± 15.0.29
      Maximum Number Drinks/24 Hours (Last 12 Months): M14.4 ± 6.67.5 ± 2.3.01
      Number Days M Is Consumed (Past 12 months): Frequency of M5.2 ± 3.433.6 ± 42.04
      Lifetime Maximum Number Drinks/24 Hours17.6 ± 9.510.3 ± 3.2.03
      Drinking binge is defined as >5 drinks in 2 hours for men and >4 drinks in 2 hours for women. Sex differences for each parameter evaluated by t test, p values shown (significant differences in bold).

      Correlations of Drinking Behavior with ΔBPND

      Of nine measures of drinking behavior tested for correlation with VST DA release (Table 2), only frequency of M over the past 12 months showed a negative correlation in men, i.e., the less frequently men drank their maximal amount, the larger the ΔBPND. As the data for this parameter were not normally distributed, correlations were analyzed with the Spearman's rank order coefficient: rho = .72, p = .012; this did not survive false discovery rate multiple comparisons correction at the .05 alpha level but did survive at trend level (corrected p = .11). While there was no a priori reason to exclude any subject, it was nonetheless noted that three female subjects had a frequency of M that met formal criterion as outliers by leave-one-out analysis (frequency of M = 120, 96, and 48 days). When excluded, the correlation became significant for the overall group (n = 18, rho = .613, p = .007; at trend level only after multiple comparison correction: p = .06) but not for women (n = 7, rho = .312, p = .50). Because frequency of M was binned into several distinct levels, we also applied ordinal logistic regression with frequency of M as an ordinal dependent variable and ΔBPND in VST as continuous independent variable. This model reached significance for men and the entire cohort but not for women alone (Figure 1).
      Figure thumbnail gr1
      Figure 1Frequency of M vs. ΔBPND in VST. Left panel is in men only, n = 11, rho = .73, p = .012 (Spearman's rank order coefficient). Right panel includes all men and seven women, three outlier female subjects with very high frequency of M excluded, n = 18, rho = .613, p = .007. Ordinal logistic regression with frequency of M as an ordinal dependent variable and ΔBPND in VST as continuous independent variable reached significance for men alone (n = 11, χ2 = 8.28, p = .004) and for the entire cohort (n = 21, χ2 = 5.46, p = .019) but not for women alone. ΔBPND, difference in [11C]raclopride binding potential; M, maximum number of drinks per 24 hours; VST, ventral striatum.

      Blood Alcohol Levels

      Subjects were distinctly, but not heavily, intoxicated with blood alcohol levels slightly above the legal limit. Blood alcohol level peaked at 55 minutes after drink (1.15 ± .3 mg/mL in men and 1.02 ± .4 mg/mL in women, p = .37, Figure S1 in Supplement 1) and did not differ between groups at any time point (25, 40, 55, and 70 minutes). There was no correlation between blood alcohol level at any of the time points and ventrostriatal DA release. Table S1 in Supplement 1 shows mean alcohol content of the drink.

      Subjective Effects of Alcohol

      The group as a whole showed a significant increase in total scores (sum of scores for each item) of subjective activation and sedation, at all time points (alcohol vs. placebo condition, Table S2 in Supplement 1). Baseline scores for activation or sedation did not differ significantly between conditions; however, activation at baseline was higher on the first scan day, independent of the nature of the drink (35 ± 14 first day vs. 28 ± 12 second day, p < .01). For men, difference in activation scores between conditions was significant after 30 minutes and for women only after 60 minutes.
      Total scores for subjective sedation differed between conditions: peak total scores (at 60 minutes) were 27.8 ± 9.5 for alcohol and 19.2 ± 11.7 for placebo drink (p < .01) but were not different between groups.

