Quantitative determination of the effects of catecholaminergic agonists and antagonists on the rewarding efficacy of brain stimulation.

The effects of amphetamine, clonidine, molindone, pimozide and yohimbine on the rewarding efficacy of electrical stimulation of the medial forebrain bundle in the rat were determined from the effects of these drugs on the rate-frequency function, which is the plot of the rat's rate of pressing a lever against the frequency of the pulses in a rewarding train of fixed duration. These catecholaminergic agonists and antagonists produced dose-dependent alterations in the measurable rewarding efficacy, but only up to a factor of about 2, even though the method is capable of measuring 25-30-fold changes. At elevated doses, the effects on rewarding efficacy became unmeasurable, because the animals would not consistently self-stimulate at any parameters of stimulation. Amphetamine (0.5-3 mg/kg) enhanced rewarding efficacy. Clonidine (0.05-0.4 mg/kg), molindone (0.25-1 mg/kg) and pimozide (0.1-0.6 mg/kg) attenuated it. Pimozide and clonidine were equipotent despite their radically different receptor affinities. The effects of pimozide, clonidine and amphetamine were approximately additive (amphetamine cancelled the effects of pimozide and clonidine, while clonidine augmented the effect of pimozide). The alpha 2 antagonist yohimbine (0.05-10 mg/kg) had the same effect as the alpha 2 agonist clonidine (attenuation of rewarding efficacy), but these effects did not combine additively: yohimbine neither cancelled nor augmented the effect of clonidine. It is suggested that catecholaminergic agonists and antagonists do not alter the magnitude of the rewarding signal by acting on postsynaptic receptors in the reward pathway; rather, they may drive beyond functional limits a variable that is crucial to the proper recording of the magnitude of the rewarding signal.