Discriminative stimuli produced by clonidine: an investigation of the possible relationship to adrenoceptor stimulation and hypotension.

In a leverpressing operant procedure, male rats were trained to respond for food reinforcement on one lever after an injection of clonidine (0.04 mg/kg) and to respond on an alternate lever for food reinforcement after an injection of saline. All 36 rats learned to discriminate the drug reliably from saline, thereby indicating that clonidine produces discriminative interoceptive stimuli. The discriminative stimulus was both dose- and time-dependent, with an ED50 of 0.018 mg/kg and an optimum time of action occurring from 15 to 60 min after injection. Although clonidine produced a reduction in response rate, this was not the basis of the discriminative stimulus as other drugs with similar depressant action did not generalize. The clonidine stimulus was dose-dependently antagonized by the alpha-2 adrenergic antagonist, yohimbine, whereas receptor antagonists of alpha-1 adrenergic, beta adrenergic, dopaminergic, serotonergic, cholinergic or opioid systems were ineffective in blocking the interoceptive stimulus produced by clonidine Lofexidine, guanabenz and methyldopa, all centrally acting hypotensive drugs that act through alpha-2 adrenoceptor mechanisms dose-dependently generalized to the clonidine cue, whereas hydralazine, minoxidil, propranolol and prazosin, hypotensive drugs acting through other mechanisms, did not generalize. These results suggest that clonidine produces interoceptive stimuli that are discriminable by rats and mediated through central alpha-2 adrenoceptor stimulation.