      Correlations of Subjective Effects with VST DA Release

      The difference in activation total scores between conditions over 90 minutes was significantly correlated to VST DA release for the group as a whole at all time points. For men, there was significant correlation at 30 minutes and 60 minutes but not for women (Figure 2; Table S2 in Supplement 1). There was no significant correlation between subjective sedation and ΔBPND at any time.
      Figure thumbnail gr2
      Figure 2Striatal change in [11C]raclopride binding potential maps and subjective activation in response to alcohol. Binding potential maps averaged across men (n = 11, top) and women (n = 10, bottom) following placebo drink (left) and alcohol drink (right). The magnetic resonance imaging (MRI) images (center) are averaged across all 21 subjects. Images were all nonlinearly warped into Montreal Neurological Institute space in the SPM2 software environment (Wellcome Trust Centre for Neuroimaging, London, United Kingdom) (
      • Ashburner J.
      Computational anatomy with the SPM software.
      ). The regions of interest on the coronal MRI image (left) are the precommissural caudate and putamen and ventral striatum. The line through the sagittal MRI slice (right) shows the coronal slice level of the other images. The graphs on the right show the correlation between subjective activation at 30 minutes after drink (total score postalcohol minus total score postplacebo, not adjusted for baseline) and absolute difference in [11C]raclopride binding potential. The relationship is stronger for men (top). Note that the absolute value of difference in [11C]raclopride binding potential is presented here. ΔBPND, difference in [11C]raclopride binding potential.

      Imaging Results

      There were no differences in ROI volumes or scan parameters (Table 1 (all subjects)).

      Effect of Alcohol on DA Release

      The effect of alcohol on DA release in the group as a whole was significant for all striatal substructures with the greatest effect observed in the VST (ΔBPND = −9 ± 8%, p < .0001). The ΔBPND were −7 ± 8% in the preDPU, −5 ± 8% in the preDCA, −6 ± 8% in the postCA, −5 ± 6% in the postPU, −6 ± 7% for associative striatum, −6 ± 6% in the putamen, and −6 ± 7% for the striatum as a whole (p < .05 for all ROI). When separated by sex, men showed a significant effect of alcohol on ΔBPND in all ROIs (VST: −12 ± 8%, p < .001) and an overall greater magnitude of change than women (VST: −6 ± 8%, p = .02; statistically significant also in preDPU: 5 ± 7%, p < .05; Table 3).
      Table 3Binding Potential: [11C]Raclopride Binding for All Regions of Interest After Each Condition (Placebo Versus Alcohol) and Percent Change of [11C]Raclopride Displacement for Both Men and Women
      ROIMen (n = 11)Women (n = 10)Men Versus Women
      BPND (Placebo)BPND (Alcohol)% ΔBPND
      Changes were significant for all regions in men. VST: p < .001.
      BPND (Placebo)BPND (Alcohol)% ΔBPND
      Changes were only significant for VST and preDPU in women. VST: p = .02, preDPU: p = .04.
      p (t Test)
      Analysis with a linear mixed model across all striatal subregions showed a highly significant effect of sex (p < .001) with significantly greater ΔBPND in men.
      VST2.28 ± .232.00 ± 0.18−12.1% ± 8%2.23 ± .212.09 ± .19−6.2% ± 8%.10
      PreDCA2.51 ± .312.32 ± 0.29−7.3% ± 8%2.49 ± .242.43 ± .28−2.2% ± 6%.12
      PreDPU3.02 ± .332.75 ± 0.28−8.5% ± 8%2.99 ± .312.85 ± .38−4.7% ± 7%.26
      PostCA1.83 ± .251.68 ± 0.26−8.5% ± 7%2.09 ± .282.03 ± .25−2.4% ± 9%.08
      PostPU3.17 ± .232.93 ± 0.25−7.6% ± 6%3.35 ± .253.24 ± .20−3.0% ± 5%.08
      ΔBPND, difference in [11C]raclopride binding potential; BPND, [11C]raclopride binding potential; postCA, postcommissural caudate; postPU, postcommissural putamen; preDCA, precommissural caudate; preDPU, precommissural putamen; ROI, region of interest; VST, ventral striatum.
      a Changes were significant for all regions in men. VST: p < .001.
      b Changes were only significant for VST and preDPU in women. VST: p = .02, preDPU: p = .04.
      c Analysis with a linear mixed model across all striatal subregions showed a highly significant effect of sex (p < .001) with significantly greater ΔBPND in men.
      Two group t tests for effect of sex on ΔBPND did not reach statistical significance in individual ROIs (for VST, p = .10), but application of a linear mixed model across all striatal subregions with regional ΔBPND as the dependent variable and regions of interest as repeated measures showed a highly significant effect of sex (p < .001) with larger DA release in men. Because drink order was balanced for the group as a whole but not across sex (three women and seven men had alcohol on the first day), the model was repeated with drink order as a covariate. Effect of sex remained significant (p = .027). There was also a significant independent effect of scan order (p < .001), but there was no sex by order interaction (p = .35). Figure 2 illustrates the sex difference with binding potential maps averaged across subjects.
      The BPND for the placebo condition only was not significantly different between men and women for any ROI apart from the postCA (BPND men = 1.83 ± .25, BPND women = 2.09 ± .28, p = .04).
      There was no difference in ΔBPND between smokers (n = 4) and nonsmokers (n = 17) in any ROI. A two-way test with sex and smoking as covariates and ΔBPND as the dependent variable showed no effect of smoking status (p = .92).
      To further explore the effect of drinking history on DA release, we used general linear model analysis of ΔBPND in VST with frequency of M as a covariate and grouping by sex as fixed factor. Whether all subjects (n = 21) or only n = 18 were included (three female outliers with higher frequency of M removed), we found a significant sex by frequency interaction (p = .016, n = 21; p = .009, n = 18), as well as a significant effect of frequency of M (p = .02, n = 21; p = .002, n = 18); sex remained a significant factor in this model (p = .005; p = .007 after outliers removed).

