Dopamine D4 receptors in psychostimulant addiction.
Since the cloning of the D4 receptor in the 1990s, interest has been building in the role of this receptor in drug addiction, given the importance of dopamine in addiction. Like the D3 receptor, the D4 receptor has limited distribution within the brain, suggesting it may have a unique role in drug abuse. However, compared to the D3 receptor, few studies have evaluated the importance of the D4 receptor. This may be due, in part, to the relative lack of compounds selective for the D4 receptor; the early studies were mainly conducted in mice lacking the D4 receptor. In this review, we summarize the literature on the structure and localization of the D4 receptor before reviewing the data from D4 knockout mice that used behavioral models relevant to the understanding of stimulant use. We also present evidence from more recent pharmacological studies using selective D4 agonists and antagonists and animal models of drug-seeking and drug-taking. The data summarized here suggest a role for D4 receptors in relapse to stimulant use. Therefore, treatments based on antagonism of the D4 receptor may be useful treatments for relapse to nicotine, cocaine, and amphetamine use.
Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada.
Patricia
P
Di Ciano
Department of Physiology & Pharmacology, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA.
David K
DK
Grandy
Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada; Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada. Electronic address: bernard.lefoll@camh.ca.
Bernard
B
Le Foll
D000818:Animals; D000697:Central Nervous System Stimulants / Q000009:adverse effects; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000188:drug therapy* / Q000378:metabolism
C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D011725:Pyridines; D011758:Pyrroles; D050638:Receptors, Dopamine D4
Amphetamine; Cocaine; D4; Dopamine; Nicotine; Smoking