Effect of neuroleptics and tricyclic antidepressants upon d-amphetamine discrimination

After rats were trained to differentiate between the effects of intraperitqoneal administration of 0.6 mg/kg d-amphetamine and saline, pretreatment with various neuroleptic drugs was observed to significantly inhibit d-amphetamine discrimination. Thus, trifluoperazine, haloperidol, fluphenazine, chlorpromazine and thioridazine, but not clozapine, decreased d-amphetamine-induced control of discriminative performance. The ED50s of the effective neuroleptics for this inhibition were similar to those reported for antagonism of amphetamine-induced stereotypic behavior in the rat and the slopes of the dose-response curves were parallel indicating a common site and mechanism of action, presumably blockade of postsynaptic dopaminergic receptors. In contrast, pretreatment with the tricyclic antidepressant agents, imipramine, nortryptiline and desipramine had no significant effect on the discrimination of a dose of d-amphetamine which produced a low degree of discriminative control. The results are viewed in relation to the "dopamine hypothesis" of schizophrenia and affective disorders and the use of this animal behavioral method for determining brain dopamine interactions is discussed.