      Discussion

      This report presents conclusive evidence in a large group of young adults for alcohol-induced DA release measured in vivo and shows, for the first time, sex differences in the magnitude of release. Although exposed to similar levels of alcohol, men had greater DA release than women. Furthermore, we show that alcohol stimulates DA release throughout the human striatum but most significantly in striatal regions implicated in reward and motivation. Whereas large effects were seen in both VST and postPU following amphetamine (
      • Martinez D.
      • Slifstein M.
      • Broft A.
      • Mawlawi O.
      • Hwang D.R.
      • Huang Y.
      • et al.
      Imaging human mesolimbic dopamine transmission with positron emission tomography Part II: Amphetamine-induced dopamine release in the functional subdivisions of the striatum.
      ,
      • Slifstein M.
      • Kegeles L.
      • Xu X.
      • Thompson J.
      • Urban N.
      • Castrillon J.
      • et al.
      Striatal and extrastriatal dopamine release measured with PET and [18F] fallypride.
      ,
      • Munro C.A.
      • McCaul M.E.
      • Wong D.F.
      • Oswald L.M.
      • Zhou Y.
      • Brasic J.
      • et al.
      Sex differences in striatal dopamine release in healthy adults.
      ) with smaller effects in other striatal subregions, only the VST displayed large ΔBPND after alcohol. We can estimate the level of fractional increase in ventrostriatal DA induced by our alcohol administration by using the simplifying assumptions that 1) the interaction between DA and [11C]raclopride at the D2/3 receptor is purely competitive, 2) DA dissociation constant for D2/3 receptors does not change between conditions, and 3) receptor-bound DA during the placebo condition is comparable with baseline values. Using the baseline occupancy of D2/3 receptors by DA in healthy volunteers estimated by Laruelle et al. (
      • Laruelle M.
      • D'Souza C.D.
      • Baldwin R.M.
      • Abi-Dargham A.
      • Kanes S.J.
      • Fingado C.L.
      • et al.
      Imaging D2 receptor occupancy by endogenous dopamine in humans.
      ) (10%) and in vivo estimates of the fraction of D2/3 receptors in a high-affinity state for agonists (80%) (
      • Narendran R.
      • Hwang D.-R.
      • Slifstein M.
      • Talbot P.
      • Erritzoe D.
      • Huang Y.
      • Cooper T.
      • et al.
      Measurement of in vivo affinity of [11C]NPA and the proportion of D2 receptors configured in agonist high affinity state (%Rhigh) in baboons using PET.
      ), we estimate that the alcohol challenge increased extracellular DA levels by 138% in men and 69% in women. The magnitude of the effect of alcohol is comparable with that measured with a low dose of amphetamine in young subjects (
      • Anand A.
      • Verhoeff P.
      • Seneca N.
      • Zoghbi S.S.
      • Seibyl J.P.
      • Charney D.S.
      • Innis R.B.
      Brain SPECT imaging of amphetamine-induced dopamine release in euthymic bipolar disorder patients.
      ,
      • Abi-Dargham A.
      • Kegeles L.S.
      • Martinez D.
      • Innis R.B.
      • Laruelle M.
      Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naive healthy volunteers: Results from a large cohort.
      ) and similar to that reported for challenge with nicotine or smoking (
      • Brody A.L.
      • Mandelkern M.A.
      • Olmstead R.E.
      • Allen-Martinez Z.
      • Scheibal D.
      • Abrams A.L.
      • et al.
      Ventral striatal dopamine release in response to smoking a regular vs a denicotinized cigarette.
      ). Similar sex differences have been previously reported after an amphetamine challenge (
      • Munro C.A.
      • McCaul M.E.
      • Wong D.F.
      • Oswald L.M.
      • Zhou Y.
      • Brasic J.
      • et al.
