Effects of the dopamine autoreceptor antagonist (-)-DS121 on the discriminative stimulus properties of d-amphetamine and cocaine.
(-)-DS121 [S-(-)-3-(3-cyanophenyl)-N-n-propyl piperidine) is a recently synthesised phenylpiperidine derivative suggested to be a dopamine receptor antagonist acting preferentially at dopamine autoreceptors. The drug exerts 'agonist-like' behavioural effects by enhancing dopamine release, but also shares properties in common with neuroleptics. The ability of (-)-DS121 to both generalise to and antagonise the stimulus effects of psychostimulants was determined in rats trained to discriminate d-amphetamine (0.5 mg/kg) or cocaine (5.0 mg/kg) from saline in a two-lever, food-reinforced, drug discrimination task. (-)-DS121 (3.5-14.0 mg/kg) produced small, but significant, increases in drug lever-appropriate responding in both d-amphetamine and cocaine-trained rats. However, there was no indication of a dose-dependent effect in either case. On the other hand, (-)-DS121 dose-dependently reduced response rate. Caffeine produced a higher level of drug lever-appropriate responding than (-)-DS121 in d-amphetamine-trained rats. (-)-DS121 (7.0-14.0 mg/kg) also weakly antagonised the cueing properties of both d-amphetamine and cocaine. A marked response disruption with the drug combination precluded testing of higher doses of (-)-DS121. A combination of subthreshold doses of (-)-DS121 (3.5 mg/kg) and d-amphetamine (0.0625 mg/kg) produced a significant degree of drug lever-appropriate responding, suggesting a synergistic interaction between these drugs. However, such an interaction was not noted with a higher dose of (-)-DS121, or when this drug was administered with a low dose of cocaine (0.25 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
Clark
D
D
Department of Psychology, University of Wales, Swansea, UK.
Exner
M
M
Furmidge
L J
LJ
Svensson
K
K
Sonesson
C
C
D000661:Amphetamine / Q000008:administration & dosage / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002110:Caffeine / Q000008:administration & dosage / Q000633:toxicity; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity*; D004192:Discrimination, Psychological / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D018492:Dopamine Antagonists; D009570:Nitriles; D010880:Piperidines; C094012:3-(3-cyanophenyl)-N-n-propylpiperidine; D002110:Caffeine; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine