Actions in vitro and in vivo of chlorpromazine and haloperidol on cyclic nucleotide systems in mouse cerebral cortex and cerebellum

Three different procedures were utilized to study the action of chlorpromazine (CPZ) and haloperidol on adenylate cyclase-cyclic nucleotide systems in the mouse cerebral cortex and cerebellum. Using incubated tissue slices which in both tissues demonstrate an activation of adenylate cyclase by norepinephrine (NE), CPZ was found to be more effective than haloperidol in reducing this response. With the second method it was shown that adenylate cyclase in homogenates was stimulated in both tissues by NE while dopamine (DA) was active in only the cerebral cortex. With this broken cellular preparation, CPZ exerted greater antagonism than haloperidol on both the NE- and DA-sensitive enzymes. Moreover, the DA-responsive enzymes were blocked by both agents to a greater extent than was observed with the NE-induced stimulation. In the third experiment haloperidol and three doses of CPZ were injected into mice in vivo, at specified intervals; thereafter the tissues were rapidly inactivated by focused microwave irradiation (0.5 sec), and cyclic AMP and cyclic GMP levels were subsequently determined. In general, the acute injections ( 1 2-8 hr) of CPZ and haloperidol diminished the steady-state levels of the two nucleotides. Subchronic administration (24-48 hr) usually resulted in elevated cyclic AMP amounts. The data indicate that under both in vitro and in vivo conditions, neuroleptics inhibit neurohumorally-induced activation of adenylate cyclase. Subchronic injections, however, suggest other factors become prominent i.e. inhibition of phosphodiesterase or enhanced receptor sensitivity.