Abstract

The 5-hydroxytryptamine₇ (5-HT₇) receptor was originally defined by molecular biology techniques. The 5-HT₇ receptor protein and mRNA are found in brain areas, such as the CA3 subfield of the hippocampus, that are involved in various neuropsychiatric disease states. No functional response has previously been attributed to activation of the 5-HT₇receptor in any of these brain areas. Calcium spike-induced slow afterhyperpolarizations (sAHP) were recorded from CA3 hippocampal pyramidal cells using intracellular recording techniques in a brain slice preparation maintained in vitro. A concentration-dependent inhibition of the sAHP amplitude was obtained when 5-HT was used as the agonist. To identify whether the 5-HT₇ receptor was one of the receptors mediating the inhibition of the sAHP amplitude, 5-HT agonists and antagonists were tested in the presence of WAY-100635 and GR-113808 to block 5-HT_1A and 5-HT₄ receptor activation, respectively. The rank order potency of the agonists was 5-carboxyamidotryptamine (5-CT) > 5-HT > 5-methoxytryptamine (5-MeOT). Other agonists with high affinity at 5-HT₂, 5-HT₃, 5-HT_1B, 5-HT_1D, or 5-HT₆ receptors did not produce any response when tested at 10 μM. Ritanserin, mesulergine, and SB-269770 were competitive antagonists of the 5-CT inhibition of sAHP amplitude, with affinity (pA₂) values of 6.8, 7.9, and 8.8, respectively. Methiothepin was also an effective antagonist 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 the agonists and antagonists, one of the receptors that mediates the decrease in sAHP amplitude in CA3 hippocampal pyramidal cells was concluded to be the 5-HT₇ receptor.