Atypical antipsychotics block the excitatory effects of serotonin in septohippocampal neurons in the rat

We recently reported that serotonin excites a subpopulation of GABAergic neurons in the rat medial septum/diagonal band of Broca complex via multiple serotonin receptors, including the serotonin2A subtype. Since a subpopulation of medial septum/diagonal band GABAergic neurons projects to the hippocampus, in the present study we tested the effect of serotonin on antidromically-activated septohippocampal neurons using extracellular recordings. Bath-applied serotonin had an excitatory effect in a majority of septohippocampal neurons; serotonin-excited septohippocampal neurons had a mean conduction velocity -1.63 +/- 0.07 m/s (n=101). Pharmacologically, MDL 100,907, a selective serotonin2A antagonist blocked the excitatory effect of serotonin in 78% of septohippocampal neurons tested, with a mean pA2 of 8.51 +/- 0.12 (n=22). Additionally, the atypical antipsychotics risperidone and clozapine but not the typical antipsychotic haloperidol, blocked the excitatory effects of serotonin at clinically relevant concentrations. The pA2 values of 8.84 +/- 0.11, 6.57 +/- 0.13 and 5.94 +/- 0.27 for risperidone, clozapine and haloperidol, respectively, obtained in the present study, give a rank order of potency risperidone (1.6 nM) clozapine (269 nM) haloperidol (1.1 microM) which corresponds to that reported in binding studies. Additionally, in whole-cell patch-clamp recordings, risperidone (10 nM) blocked serotonin-induced increase in GABAergic synaptic currents. In conclusion, serotonin excites septohippocampal neurons primarily via the serotonin2A receptor and atypical antipsychotics block this excitation at clinically relevant concentrations.