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 (ΔBP(ND)) 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 ΔBP(ND) 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 ΔBP(ND) (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.

[1]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[2]  Mark Slifstein,et al.  Striatal and extrastriatal dopamine release measured with PET and [18F] fallypride , 2010, Synapse.

[3]  J. Engel,et al.  Ethanol enhances the calcium-dependent stimulus-induced release of endogenous dopamine from slices of rat striatum and nucleus accumbens in vitro , 1988, Neuropharmacology.

[4]  Karmen K. Yoder,et al.  Heterogeneous effects of alcohol on dopamine release in the striatum: a PET study. , 2007, Alcoholism, clinical and experimental research.

[5]  Elizabeth L. Ogburn,et al.  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. , 2007, Archives of general psychiatry.

[6]  D. Clark.  The natural history of adolescent alcohol use disorders. , 2004, Addiction.

[7]  J. Krystal,et al.  ETHANOL ABUSE , DEPENDENCE , AND WITHDRAWAL : NEUROBIOLOGY AND CLINICAL IMPLICATIONS , 2002 .

[8]  M. Brodie,et al.  Ethanol Excitation of Dopaminergic Ventral Tegmental Area Neurons Is Blocked by Quinidine , 2003, Journal of Pharmacology and Experimental Therapeutics.

[9]  Marc A Schuckit,et al.  Alcohol-use disorders , 2009, The Lancet.

[10]  V. Russell,et al.  Effect of ethanol on [3H]Dopamine release in rat nucleus accumbens and striatal slices , 1988, Neurochemical Research.

[11]  Osama Mawlawi,et al.  Imaging Human Mesolimbic Dopamine Transmission with Positron Emission Tomography: I. Accuracy and Precision of D2 Receptor Parameter Measurements in Ventral Striatum , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[12]  B. Grant,et al.  Influence of a drinking quantity and frequency measure on the prevalence and demographic correlates of DSM-IV alcohol dependence. , 2009, Alcoholism, clinical and experimental research.

[13]  E. C. Howard,et al.  The shell of the nucleus accumbens has a higher dopamine response compared with the core after non-contingent intravenous ethanol administration , 2008, Neuroscience.

[14]  S. Haber,et al.  Imaging Human Mesolimbic Dopamine Transmission with Positron Emission Tomography. Part II: Amphetamine-Induced Dopamine Release in the Functional Subdivisions of the Striatum , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[15]  T. Schallert,et al.  Comparison of local and systemic ethanol effects on extracellular dopamine concentration in rat nucleus accumbens by microdialysis. , 1998, Alcoholism, clinical and experimental research.

[16]  L. Degenhardt,et al.  Substance use, dependence and treatment seeking in the United States and Australia: a cross-national comparison. , 2006, Drug and alcohol dependence.

[17]  Nora D. Volkow,et al.  Profound Decreases in Dopamine Release in Striatum in Detoxified Alcoholics: Possible Orbitofrontal Involvement , 2007, The Journal of Neuroscience.

[18]  Ting-kai Li,et al.  Regional brain levels of monoamines in alcohol-preferring and -nonpreferring lines of rats , 1982, Pharmacology Biochemistry and Behavior.

[19]  W. Mcbride,et al.  Effects of acute ethanol administration on monoamine and metabolite content in forebrain regions of ethanol-tolerant and -nontolerant alcohol-preferring (P) rats , 1988, Pharmacology Biochemistry and Behavior.

[20]  T. Schallert,et al.  Effect of Ethanol on Extracellular Dopamine in Rat Striatum by Direct Perfusion with Microdialysis , 1997, Journal of neurochemistry.

[21]  Dean F. Wong,et al.  Sex Differences in Striatal Dopamine Release in Healthy Adults , 2006, Biological Psychiatry.

[22]  G. Gessa,et al.  Low doses of ethanol inhibit the firing of neurons in the substantia nigra, pars reticulata: a GABAergic effect? , 1985, Brain Research.

[23]  Christer Halldin,et al.  Distribution of D1- and D2-Dopamine Receptors, and Dopamine and Its Metabolites in the Human Brain , 1994, Neuropsychopharmacology.

[24]  K. Bucholz,et al.  The histories of withdrawal convulsions and delirium tremens in 1648 alcohol dependent subjects. , 1995, Addiction.

[25]  M. Earleywine,et al.  Development and validation of the Biphasic Alcohol Effects Scale. , 1993, Alcoholism, clinical and experimental research.

[26]  H. Fibiger.  Drugs and reinforcement mechanisms: a critical review of the catecholamine theory. , 1978, Annual review of pharmacology and toxicology.

