Striatal Dopamine D2/D3 Receptor Availability Is Reduced in Methamphetamine Dependence and Is Linked to Impulsivity

While methamphetamine addiction has been associated with both impulsivity and striatal dopamine D2/D3 receptor deficits, human studies have not directly linked the latter two entities. We therefore compared methamphetamine-dependent and healthy control subjects using the Barratt Impulsiveness Scale (version 11, BIS-11) and positron emission tomography with [18F]fallypride to measure striatal dopamine D2/D3 receptor availability. The methamphetamine-dependent subjects reported recent use of the drug 3.3 g per week, and a history of using methamphetamine, on average, for 12.5 years. They had higher scores than healthy control subjects on all BIS-11 impulsiveness subscales (p < 0.001). Volume-of-interest analysis found lower striatal D2/D3 receptor availability in methamphetamine-dependent than in healthy control subjects (p < 0.01) and a negative relationship between impulsiveness and striatal D2/D3 receptor availability in the caudate nucleus and nucleus accumbens that reached statistical significance in methamphetamine-dependent subjects. Combining data from both groups, voxelwise analysis indicated that impulsiveness was related to D2/D3 receptor availability in left caudate nucleus and right lateral putamen/claustrum (p < 0.05, determined by threshold-free cluster enhancement). In separate group analyses, correlations involving the head and body of the caudate and the putamen of methamphetamine-dependent subjects and the lateral putamen/claustrum of control subjects were observed at a weaker threshold (p < 0.12 corrected). The findings suggest that low striatal D2/D3 receptor availability may mediate impulsive temperament and thereby influence addiction.

[1]  M. Layton.  Methamphetamine Addiction: From Basic Science to Treatment , 2011 .

[2]  S. Faraone,et al.  Molecular genetics of attention deficit hyperactivity disorder. , 2010, The Psychiatric clinics of North America.

[3]  J. McGeary,et al.  Associations of the DRD2 TaqIA polymorphism with impulsivity and substance use: Preliminary results from a clinical sample of adolescents , 2009, Pharmacology Biochemistry and Behavior.

[4]  Sang-Woo Lee,et al.  Dose-dependent frontal hypometabolism on FDG-PET in methamphetamine abusers. , 2009, Journal of psychiatric research.

[5]  Stephen M. Smith,et al.  Threshold-free cluster enhancement: Addressing problems of smoothing, threshold dependence and localisation in cluster inference , 2009, NeuroImage.

[6]  Robert M. Kessler,et al.  Midbrain Dopamine Receptor Availability Is Inversely Associated with Novelty-Seeking Traits in Humans , 2008, The Journal of Neuroscience.

[7]  C. P. Morris,et al.  Behavioral and Brain Functions , 2008 .

[8]  Yu-Shin Ding,et al.  Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: Possible contributing factors , 2008, NeuroImage.

[9]  T. Robbins,et al.  Neurobehavioral mechanisms of impulsivity: Fronto-striatal systems and functional neurochemistry , 2008, Pharmacology Biochemistry and Behavior.

[10]  Trevor W. Robbins,et al.  High Impulsivity Predicts the Switch to Compulsive Cocaine-Taking , 2008, Science.

[11]  J. Cadet,et al.  Methamphetamine Causes Microglial Activation in the Brains of Human Abusers , 2008, The Journal of Neuroscience.

[12]  A. Arnsten,et al.  Neuronal Mechanisms Underlying Attention Deficit Hyperactivity Disorder , 2008, Annals of the New York Academy of Sciences.

[13]  James Robert Brašić,et al.  Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users , 2008, Synapse.

[14]  R. Carson,et al.  Noninvasive Estimation of Normalized Distribution Volume: Application to the Muscarinic-2 Ligand [18F]FP-TZTP , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[15]  T. Robbins,et al.  Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans , 2008, Psychopharmacology.

[16]  G. Logan,et al.  Converging Evidence for a Fronto-Basal-Ganglia Network for Inhibitory Control of Action and Cognition , 2007, The Journal of Neuroscience.

[17]  R. P. Maguire,et al.  Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[18]  Young T. Hong,et al.  Nucleus Accumbens D2/3 Receptors Predict Trait Impulsivity and Cocaine Reinforcement , 2007, Science.

[19]  J. Jentsch,et al.  Dopamine D2/D3 Receptors Play a Specific Role in the Reversal of a Learned Visual Discrimination in Monkeys , 2007, Neuropsychopharmacology.

[20]  L. Vanderschuren,et al.  Involvement of dopamine D1 and D2 receptors in the nucleus accumbens core and shell in inhibitory response control , 2007, Psychopharmacology.

[21]  J. MacKillop,et al.  Examining impulsivity as an endophenotype using a behavioral approach: a DRD2 TaqI A and DRD4 48-bp VNTR association study , 2007, Behavioral and Brain Functions.

[22]  T. Robbins,et al.  Reflection Impulsivity in Current and Former Substance Users , 2006, Biological Psychiatry.

[23]  L. Vanderschuren,et al.  Critical Involvement of Dopaminergic Neurotransmission in Impulsive Decision Making , 2006, Biological Psychiatry.

