Effects of the selective dopamine D3 receptor antagonist SB-277011A on the reinforcing effects of nicotine as measured by a progressive-ratio schedule in rats.
The dopamine D3 receptor is primarily localized within the mesocorticolimbic system, and may therefore have potential as a pharmacotherapeutic target for the treatment of drug dependence. Studies have shown that the selective dopamine D3 receptor antagonist SB-277011A reduces a variety of dependence-related behavioral effects of cocaine, alcohol and heroin. A previous study examining SB-277011A on nicotine self-administration using relatively low doses of the antagonist and a low response requirement for nicotine found no effect on drug-taking behavior per se, whereas reinstatement of nicotine-seeking was reduced. The purpose of the present study was to further examine the effects of higher doses of SB-277011A on nicotine self-administration in rats under a progressive-ratio (PR) schedule, which imposes relatively high response requirements for nicotine. Rats were trained to respond under a PR schedule of either nicotine or food reinforcement. Once responding was stable, SB-277011A (3-56 mg/kg) or vehicle was administered i.p. 1 h prior to the operant session. The highest dose tested significantly decreased the mean number of reinforcers and mean response rates in the nicotine self-administration group, but had no effect on either the mean number of reinforcers or response rate in the food group. In a separate set of experiments, the effects of SB-277011A on locomotor activity were measured. At the dose that significantly decreased nicotine self-administration, total distance traveled was also significantly decreased, suggesting that the effect on operant responding at the high dose of SB-277011A is at a threshold for motor effects and may not be directly mediated by an action at dopamine D3 receptors.
Ross
Jason T
JT
Minneapolis Medical Research Foundation, 914 South 8th Street, Minneapolis, MN 55404, USA.
Corrigall
William A
WA
Heidbreder
Christian A
CA
LeSage
Mark G
MG
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003216:Conditioning, Operant / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004435:Eating; D007262:Infusions, Intravenous; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D014029:Tobacco Use Disorder / Q000378:metabolism / Q000523:psychology
D018492:Dopamine Antagonists; D018722:Nicotinic Agonists; D009570:Nitriles; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D009538:Nicotine