5-HT1A AND 5-HT4, RECEPTOR COLOCALIZATION ON HIPPOCAMPAL PYRAMIDAL CELLS

The mixed inhibitory and excitatory effects of 5-HT on hippocampal pyr amidal cells were studied on hippocampal slices perfused with a low-Ca 2+/high Mg2+ solution that blocked synaptic activity and induced spont aneous pyramidal cell discharge. Extracellular recordings of the spont aneous discharge revealed that, in 65% of the cells, 5-HT (0.5-10 mu M ) initially inhibited and then, upon washout, facilitated spontaneous discharge. Sometimes the off-stimulation persisted for the duration of the experiment. In 17% of the cells the response to 5-HT was only sti mulatory, and in 15% the response was exclusively inhibitory. The 5-HT 1 agonists, 8-hydroxy-dipropylamino-tetraline, and 5-carboxamidotrypta mine produced inhibition with no excitatory responses upon washout. Th e inhibition was blocked by spiroxitrine indicating it was mediated by 5-HT1A receptors. The 5-H-3, agonist, 2-methyl 5-HT, had no effect, a nd the 5-HT2 antagonist, ketanserin, did not alter the excitatory resp onses to 5-HT. This indicates the excitatory response is not mediated by 5-HT2 or 3 receptors. Cisapride, a 5-HT4 agonist increased pyramida l cell discharge. The 5-HT3 & 4 antagonist, ICS 205-930 antagonized th e excitatory responses to 5-HT, alpha-methyl 5-HT, and cisapride, indi cating the excitatory response is mediated, in part, by 5-HT4 receptor s. The phosphodiesterase inhibitor, isobutyl-methyl-xanthine, stimulat ed pyramidal cell discharge and potentiated the response to cisapride. This further suggests 5-HT4 receptor involvement since these receptor s are positively coupled to adenylyl cyclase.