A comparison of the effects of psychotomimetics and anxiolytics on punished and unpunished responding maintained by fixed interval schedules of food reinforcement in the rat.
Characterization of anxiolytic drugs often employs conflict paradigms in which the drug effects on punished and unpunished responding can be compared. In this study, a fixed interval schedule generating a range of baseline response rates allowed comparison of the effects of anxiolytic drugs with those of psychotomimetic drugs on equivalent and differing rates of punished and unpunished responding. The first response made by the rat after a 40-s fixed interval elapsed resulted in food pellet delivery. In punished intervals, signalled by the illumination of stimulus lamps above each lever, a 0.6-mA shock was delivered after every 20th response, resulting in a lower rate of responding than that in the unpunished intervals. Three psychotomimetic agents, D-amphetamine, MK801 and DOI were compared with the anxiolytics chlordiazepoxide, NS2710 and pregabalin. The three psychotomimetics preferentially increased rates of unpunished responding compared with those of punished responding. Chlordiazepoxide, NS2710 and, to a lesser extent, pregabalin increased rates of both unpunished and punished responding. In comparison studies, yohimbine also increased rates of both unpunished and punished responding whereas the antidepressant citalopram had no effect. In conclusion, stable baseline performance over many months allowed the direct comparison of several different drugs in the same subjects with no need to adjust shock levels or equate baseline response rates. The drugs had systematic and replicable effects in this procedure, which, in the case of amphetamine and chlordiazepoxide, were similar to those in other species, and psychotomimetic drugs could clearly be distinguished from anxiolytic drugs. The procedure, however, has limited value for characterizing novel anxiolytic agents as the examples used here increased punished and unpunished responding to the same extent, and were indistinguishable in that regard from the clinically anxiogenic agent, yohimbine.
Evenden
John
J
Department of Neuroscience, CNS Discovery, AstraZeneca R&D Wilmington, Wilmington, Delaware 19850, USA. john.evenden@astrazeneca.com
Duncan
Bertina
B
Ko
Tracey
T
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001070:Appetitive Behavior / Q000187:drug effects*; D001245:Association Learning / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D003913:Dextroamphetamine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004597:Electroshock; D006213:Hallucinogens / Q000494:pharmacology*; D010091:Oximes / Q000494:pharmacology; D000069583:Pregabalin; D011678:Punishment; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects; D012055:Reinforcement Schedule; D015016:Yohimbine / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
C514343:1-(1-(3-(3-pyridyl)phenyl)benzimidazol-5-yl)ethanone O-ethyloxime; D000662:Amphetamines; D014151:Anti-Anxiety Agents; D001562:Benzimidazoles; D006213:Hallucinogens; D010091:Oximes; D011963:Receptors, GABA-A; D015016:Yohimbine; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; D002707:Chlordiazepoxide; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D003913:Dextroamphetamine