Imipramine but not 5-HT1A receptor agonists or neuroleptics induces adaptive changes in hippocampal 5-HT1A and 5-HT4 receptors

It has been reported that the treatment with a tricyclic antidepressant imipramine induces an increase in the sensitivity of 5-HT1A receptors and a decrease in the sensitivity of 5-HT4 receptors in the rat hippocampus. 5-HT1A receptor agonists and neuroleptics also affect 5-HT1A receptors in different brain areas; therefore, it was of interest to compare their effects on hippocampal 5-HT receptors with the influence of the well-established antidepressant imipramine. We studied the effects of repeated treatment with imipramine, the 5-HT1A receptor agonists 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, and the neuroleptics haloperidol and clozapine on the sensitivity of rat hippocampal CA1 neurons to 5-HT1A- and 5-HT4 receptor activation. Imipramine was administered for 21 days (10 mg/kg p.o., twice daily), 8-OH-DPAT for 7 days (1 mg/kg s.c., twice daily) and buspirone for 21 days (5 mg/kg s.c., twice daily). The rats received haloperidol (1 mg/kg) and clozapine (30 mg/kg) for 6 weeks in drinking water. Hippocampal slices were prepared 2 days after the last treatment with imipramme, 8-OH-DPAT or buspirone, and 5 days after the last treatment with the neuroleptics. Using an extracellular in vitro recording, we studied changes in the amplitude of stimulation-evoked population spikes, induced by 5-HT, 8-OH-DPAT and the 5-HT4 receptor agonist zacopride. Activation of 5-HT1A receptors decreased, while activation of 5-HT4 receptors increased the amplitude of population spikes. Imipramine significantly enhanced the inhibitory effects of 5-HT and 8-OH-DPAT, and attenuated the excitatory effect of zacopride. No other treatment used in the present study changed the sensitivity of hippocampal CA1 neurons to 5-HT1A and 5-HT4 receptors activation. These findings indicate that adaptive changes in the sensitivity of hippocampal neurons to 5-HT1A and 5-HT4 receptors agonists are specific to imipramine and may thus-at least partly-mediate its effects. (C) 2002 Elsevier Science B.V. All rights reserved.