INFLUENCE OF TRICYCLIC ANTIDEPRESSANTS ON ADENYLATE CYCLASE-PHOSPHODIESTERASE SYSTEM IN RAT CORTEX

The actions of 10 tricyclic antidepressant drugs were evaluated with respect to inhibition of the adenylate cyclase cyclic AMP phosphodiesterase system in various preparations of rat cerebral cortex. At highest concentrations (10-4 M) all drugs exhibited antagonism of the stimulation of cyclic AMP accumulation by norepinephrine in incubated tissue slice (whole cell) preparations. In these experiments iprindole and desipramine (10-4-10-8 M) were the most potent agents, while lesser degrees of inhibition were seen with amitriptyline, chlorimipramine, nortriptyline, protriptyline, imipramine, opipramol, 2-hydroxyimipramine and 2-hydroxydesipramine in approximately that order. In broken cellular preparations from isolated neuronal and glial-enriched fractions, extremely high concentrations (1-10 mM) of the tricyclic antidepressants were necessary to inhibit by 50% the basal, fluoride-sensitive (catalytic site) and norepinephrine-sensitive (receptor) components of adenylate cyclase. In similar studies with isolated neuronal and glial fractions somewhat lower concentrations (0.1-1 mM) of tricyclic antidepressants were required to inhibit by 50% the total phosphodiesterase activity. A basic problem is indicated relating to drug experimentation on cyclic nucleotide systems. Results obtained from intact cellular investigations, i.e., tissue slices, may not always be extrapolated to similar findings with enzyme preparations derived from broken cells.