BIMT-17, A 5-HT1A RECEPTOR AGONIST 5-HT2A RECEPTOR ANTAGONIST, DIRECTLY ACTIVATES POSTSYNAPTIC 5-HT INHIBITORY RESPONSES IN THE RAT CEREBRAL-CORTEX

BIMT 17 (1-[2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] ethyl] ben zimidazol- [1H]-2-one), a 5-HT1A receptor agonist/5-HT2A receptor anta gonist (see Borsini et al., accompanying paper), in a dose range of 1- 10 mg/kg i.v., dose-dependently inhibited the electrical activity of r at medial prefronto-cortical neurons, whereas buspirone, in a dose ran ge of 0.1-1000 mu g/kg, increased it. 8-hydroxy-2-(di-n-propylamino) t etralin (8-OH-DPAT) and 2-(2-thenoylamino)ethyl]-4-[1-(7-methoxynaphth yl)] piperazine (S 14671) presented biphasic patterns of response; the y increased electrical activity at doses in the range of 0.1-10 mu g/k g and 0.1-3 mu g/kg i.v. respectively, and reduced it at higher doses, 30-300 mu g/kg and 10-30 mu g/kg i.v., respectively. The inhibitory e ffect of BIMT 17 on the firing rate of neurons in the frontal cortex w as antagonized by the 5-HT1A antagonists tertatolol and WAY 100135, an d was still present after destruction of serotonin (5-HT) containing n euronal endings by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 15 0 mu g/rat, given intraventricularly), which reduced the cortical 5-HT content by 85%. This destruction of 5-HT neurons, while suppressing t he ability of 8-OH-DPAT to inhibit the firing rate at high doses, did not change the excitatory action of this compound at low doses. The ad dition of ritanserin, a 5-HT2A receptor antagonist, potentiated both t he excitatory and inhibitory effects of 8-OH-DPAT on neuronal electric al activity. Direct microiontophoretic application (100 nA/20 s) of 5- HT and BIMT 17, but not that of 8-OH-DPAT, onto medial prefronto-corti cal neurons, decreased the firing rate of these neurons. These finding s suggest that BIMT 17 directly inhibits the electrical activity of me dial prefronto-cortical neurons through its dual mode of receptor inte raction.