Effects of dopaminergic drugs on working and reference memory in rats.
Changes in dopaminergic function have been associated with alterations in motor and cognitive function in man and in animals. This study was designed to assess the effects of dopaminergic drugs on these aspects of conditioned behavior in animals. Male Long-Evans rats were trained to perform an appetitive operant task that allowed daily quantification of working memory (accuracy of spatial delayed nonmatching-to-position), reference memory (accuracy of visual discrimination) and motor function [choice lever-press latency and nosepoke interresponse time (IRT) during delay]. The indirect dopamine agonist d-amphetamine (0.3-1.0 mg/kg) reduced nonmatching accuracy without significantly affecting discrimination accuracy, response latency, or nosepoke IRT. The D2/D3 agonist quinpirole (0.01-0.056 mg/kg) also decreased nonmatching accuracy without changing discrimination accuracy, but increased choice response latency and nosepoke IRT as well. The D1 agonist SKF 38393 (1.0-3.0 mg/kg) and the D1 antagonist SCH 23390 (0.01-0.03 mg/kg) only affected nosepoke IRT, at doses below those causing response failure. The D2 antagonist raclopride (0.056-0.177 mg/kg) exerted no significant effects at doses that did not suppress responding completely. The selective reduction of nonmatching accuracy by d-amphetamine and quinpirole indicates a mnemonic impairment specific to working memory (relative to reference memory). These results suggest further 1) that stimulation of D2/D3, but not D1, receptors may account for the d-amphetamine-induced deficit in working memory; 2) that stimulation of D2/D3 receptors alone by quinpirole may also impair spatial working memory, but only in conjunction with motor slowing; and 3) that antagonism of either receptor type (by SCH 23390 or raclopride) does not significantly affect memory at doses causing motor slowing and response failure.
Bushnell
P J
PJ
Neurotoxicology Division, United States Environmental Protection Agency, Research Triangle Park, NC 27711.
Levin
E D
ED
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003913:Dextroamphetamine / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects; D015259:Dopamine Agents / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004873:Ergolines / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects*; D008570:Memory, Short-Term / Q000187:drug effects*; D011597:Psychomotor Performance / Q000187:drug effects; D019257:Quinpirole; D020891:Raclopride; D051381:Rats; D012457:Salicylamides / Q000494:pharmacology
D001552:Benzazepines; D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; D004873:Ergolines; D012457:Salicylamides; D019257:Quinpirole; D020891:Raclopride; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D003913:Dextroamphetamine