Repeated treatment with antidepressant drugs induces subsensitivity to the excitatory effect of 5-HT4 receptor activation in the rat hippocampus

The effect of repeated treatment with various antidepressant drugs on the reactivity of CA1 neurons to the 5-HT₄ receptor agonist zacopride was examined. Zacopride decreased the calcium-activated afterhyperpolarization and adaptation, it also elicited a slow membrane depolarization associated with an increase in input resistance. All those effects may have contributed to the zacopride-induced increase in the amplitude of population spikes, evoked in the CA1 cell layer by stimulation of the Schaffer collateral/commissural pathway. The later effect of zacopride was concentration-dependent and was antagonized by the 5-HT₄ receptor antagonist DAU 62805. Repeated (14 days, twice daily), but not single, administration of the antidepressant drugs imipramine, citalopram, fluvoxamine and paroxetine (10 mg/kg) attenuated the effect of zacopride on population spikes. Because inhibitory 5-HT_1A and excitatory 5-HT₄ receptors are colocalized on pyramidal neurons, and our previous data demonstrated an increase in the 5-HT_1A receptor-mediated inhibition after repeated treatment with antidepressants, we conclude that treatment with antidepressant drugs may enhance the inhibitory effect of 5-HT directly, by increasing the 5-HT_1A receptor responsiveness, and indirectly, by inducing subsensitivity to the 5-HT₄ receptor activation. Received: 24 June 1996 / Accepted: 28 August 1996