INHIBITION OF [H-3] GAMMA-AMINOBUTYRIC-ACID RELEASE FROM GUINEA-PIG HIPPOCAMPAL SYNAPTOSOMES BY SEROTONERGIC AGENTS

We studied the effects of (m-trifluoromethyl-phenyl)piperazine (TFMPP) and quipazine on the K+-evoked [H-3]GABA release from guinea-pig hippocampal synaptosomes loaded with [H-3]GABA.TFMPP and quipazine inhibited the K+-evoked release of [H-3]GABA dose-dependently (IC50 = 153 and 123 muM, respectively). Serotonergic antagonists such as methiothepin (0.1, 0.3 and 1 muM), ketanserin (0.1, 0.3 and 1 muM), dihydroergotamine (0.1 muM), metergoline (0.1 and 0.3 muM), methysergide (0.3 muM), propranolol (1 muM) and yohimbine (1 muM) did not significantly alter the inhibitory effect of TFMPP on [H-3]GABA release suggesting that neither 5-HT1 nor 5-HT2 receptors are involved in this process. By contrast, the effect of TFMPP was diminished by selective 5-HT3 receptor antagonists: MDL 72222 (0.3 muM), tropisetron (0.3 and 1 muM), ondansetron (0.3 muM) and metoclopramide (1 muM). Tropisetron (1 muM) and ondansetron (0.3 muM) also inhibited significantly the quipazine effect whereas methiothepin (1 muM), dihydroergotamine (0.1 muM), yohimbine (1 muM) and ketanserin (1 muM) were ineffective on the quipazine inhibition of [H-3]GABA release. Our results show a serotonergic modulatory effect on the K+-evoked [H-3]GABA release from guinea-pig hippocampal synaptosomes by receptors which are neither 5-HT1, 5-HT2 or 5-HT4. They appear to be pharmacologically related to the 5-HT3 type but different from the 5-HT3 ionic channel receptors.