Presynaptic activation of the spinal serotonergic system in the rat by phencyclidine in vitro.
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.
Ohno
Y
Y
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore.
Warnick
J E
JE
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012018:Reflex / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D010133:p-Chloroamphetamine / Q000494:pharmacology
D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D010133:p-Chloroamphetamine; D010622:Phencyclidine; D007099:Imipramine