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 afterhyperpola rization and adaptation, it also elicited a slow membrane depolarizati on associated with an increase in input resistance. All those effects may have contributed to the zacopride-induced increase in the amplitud e of population spikes, evoked in the CA1 cell layer by stimulation of the Schaffer collateral/commissural pathway. The later effect of zaco pride was concentration-dependent and was antagonized by the 5-HT4 rec eptor antagonist DAU 62805. Repeated (14 days, twice daily), but not s ingle, administration of the antidepressant drugs imipramine, citalopr am, fluvoxamine and paroxetine (10 mg/kg) attenuated the effect of zac opride on population spikes. Because inhibitory 5-HT1A and excitatory 5-HT4 receptors are colocalized on pyramidal neurons, and our previous data demonstrated an increase in the 5-HT1A receptor-mediated inhibit ion after repeated treatment with antidepressant drugs may enhance the inhibitory effect of 5-HT directly, by increasing the 5-HT1A receptor responsiveness, and indirectly, by inducing subsensitivity to the 5-H T4 receptor activation.