      Sex differences in striatal dopamine release in healthy adults.
      ) showing greater change in [11C]raclopride binding in men in several striatal subregions (VST: 12 ± 6% in men, 7 ± 5% in women, p = .01) but no difference in baseline D2 binding.
      The effect of sex was apparent across the whole striatum, suggesting that alcohol affects a broader dopaminergic pathway than the classic ventral tegmental area-VST circuit.
      While amphetamine works by a mechanism of facilitated exchange diffusion at the DA transporter (
      • Sulzer D.
      • Rayport S.
      Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: A mechanism of action.
      ,
      • van Rossum J.M.
      • van der Schoot J.
      • Hurkmans J.A.
      Mechanism of action of cocaine and amphetamine in the brain.
      ), it is not clear how alcohol stimulates dopamine release, and it may have direct and indirect effects. Ethanol has been reported to remove gamma-aminobutyric acidergic inhibition of DA neurons (
      • Mereu G.
      • Gessa G.
      Low doses of ethanol inhibit the firing of neurons in the substantia nigra, pars reticulata, a GABAergic effect?.
      ) and to directly excite DA ventral tegmental area neurons and reduce the afterhyperpolarization that follows spontaneous action potentials by reducing a quinidine-sensitive K+ current (
      • Appel S.B.
      • Liu Z.
      • McElvain M.A.
      • Brodie M.S.
      Ethanol excitation of dopaminergic ventral tegmental area neurons is blocked by quinidine.
      ). Additionally, alcohol promotes DA release by a local calcium-dependent effect at the DA terminals in the striatum and accumbens (
      • Russell V.A.
      • Lamm M.C.
      • Taljaard J.J.
      Effect of ethanol on [3H]dopamine release in rat nucleus accumbens and striatal slices.
      ,
      • Snape B.M.
      • Engel J.A.
      Ethanol enhances the calcium-dependent stimulus-induced release of endogenous dopamine from slices of rat striatum and nucleus accumbens in vitro.
      ,
      • Wozniak K.M.
      • Pert A.
      • Mele A.
      • Linnoila M.
      Focal application of alcohols elevates extracellular dopamine in rat brain: A microdialysis study.
      ), possibly mediated by an effect on DA transporters (
      • Eshleman A.J.
      • Henningsen R.A.
      • Neve K.A.
      • Janowsky A.
      Release of dopamine via the human transporter.
      ). In animals, ethanol administered at doses typically associated with human drinking enhances DA release in the accumbens via actions at other brain sites (
      • Yim H.J.
      • Schallert T.
      • Randall P.K.
      • Gonzales R.A.
      Comparison of local and systemic ethanol effects on extracellular dopamine concentration in rat nucleus accumbens by microdialysis.
      ,
      • Yim H.J.
      • Schallert T.
      • Randall P.K.
      • Bungay P.M.
      • Gonzales R.A.
      Effect of ethanol on extracellular dopamine in rat striatum by direct perfusion with microdialysis.
      ). In rats habituated to alcohol exposure, this may be limited to the early phase after the onset of drinking, suggesting a blunted striatal DA release as an effect of habituation as seen in chronically alcohol dependent humans (
      • Martinez D.
      • Gil R.
      • Slifstein M.
      • Hwang D.R.
      • Huang Y.
      • Perez A.
      • et al.
      Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum.
      ,
      • Volkow N.D.
      • Wang G.J.
      • Telang F.
      • Fowler J.S.
      • Logan J.
      • Jayne M.
      • et al.
      Profound decreases in dopamine release in striatum in detoxified alcoholics: Possible orbitofrontal involvement.
      ) but also that DA may not be the central substrate producing the reinforcement in habituated rats (
      • Nurmi M.
      • Sinclair J.D.
      • Kiianmaa K.
