title: The dopamine D1-D2 receptor heteromer exerts a tonic inhibitory effect on the expression of amphetamine-induced locomotor sensitization.
abstract: A role for the dopamine D1-D2 receptor heteromer in the regulation of reward and addiction-related processes has been previously implicated. In the present study, we examined the effects of D1-D2 heteromer stimulation by the agonist SKF 83959 and its disruption by a selective TAT-D1 peptide on amphetamine-induced locomotor sensitization, a behavioral model widely used to study the neuroadaptations associated with psychostimulant addiction. D1-D2 heteromer activation by SKF 83959 did not alter the acute locomotor effects of amphetamine but significantly inhibited amphetamine-induced locomotor responding across the 5day treatment regimen. In addition, a single injection of SKF 83959 was sufficient to abolish the expression of locomotor sensitization induced by a priming injection of amphetamine after a 72-hour withdrawal. Conversely, inhibition of D1-D2 heteromer activity by the TAT-D1 peptide enhanced subchronic amphetamine-induced locomotion and the expression of amphetamine locomotor sensitization. Treatment solely with the TAT-D1 disrupting peptide during the initial 5day treatment phase was sufficient to induce a sensitized locomotor phenotype in response to the priming injection of amphetamine. Together these findings demonstrate that the dopamine D1-D2 receptor heteromer exerts a tonic inhibitory control on neurobiological processes involved in sensitization to amphetamine, indicating that the dopamine D1-D2 receptor heteromer may be a novel molecular substrate in addiction processes involving psychostimulants.
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Maurice Y F
authors.initials: MY
authors.lastname: Shen
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Perreault
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Theresa
authors.initials: T
authors.lastname: Fan
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: s.george@utoronto.ca.
authors.forename: Susan R
authors.initials: SR
authors.lastname: George
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology*; D019969:Amphetamine-Related Disorders / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology*; D046912:Multiprotein Complexes / Q000737:chemistry / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000502:physiology*; D012201:Reward
chemical_list: D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D046912:Multiprotein Complexes; D010446:Peptide Fragments; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C080703:SK&F 83959; D000661:Amphetamine
keywords: Amphetamine; Dopamine D1–D2 receptor heteromer; Locomotor sensitization