CHRONIC ANTIDEPRESSANT TREATMENT FACILITATES G-PROTEIN ACTIVATION OF ADENYLYL-CYCLASE WITHOUT ALTERING G-PROTEIN CONTENT

It has been suggested that the molecular basis of antidepressant actio n involves postreceptor components. Results from our studies have sugg ested that a G protein (G(s)) is one of those targets and that chronic antidepressant treatment facilitates the activation of adenylyl cycla se by G(s alpha). This report represents an attempt to define which as pects of G protein function are altered by chronic antidepressant trea tment. Rats were treated for 21 days with amitriptyline, desipramine, ABT 200 (a pyrollidine with putative antidepressant effects) or electr oconvulsive shock, and membranes were prepared from the cerebral corte xes. Each of these treatments caused an increase in membrane adenylyl cyclase assayed in the presence of guanyl-5'-imidodiphosphate (greater than or equal to 1 mu M). Results of acute antidepressant treatments were no different than those of control treatment. Chronic treatment w ith amphetamine, which inhibits neurotransmitter reuptake without disp laying antidepressant effect, was also ineffective in increasing G(s a lpha) stimulation of adenylyl cyclase. Chronic antidepressant treatmen t did not change the content of G protein, as no change at the level o f G(s alpha), G(i alpha), G(o alpha) or G(beta) protein was detected b y immunoblotting. Although there or G was no change in the amount of G proteins, antidepressant treatment increased the number of active G(s alpha)/adenylyl cyclase complexes immunoprecipitated by an anti-G(s a lpha) antibody. It is suggested that chronic antidepressant treatment alters certain membrane components such that a greater proportion of G (s alpha) is activated, G(s alpha) enjoys a more fruitful interaction with adenylyl cyclase, or both.