      Dopamine release during ethanol drinking in AA rats.
      ). While passively administered intravenous ethanol can stimulate DA release, ethanol-related cues evoke an additional component of DA release (
      • Doyon W.M.
      • Anders S.K.
      • Ramachandra V.S.
      • Czachowski C.L.
      • Gonzales R.A.
      Effect of operant self-administration of 10% ethanol plus 10% sucrose on dopamine and ethanol concentrations in the nucleus accumbens.
      ,
      • Howard E.C.
      • Schier C.J.
      • Wetzel J.S.
      • Duvauchelle C.L.
      • Gonzales R.A.
      The shell of the nucleus accumbens has a higher dopamine response compared with the core after non-contingent intravenous ethanol administration.
      ). Repeated alcohol intake may induce salience attribution to alcohol-associated cues.
      In this study, we did not test for the effect of cues but endeavored to minimize olfactory cues. Comparison of the placebo condition BPND in our study with baseline [11C]raclopride BPND values from a cohort of age- and sex-matched healthy control subjects (n = 20, mean age 24.8 ± 3 years, 11 men, 9 women, unpublished observations) shows no statistically significant differences in binding potential in any region: BPND in the baseline cohort was 2.21 ± .3 in the VST (vs. 2.26 ± .2 after placebo drink in this study, p = .57) and 2.8 ± .3 for the striatum as a whole (vs. 2.7 ± .2 after placebo, p = .31). This suggests that the placebo drink in our hands was associated with negligible or no change in DA release and provided a neutral stimulus rather than an appetitive cue. This interpretation is limited by the fact that we are comparing different cohorts. A better paradigm would include an additional baseline scan to test the effects of all sensory cues.
      The alcoholic drink supplied both the sensory properties of alcohol (taste and smell), as well as the pharmacological effects once absorbed, which may both contribute to dopamine release and are not easily separated in this study design.
      The fact that women received drinks with slightly lower concentrations of alcohol may support the contribution of sensory stimuli to the difference in VST DA release; however, as sensory organs generally respond logarithmically to increase in stimuli intensity, rather than linearly (
      • Young P.T.
      The role of affective processes in learning and motivation.
      ), it is unlikely that the absolute difference in concentrations of 10% (49% in women and 59% in men) was detectable. We consider it unlikely that sensory properties of alcohol alone are able to explain the large effect on ΔBPND and the significant sex differences in the striatum as a whole. The effects sizes for alcohol (1.125 total group, 1.5 for men, .75 for women) and sex (= .75) here are comparable with those in the Boileau et al. (
      • Boileau I.
      • Assaad J.M.
      • Pihl R.O.
      • Benkelfat C.
      • Leyton M.
      • Diksic M.
      • et al.
      Alcohol promotes dopamine release in the human nucleus accumbens.
      ) study: alcohol effect size of 1.03 in an all male sample.
      As a further caveat, we did not control for estrogen levels among subjects and its possible effect on the magnitude of DA release in women. However, so far, only behavioral and biochemical studies in animals indicate central dopaminergic neurotransmission may be modulated by sex steroids, while human studies have not confirmed these findings (
      • Kaasinen V.
      • Kemppainen N.
      • Nagren K.
      • Helenius H.
      • Kurki T.
      • Rinne J.O.
      Age-related loss of extrastriatal dopamine d(2) -like receptors in women.
      ,
      • Nordstrom A.L.
      • Olsson H.
      • Halldin C.
      A PET study of D2 dopamine receptor density at different phases of the menstrual cycle.
      ).

