Electrophysiologic interactions of antipsychotic drugs with central noradrenergic pathways

The pathway from the nucleus coeruleus to Purkinje neurons in rat cerebellar cortex was used to analyze effects of antipsychotic neuroleptic drugs on a central noradrenergic pathway. Fluphenazine and haloperidol produced a dose-dependent increase in Purkinje neuron spontaneous discharge. This effect was not seen in animals in which the noradrenergic input had been removed by the neurotoxin 6-hydroxydopamine. In contrast, the effects of neuroleptics were still present in animals which had received neonatal X-ray irradiation, which destroys intrinsic inhibitory and excitatory pathways in cerebellar cortex. Chlorpromazine produced the same increase in discharge rate, but was significantly less potent. alpha-Flupenthixol was equipotent with fluphenazine, but beta-flupenthixol, a behaviorally inactive stereoisomer, was without effect. The dose-response curves showed potencies similar to those in several animal behavioral paradigms. In addition, the rank order of potency was identical to that in clinical tests of antipsychotic activity. Three-week chronic administration of fluphenazine resulted in complete blockage of noradrenergic activity, with no further increase in Purkinje neurons spontaneous discharge rate by additional doses of drug. Thus, tolerance does not develop to the noradrenergic blocking effect of the neuroleptic. Taken together, this evidence suggests that antipsychotic neuroleptic drugs block noradrenergic neurotransmission in the CNS.