title: Cocaine self-administration in dopamine D₃ receptor knockout mice.
abstract: The dopamine D₃ receptor has received attention over the last two decades as a target for medications development for substance abuse disorders. Results have remained mixed. Despite emergence of more D₃-selective ligands, possible attribution of observed effects to D₂ receptors remains a concern. Knockout mice may help shed light on mechanisms. Here we evaluated the effect of constitutive D₃ receptor inactivation ("knockout") on the reinforcing effects of cocaine. We tested D₃ wild-type (WT), heterozygous (D₃⁺/⁻), and knockout (D₃⁻/⁻), mice in acquisition and maintenance of intravenous self-administration across a broad range of cocaine doses, using a fixed ratio (FR) 1 and a progressive ratio (PR) schedule of reinforcement, along with parallel food-reinforced studies. Generally, D₃⁻/⁻ mice showed cocaine self-administration comparable to WT controls across assays. Moderate and nonsignificant trends toward lesser reinforcing effects of a low cocaine dose (0.32 mg/kg) were apparent in acquisition and PR studies, consistent with the idea that the D₃ receptor may play a subtle role in the reinforcing effects of low cocaine doses under low FR conditions. However, those effects with cocaine self-administration were more subtle than the lower responding of D₃ knockout mice observed with food-maintained behavior. In addition, the D₃ antagonist PG01037 failed to affect cocaine self-administration under an FR 1 schedule in WT mice. The present data do not support a necessary role for the D₃ receptor in the direct reinforcing effects of cocaine.
authors.affiliation: Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, MA 02478, USA. barak@mclean.harvard.edu
authors.forename: S Barak
authors.initials: SB
authors.lastname: Caine
authors.forename: Morgane
authors.initials: M
authors.lastname: Thomsen
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Barrett
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Collins
authors.forename: Peter
authors.initials: P
authors.lastname: Grundt
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
authors.forename: Paul
authors.initials: P
authors.lastname: Butler
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D012055:Reinforcement Schedule; D012646:Self Administration
chemical_list: D001549:Benzamides; C497150:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-pyridine-2-ylbenzamide; D011725:Pyridines; D050637:Receptors, Dopamine D3; D003042:Cocaine