The effect of neuroleptic drugs of various chemical classes on adenylate cyclase from a variety of rat tissues has been investigated. These were the dopamine-stimulated adenylate cyclase in rat striatal homogenates, the noradrenaline-stimulated adenylate cyclase in adipocyte membrane fragments and the glucagon-stimulated adenylate cyclase in liver membranes. The stimulatory effects of dopamine on rat striatal adenylate cyclase were apparent within a minute of the start of incubations and over a wide range of temperatures. Moreover the stimulation could be rapidly inhibited by several classes of neuroleptic agent. The inhibitory effect of neuroleptics of all classes was completely reversed by high concentrations of dopamine and this reversal took place rapidly at 30°. Neuroleptics were also able to inhibit the stimulatory effects of noradrenaline on adipocyte adenylate cyclase at concentrations where the basal enzyme activity was not affected. However the effects of drugs in this system occurred at much higher concentrations than in the dopamine-stimulated system. In addition drug potencies as inhibitors of noradrenaline did not correlate with neuroleptic activity, α and β-flupenthixol for example were equipotent as noradrenaline antagonists. Neuroleptics were able to inhibit the stimulation of liver membrane adenylate cyclase by glucagon. The potencies of drugs as inhibitors in this system agian did not correlate with neuroleptic potencies. Higher concentrations of glucagon were not able to reverse the inhibition produced by neuroleptics. It is concluded that the effects of neuroleptic drugs on dopamine-stimulated adenylate cyclase correlate most closely with their clinical neuroleptic potencies.
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