5-Hydroxytryptamine(7) receptor activation decreases slow afterhyperpolarization amplitude in CA3 hippocampal pyramidal cells

The 5-hydroxytryptamine(7) (5-HT7) receptor was originally defined by molec ular biology techniques. The 5-HT7 receptor protein and mRNA are found in b rain areas, such as the CA3 subfield of the hippocampus, that are involved in various neuropsychiatric disease states. No functional response has prev iously been attributed to activation of the 5-HT7 receptor in any of these brain areas. Calcium spike-induced slow afterhyperpolarizations (sAHP) were recorded from CA3 hippocampal pyramidal cells using intracellular recordin g techniques in a brain slice preparation maintained in vitro. A concentrat ion-dependent inhibition of the sAHP amplitude was obtained when 5-HT was u sed as the agonist. To identify whether the 5-HT7 receptor was one of the r eceptors mediating the inhibition of the sAHP amplitude, 5-HT agonists and antagonists were tested in the presence of WAY-100635 and GR-113808 to bloc k 5-HT1A and 5-HT4 receptor activation, respectively. The rank order potenc y of the agonists was 5-carboxyamidotryptamine (5-CT) > 5-HT > 5-methoxytry ptamine (5-MeOT). Other agonists with high affinity at 5-HT2, 5-HT3, 5-HT1B , 5-HT1D, or 5-HT6 receptors did not produce any response when tested at 10 mu M. Ritanserin, mesulergine, and SB-269770 were competitive antagonists of the 5-CT inhibition of sAHP amplitude, with affinity (pA(2)) values of 6 .8, 7.9, and 8.8, respectively. Methiothepin was also an effective antagoni st but was insurmountable. Other antagonists with affinity for the 5-HT2, 5 -HT3, or 5-HT6 receptor had no effect. Based on the rank order potency of t he agonists and antagonists, one of the receptors that mediates the decreas e in sAHP amplitude in CA3 hippocampal pyramidal cells was concluded to be the 5-HT7 receptor.