      Correlations with Clinical Measures

      We observed correlations in men between magnitude of release and subjective activation, as well as with maximal number of drinks per 24 hours. These observations should be regarded as preliminary, but they allow us to speculate on the functional significance of the observed DA release.
      Alcohol induced greater subjective activation than placebo and the difference in activation scores across days between conditions correlated with greater DA release in the VST (p < .05). Greater activation between alcohol and placebo was no longer observed when the ratings were corrected for baseline for each day, due to an order effect where subjective activation at baseline on the first day was higher than second day regardless of the nature of the drink. This effect is possibly related to the novelty of the situation on the first day. This is an unexpected effect of the 2-day paradigm and presents a limitation in our study. To bypass this order effect, we compared ratings of subjective activation at specific time points across days, and we observed that men showed greater activation in the early phase after alcohol consumption (Figure 2), which correlated with ΔBPND in VST only in men. It is tempting to speculate, based on this observation, that the larger effect on DA transmission may contribute to the initial reinforcing properties of alcohol and may be related to the higher incidence of alcoholism in men.
      We also observed an effect of scan order on ΔBPND: alcohol administered in the first PET session evoked greater DA release. However, sex was an independent factor: men still had greater alcohol-evoked DA release than did women after controlling for the order effect; there was no sex by order interaction.
      Finally, we observed that larger DA release was associated with smaller frequency of maximum number of drinks per 24 hours (M), a strong relationship that survived correction for multiple comparisons. This observation is interesting, as it could suggest that habitual drinking of large numbers of alcoholic drinks at individual occasions, as measured by M, a parameter proposed to indicate greater potential for addiction (
      • Begleiter H.
      • Hesselbrock V.
      • Porjesz B.
      • Li T.-K.
      • Schucki M.A.
      • Edenberg H.J.
      • Rice J.P.
      The collaborative study on the genetics of alcoholism.
      ) and withdrawal symptoms (
      • Schuckit M.A.
      • Tipp J.E.
      • Reich T.
      • Hesselbrock V.M.
      • Bucholz K.K.
      The histories of withdrawal convulsions and delirium tremens in 1648 alcohol dependent subjects.
      ), is associated with smaller release. In other terms, the beginning of a transition to habit, detected here by frequent drinking, may be associated with a decrease in the magnitude of DA release in men. In women, this relationship was not significant, possibly due to lack of power in the presence of large variance. When outliers among women were removed, the same relationship of lower DA release with higher frequency was true for the group as a whole but not for women. Our interpretation of lowered DA release as a correlate of transition to habit is consistent with preclinical animal models of addiction (
      • Murphy J.M.
      • McBride W.J.
      • Gatto G.J.
      • Lumeng L.
      • Li T.K.
      Effects of acute ethanol administration on monoamine and metabolite content in forebrain regions of ethanol-tolerant and -nontolerant alcohol-preferring (P) rats.
      ).
