Effects of chronic antidepressant treatment on serotonin receptor activity in mice

The effect of acute and chronic treatments with conventional and atypical antidepressant drugs on serotonin receptor activity was assessed by the responsiveness of mice to the serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine. Acute treatment with 10 mg/kg of amitriptyline, imipramine, trazodone, mianserin or viloxazine reduced the head twitch response measured 1 h following a challenged dose of the serotonin agonist. Acute iprindole and desmethylimipramine, however, had no effect on the serotonergic response. Chronic treatment with the clinically effective antidepressants amitriptyline, imipramine, desmethylimipramine, iprindole, and trazodone produced an enhanced responsiveness to 5-MeODMT. The enhanced responsiveness was first observed 24 h after cessation of treatment with most drugs. The effect lasted for at least 48 h. Chronic treatment with the neuroleptic haloperidol did not result in altered responsivity to the serotonin agonist. Brain accumulation of imipramine and amitriptyline and their deaminated metabolites were measured. Brain drug and metabolite levels peaked 1 h following both acute and chronic treatments. Brain accumulations of amitriptyline and its metabolite were much greater than those of imipramine and its metabolite. This pharmacokinetic data is consistent with an early (1 h) antagonism of the 5-MeODMT response and the emergence of hightened responsiveness to 5-MeODMT after chronic treatment, when brain drug levels are reduced. These findings are also consistent with the greater inhibitory effect found after treatment with amitriptyline than with imipramine. It is concluded that enhanced serotonin neurotransmission which develops during chronic treatment with antidepressant drugs may be related to the clinical action of these drugs.