title: Dysregulation of D₂-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure.
abstract: Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D₂ receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D₂-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D₂-like receptor and DAT availability and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D₂-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D₂-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence.
authors.affiliation: Department of Psychology, Psychiatry and Biobehavioral Sciences, and Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Groman
authors.forename: Buyean
authors.initials: B
authors.lastname: Lee
authors.forename: Emanuele
authors.initials: E
authors.lastname: Seu
authors.forename: Alex S
authors.initials: AS
authors.lastname: James
authors.forename: Karen
authors.initials: K
authors.lastname: Feiler
authors.forename: Mark A
authors.initials: MA
authors.lastname: Mandelkern
authors.forename: Edythe D
authors.initials: ED
authors.lastname: London
authors.forename: J David
authors.initials: JD
authors.lastname: Jentsch
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D002522:Chlorocebus aethiops; D002755:Choice Behavior / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D056228:Feedback, Sensory / Q000187:drug effects / Q000502:physiology; D006719:Homovanillic Acid / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D049268:Positron-Emission Tomography; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012153:Retention, Psychology / Q000187:drug effects; D012193:Reversal Learning / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D004298:Dopamine; D006719:Homovanillic Acid