Imipramine-induced subsensitivity to the 5-HT4 receptor activation, a possible mediation via an alteration in the postreceptor transduction mechanism involving adenylate cyclase.

The effects of repeated treatment with imipramine on the reactivity of CA1 neurons in the rat hippocampus to the 5-HT4 receptor agonist zacopride and the direct adenylate cyclase activator forskolin were compared ex vivo to assess whether a modulation of signal transduction pathway may contribute to the antidepressant-induced adaptive changes in the responsiveness of pyramidal neurons to 5-HT4 receptor activation. The population spike recorded in the CA1 cell layer was a measure of pyramidal cell excitability, while the dendritic field excitatory postsynaptic potential (fEPSP) recorded in the stratum radiatum of the CA1 region was employed to assess the effects of the tested drugs on the excitatory amino-acid-mediated synaptic transmission. Zacopride (5 microM) and forskolin (1 microM) increased the amplitude of the half-maximal population spike (by 37 +/- 5% and 42 +/- 4%, respectively). Forskolin, but not zacopride, increased the slope of the fEPSP (by 13 +/- 2%). Repeated treatment with imipramine (14 days, twice daily, 10 mg/kg po) attenuated the excitatory effect of zacopride and forskolin on the population spike and the effect of forskolin on the fEPSP. It is concluded that the reduction in the responsiveness of CA1 cells to zacopride, induced by repeated administration of imipramine, may be due to modifications of the signal transduction pathway, i.e. adenylate cyclase and protein kinase A, which is responsible for the 5-HT4 receptor-mediated decrease in the activity of potassium channels.