Coupling of the stimulatory GTP-binding protein Gs to rat synaptic membrane adenylate cyclase is enhanced subsequent to chronic antidepressant treatment.

In an attempt to resolve a unified postreceptor mechanism of action for antidepressant therapy, rats were treated with amitriptyline, desipramine or iprindole. Chronic treatment with these antidepressant drugs increased guanylylimidodiphosphate-[Gpp(NH)p-], NaF-, or forskolin-activated adenylate cyclase in synaptic membranes prepared from cerebral cortexes of treated rats. Gpp(NH)p-dependent inhibition of adenylate cyclase was unaffected. Maximal binding of the photoaffinity GTP analog azidoanilido-GTP (AAGTP) to the adenylate cyclase stimulatory (Gs alpha) and inhibitory (Gi alpha) G proteins was unaffected by antidepressant treatment. The chemical elimination of Gs (low pH treatment) eliminated all differences between control and antidepressant-treated groups. Further, nonneural tissues from rats receiving chronic antidepressants showed no changes in adenylate cyclase activity or AAGTP binding. The results of these studies suggest that chronic antidepressant administration promoted increased coupling between Gs and catalytic unit of adenylate cyclase. Thus, the molecular locus of antidepressant action may reside at the stimulatory GTP-binding protein, Gs.