Response-rate suppression in operant paradigm as predictor of soporific potency in rats and identification of three novel sedative-hypnotic neuroactive steroids

Novel neuroactive steroids were evaluated for their effects on operant resp onding, rotorod motor performance, and electroencephalogram recording in ra ts. Co 134444, Co 177843, and Co 127501 were compared with the prototypical gamma-aminobutyric acid(A)-positive allosteric modulators triazolam, zolpi dem, pentobarbital, pregnanolone, and CCD 3693. Each of the compounds produ ced a dose-related decrease in response rates under a variable-interval 2-m in schedule of positive reinforcement in an operant paradigm. In addition, all compounds produced a dose-related increase in ataxia and significant in creases in nonrapid eye movement sleep in this experiment or have been prev iously reported to do so. Co 134444, Co 177843, and Co 127501 increased non rapid eye movement sleep at doses that had no effect on rapid eye movement sleep. All of the compounds were more potent at decreasing operant respondi ng than they were at increasing ataxia. Furthermore, the potency of compoun ds to produce response-rate suppression in an operant paradigm appeared to be a better predictor of soporific potency than did potency in the rotorod assay. The screening for sedative-hypnotic activity resulted in the identif ication of the novel orally active neuroactive steroids Co 134444, Co 17784 3, and Co 127501.