Comparison of yohimbine, mianserin, chlorpromazine and prazosin as antagonists of the suppressant effect of clonidine on operant behavior

Male Sprague-Dawley rats were trained to respond on a fixed-ratio schedule in which every 15th response produced a pellet of food. Clonidine (1-300 μg/kg i.p.), administered 30 min before the sessions, produced a dose-dependent suppression of operant responding. The ED₅₀ for the suppression of operant responding induced by clonidine was 25 μg/kg. Coadministration of low, behaviorally inactive doses of yohimbine (0.25-1.0 mg/kg) antagonized the operant suppression produced by clonidine (15-300 μg/kg). After yohimbine (1.0 mg/kg), the ED₅₀ for the suppression of responding induced by clonidine was increased approximately 4-fold to 115 μg/kg. Higher doses of yohimbine (2.5-5.0 mg/kg) produced behavioral suppression when administered alone. These data suggest that the suppression of operant responding produced by clonidine results, at least in part, from a selective alpha-2 receptor stimulation. The behavioral suppression produced by the higher doses of clonidine (90 and 300 μg/kg) which was not blocked by yohimbine may be the result of an additional action at receptor sites other than the alpha-2 receptor. Coadministration of mianserin (1.0-35.0 mg/kg), chlorpromazine (0.5-2.5 mg/kg) or prazosin (0.01-0.5 mg/kg) failed to antagonize the suppressant effect of clonidine. The inability of chlorpromazine or prazosin to antagonize the behavioral suppression produced by clonidine indicates that clonidine is not acting solely or primarily through stimulation of the alpha-1 receptor to produce some of its behavioral effect at high doses. The inability of mianserin to antagonize the suppression of behavior produced by clonidine indicates that mianserin is probably not an alpha-2 antagonist or a yohimbine-like drug at the doses employed. Furthermore, because low doses of clonidine (1-15 μg/kg) were unable to antagonize the suppression of behavior produced by yohimbine (5 mg/kg), it appears tat yohimbine too has other actions at higher doses.