[27]  C. Hodge,et al.  Alcohol Self‐Administration: Role of Mesolimbic Dopamine a , 1992, Annals of the New York Academy of Sciences.

[28]  M. Linnoila,et al.  Focal application of alcohols elevates extracellular dopamine in rat brain: a microdialysis study , 1991, Brain Research.

[29]  J. Sinclair,et al.  Dopamine release during ethanol drinking in AA rats. , 1998, Alcoholism, clinical and experimental research.

[30]  Ting-kai Li,et al.  Densities of dopamine D2 receptors are reduced in CNS regions of alcohol-preferring P rats. , 1993, Alcohol.

[31]  Karmen K. Yoder,et al.  When what you see isn't what you get: alcohol cues, alcohol administration, prediction error, and human striatal dopamine. , 2009, Alcoholism, clinical and experimental research.

[32]  R. Wise,et al.  Brain dopamine and reward. , 1989, Annual review of psychology.

[33]  R. Gonzales,et al.  Effect of operant self‐administration of 10% ethanol plus 10% sucrose on dopamine and ethanol concentrations in the nucleus accumbens , 2005, Journal of neurochemistry.

[34]  F. Weiss,et al.  Neurochemical characteristics associated with ethanol preference in selected alcohol-preferring and -nonpreferring rats: a quantitative microdialysis study. , 2001, Alcoholism, clinical and experimental research.

[35]  P. Young.  The role of affective processes in learning and motivation. , 1959, Psychological review.

[36]  J. Seibyl,et al.  Brain SPECT imaging of amphetamine-induced dopamine release in euthymic bipolar disorder patients. , 2000, The American journal of psychiatry.

[37]  L. Bierut,et al.  Relationship of age of first drink to child behavioral problems and family psychopathology. , 2005, Alcoholism, clinical and experimental research.

[38]  R. Gonzales,et al.  Ethanol preference is inversely correlated with ethanol-induced dopamine release in 2 substrains of C57BL/6 mice. , 2007, Alcoholism, clinical and experimental research.

[39]  S. Saxena.  Alcohol, Europe and the developing countries. , 1997, Addiction.

[40]  P. Watson,et al.  Total body water volumes for adult males and females estimated from simple anthropometric measurements. , 1980, The American journal of clinical nutrition.

[41]  Kjell Någren,et al.  Age‐related loss of extrastriatal dopamine D2‐like receptors in women , 2002, Journal of neurochemistry.

[42]  D. Sulzer,et al.  Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: A mechanism of action , 1990, Neuron.

[43]  G. Di Chiara,et al.  Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S A Maisto,et al.  Comparison of two techniques to obtain retrospective reports of drinking behavior from alcohol abusers. , 1982, Addictive behaviors.

[45]  J. Hurkmans,et al.  Mechanism of action of cocaine and amphetamine in the brain , 1962, Experientia.

[46]  Y. Israel,et al.  Ethanol induces stronger dopamine release in nucleus accumbens (shell) of alcohol-preferring (bibulous) than in alcohol-avoiding (abstainer) rats. , 2008, European journal of pharmacology.

[47]  K. Neve,et al.  Release of dopamine via the human transporter. , 1994, Molecular pharmacology.

[48]  L. Bierut,et al.  Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism. , 1998, Archives of general psychiatry.

[49]  Robert B. Innis,et al.  Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naı̈ve healthy volunteers: results from a large cohort , 2003, European Neuropsychopharmacology.

[50]  A. Dagher,et al.  Alcohol promotes dopamine release in the human nucleus accumbens , 2003, Synapse.

[51]  John Ashburner,et al.  Computational anatomy with the SPM software. , 2009, Magnetic resonance imaging.

[52]  Marc Laruelle,et al.  Imaging D2 Receptor Occupancy by Endogenous Dopamine in Humans , 1997, Neuropsychopharmacology.

[53]  J. Monterosso,et al.  Ventral Striatal Dopamine Release in Response to Smoking a Regular vs a Denicotinized Cigarette , 2009, Neuropsychopharmacology.

[54]  Ulla Ruotsalainen,et al.  A PET Study on the Acute Effect of Ethanol on Striatal D2 Dopamine Receptors with [11C]Raclopride in Healthy Males , 1997 .

[55]  M. Le Moal,et al.  Mesocorticolimbic dopaminergic network: functional and regulatory roles. , 1991, Physiological reviews.

[56]  Mark Slifstein,et al.  Alcohol Dependence Is Associated with Blunted Dopamine Transmission in the Ventral Striatum , 2005, Biological Psychiatry.

[57]  C. Halldin,et al.  A PET study of D2 dopamine receptor density at different phases of the menstrual cycle , 1998, Psychiatry Research: Neuroimaging.