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J Pharmacol Exp Ther. 1995 Oct;275(1):509-17.

Chronic antidepressant treatment facilitates G protein activation of adenylyl cyclase without altering G protein content.

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  • 1Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, USA.


It has been suggested that the molecular basis of antidepressant action involves postreceptor components. Results from our studies have suggested that a G protein (Gs) is one of those targets and that chronic antidepressant treatment facilitates the activation of adenylyl cyclase by Gs alpha. This report represents an attempt to define which aspects of G protein function are altered by chronic antidepressant treatment. Rats were treated for 21 days with amitriptyline, desipramine, ABT 200 (a pyrollidine with putative antidepressant effects) or electroconvulsive shock, and membranes were prepared from the cerebral cortexes. Each of these treatments caused an increase in membrane adenylyl cyclase assayed in the presence of guanyl-5'-imidodiphosphate (> or = 1 microM). Results of acute antidepressant treatments were no different than those of control treatment. Chronic treatment with amphetamine, which inhibits neurotransmitter reuptake without displaying antidepressant effect, was also ineffective in increasing Gs alpha stimulation of adenylyl cyclase. Chronic antidepressant treatment did not change the content of G protein, as no change at the level of Gs alpha, Gi alpha, Go alpha or G beta protein was detected by immunoblotting. Although there was no change in the amount of G proteins, antidepressant treatment increased the number of active Gs alpha/adenylyl cyclase complexes immunoprecipitated by an anti-Gs alpha antibody. It is suggested that chronic antidepressant treatment alters certain membrane components such that a greater proportion of Gs alpha is activated, Gs alpha enjoys a more fruitful interaction with adenylyl cyclase, or both.

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