      In summary, the current findings indicate that alcohol stimulates DA release in humans, and this effect is greater in men than in women. We also observe that DA release is associated with subjective activation in men and inversely related to the frequency of heavy drinking. Together, these findings suggest that the ability of alcohol to stimulate DA release may play an important and complex role in its rewarding effects and abuse liability in humans. Our report further suggests a biological mechanism that may mediate the difference in vulnerability for alcoholism between men and women.
      This research was carried out at New York State Psychiatric Institute/Columbia University Medical Center under a subcontract from the Center for Translational Neuroscience of Alcoholism at Yale University, supported by Grant number P50AA-012870-09 from the National Institute on Alcohol Abuse and Alcoholism .
      The funding agency had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
      Financial Disclosures: L.S. Kegeles: Amgen , Pfizer (research grants); M. Slifstein: Amgen , GlaxoSmithKline (consultant); S.S. O'Malley: member American College of Neuropsychopharmacology work group sponsored by Eli Lilly , Janssen , Schering Plough , Lundbeck , GlaxoSmithKline , and Alkermes ; partner Applied Behavioral Research; Scientific Panel Butler Center for Research at Hazelden; Brown University and Medical College of South Carolina (consultant); Nabi pharmaceuticals (research contract); Controlled Release Society, Association for Medical Education and Research in Substance Abuse (travel reimbursement/award); J.H. Krystal reports the following: Consultant: Aisling Capital, LLC, AstraZeneca, Brintnall & Nicolini, Inc., GlaxoSmithKline, Janssen, Merz, Pfizer, F. Hoffman-La Roche, Ltd., SK Holdings Co., Ltd., Teva Pharmaceuticals, Ltd.; Scientific Advisory Board/Consultant: Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly and Co., Lohocla Research Corporation, Takeda Industries, Transcept; Exercisable Warrant Options (value less than $500): Tetragenex Pharmaceuticals; Research/Study Drug Support: Janssen Research Foundation (to the Department of Veterans Affairs); Board of Directors: American College of Neuropsychopharmacology; Editor: Biological Psychiatry; Inventions: 1) Seibyl JP, Krystal JH, Charney DS. Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. Patent #:5,447,948. September 5, 1995; 2) Co-inventor with Dr. Gerard Sanacora on a filed patent application by Yale University related to targeting the glutamatergic system for the treatment of neuropsychiatric disorders (PCTWO06108055A1); and 3) Intranasal Administration of Ketamine to Treat Depression (pending). A. Abi-Dargham: BristolNina Myers Squibb-Otsuka (consultant and speaker), Bohringer-Engelheim (consultant), GlaxoSmithKline (research grant). All other authors reported no biomedical financial interests or potential conflicts of interest.

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      Linked Article

      • Opioid–Dopamine Interactions: Implications for Substance Use Disorders and Their Treatment
        Biological PsychiatryVol. 68Issue 8
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          Two imaging reports in this volume highlight the importance of the interaction between the brain's opioid and dopamine (DA) systems in the reinforcing and addictive effects of substances of abuse. These studies use positron emission tomography (PET) to measure, in one instance (1), changes in DA induced by acute alcohol administration in healthy subjects (with [11C] raclopride, a radioligand that binds to D2 and D3 receptors (D2R and D3R) and that is sensitive to competition with endogenous DA) and, in the other (2), μ opioid receptor (mOR) availability in cocaine abusers (with [11C] carfentanil, an mOR specific radioligand).
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