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Presynaptic activation of the spinal serotonergic system in the rat by phencyclidine in vitro

Y Ohno and JE Warnick

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore.

Electrophysiological studies were carried out to investigate the mechanism of action of phencyclidine [PCP; 1- (phenylcyclohexyl)piperidine] on a segmental monosynaptic reflex using isolated spinal cord preparations from neonatal rats. PCP and its related compounds produced a concentration-dependent depression of the monosynaptic reflex with a relative potency as follows: PCP = 1-[1-(2- thienyl)cyclohexyl]piperidine greater than 1-(1-m- aminophenylcyclohexyl)piperidine much greater than 1-(1-m- nitrophenylcyclo-hexyl)piperidine approximately MK-801 [(+)-5-methyl- 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] much greater than (+)-N-allylnormetazocine. The N-methyl-D-aspartate receptor antagonists 2-amino-5-phosphonovalerate and 2-amino-7- phosphonoheptanoate had no effect on the monosynaptic reflex. The depression of the monosynaptic reflex by PCP was antagonized by serotonin (5-HT) receptor antagonists (methiothepin, spiperone and ketanserin) but unaffected by noradrenergic (phentolamine and timolol), dopaminergic (chlorpromazine and pimozide) and cholinergic antagonists (atropine and mecamylamine). Whereas 5-HT and a putative 5-HT releaser, p-chloroamphetamine, also depressed the monosynaptic reflex, the blockade of monoamine uptake by imipramine did not. Furthermore, pretreatment of rats with desipramine and 5,7-dihydroxytryptamine largely diminished the depression of the monosynaptic reflex by PCP and p-chloroamphetamine while enhancing the depressant action of 5-HT. These results suggest that PCP acts at sites located on presynaptic terminals of spinal serotonergic neurons, enhancing 5-HT release and thereby depressing the monosynaptic reflex.

Volume 250, Issue 1, pp. 177-183, 07/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics






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Copyright © 1989 by the American Society for Pharmacology and Experimental Therapeutics.