[24]  M. Iyo,et al.  Brain serotonin transporter density and aggression in abstinent methamphetamine abusers. , 2006, Archives of general psychiatry.

[25]  Eliza Congdon,et al.  The endophenotype of impulsivity: reaching consilience through behavioral, genetic, and neuroimaging approaches. , 2005, Behavioral and cognitive neuroscience reviews.

[26]  J. Feldon,et al.  Double dissociation of the effects of selective nucleus accumbens core and shell lesions on impulsive‐choice behaviour and salience learning in rats , 2005, The European journal of neuroscience.

[27]  J. Monterosso,et al.  Deficits in response inhibition associated with chronic methamphetamine abuse. , 2005, Drug and alcohol dependence.

[28]  J. Smoller,et al.  Molecular Genetics of Attention-Deficit/Hyperactivity Disorder , 2005, Biological Psychiatry.

[29]  Linda Chang,et al.  Enlarged striatum in abstinent methamphetamine abusers: A possible compensatory response , 2005, Biological Psychiatry.

[30]  M. Buonocore,et al.  Methamphetamine users in sustained abstinence: a proton magnetic resonance spectroscopy study. , 2005, Archives of general psychiatry.

[31]  T. Robbins,et al.  Inhibition and the right inferior frontal cortex , 2004, Trends in Cognitive Sciences.

[32]  Adam R Aron,et al.  Methylphenidate improves response inhibition in adults with attention-deficit/hyperactivity disorder , 2003, Biological Psychiatry.

[33]  T. Robbins,et al.  Inhibitory control in rats performing a stop-signal reaction-time task: effects of lesions of the medial striatum and d-amphetamine. , 2003, Behavioral neuroscience.

[34]  F Limosin,et al.  Impulsiveness as the intermediate link between the dopamine receptor D2 gene and alcohol dependence , 2003, Psychiatric genetics.

[35]  M. Rieger,et al.  Inhibition of ongoing responses following frontal, nonfrontal, and basal ganglia lesions. , 2003, Neuropsychology.

[36]  Richard E Carson,et al.  Noise Reduction in the Simplified Reference Tissue Model for Neuroreceptor Functional Imaging , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[37]  B. Christian,et al.  Brain imaging of 18F‐fallypride in normal volunteers: Blood analysis, distribution, test‐retest studies, and preliminary assessment of sensitivity to aging effects on dopamine D‐2/D‐3 receptors , 2002, Synapse.

[38]  F. Crawford,et al.  DRD4 and novelty seeking: results of meta-analyses. , 2002, American journal of medical genetics.

[39]  A. Pfefferbaum,et al.  Preliminary evidence of reduced cognitive inhibition in methamphetamine-dependent individuals , 2002, Psychiatry Research.

[40]  Linda Chang,et al.  Perfusion MRI and computerized cognitive test abnormalities in abstinent methamphetamine users , 2002, Psychiatry Research: Neuroimaging.

[41]  M. Solanto.  Dopamine dysfunction in AD/HD: integrating clinical and basic neuroscience research , 2002, Behavioural Brain Research.

[42]  Thomas E. Nichols,et al.  Nonparametric permutation tests for functional neuroimaging: A primer with examples , 2002, Human brain mapping.

[43]  J S Fowler,et al.  Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. , 2001, The American journal of psychiatry.

[44]  S. Faraone,et al.  Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder. , 2001, The American journal of psychiatry.

[45]  T. Robbins,et al.  Impulsive Choice Induced in Rats by Lesions of the Nucleus Accumbens Core , 2001, Science.

[46]  Yoshiro Okubo,et al.  Dopamine D2 Receptors in the Insular Cortex and the Personality Trait of Novelty Seeking , 2001, NeuroImage.

[47]  W. Ling,et al.  Cognitive impairment in individuals currently using methamphetamine. , 2000, The American journal on addictions.

[48]  T. R. Wade,et al.  Effects of dopaminergic drugs on delayed reward as a measure of impulsive behavior in rats , 2000, Psychopharmacology.

[49]  Linda Chang,et al.  Evidence for long-term neurotoxicity associated with methamphetamine abuse , 2000, Neurology.

[50]  JaneR . Taylor,et al.  Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli , 1999, Psychopharmacology.

[51]  N. Volkow,et al.  Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[52]  J. Patton,et al.  Factor structure of the Barratt impulsiveness scale. , 1995, Journal of clinical psychology.

[53]  M. K. Das,et al.  Fluorinated benzamide neuroleptics--III. Development of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2, 3-dimethoxybenzamide as an improved dopamine D-2 receptor tracer. , 1995, Nuclear medicine and biology.

[54]  C. R. Cloninger,et al.  A psychobiological model of temperament and character. , 1993, Archives of general psychiatry.

[55]  N. Volkow,et al.  Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers , 1993, Synapse.

[56]  Gordon D. Logan,et al.  Effects of methylphenidate on inhibitory control in hyperactive children , 1989, Journal of abnormal child psychology.

[57]  M. Mintun,et al.  A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography , 1984, Annals of neurology.

[58]  R. Ridley,et al.  An analysis of visual object reversal learning in the marmoset after amphetamine and haloperidol , 1981, Pharmacology Biochemistry and Behavior.