Discriminative stimuli produced by clonidine in spontaneously hypertensive rats: generalization to antihypertensive drugs with different mechanisms of action.

Spontaneously hypertensive rats were food deprived and trained to lever press on a fixed-ratio 10 schedule of food reinforcement in a paradigm in which responding was reinforced on one lever after an injection of clonidine (0.02 mg/kg) and on an alternate lever after an injection of saline. The spontaneously hypertensive rats learned the clonidine-saline discrimination to a criterion of correct lever selection on 10 consecutive days in an average of 39 training sessions. In subsequent tests, emission of clonidine discrimination responses was found to be both time dependent and dose dependent (ED50, 0.009 mg/kg). The antihypertensive drugs lofexidine (ED50, 0.03 mg/kg), guanabenz (ED50, 0.019 mg/kg), p-aminoclonidine (ED50, 0.23 mg/kg), methyldopa (ED50, 21.8 mg/kg), hydralazine (ED50, 0.98 mg/kg), prazosin (ED50, 0.72 mg/kg), minoxidil (ED50, 12.4 mg/kg) and pergolide (ED50, 0.021 mg/kg) were generalized to clonidine in a dose-dependent manner. Yohimbine antagonized both the antihypertensive action and the discriminative stimulus properties of clonidine in parallel without antagonizing those actions of hydralazine. Similarly, the discriminative stimulus properties and antihypertensive action of pergolide were antagonized by sulpiride in parallel without antagonizing any of those effects when produced by clonidine or hydralazine. Although the stimulus properties and response-suppressive actions of the antihypertensive or other drugs were not related, the ED50 values for generalization of the drugs to the clonidine stimulus and for their antihypertensive action were highly correlated (r = 0.99). These data suggest that clonidine produces an interoceptive discriminative stimulus that is based upon its antihypertensive action in spontaneously hypertensive rats.