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Leysen JE, Niemegeers CE, Tollenaere JP, Laduron PM.
“Serotonergic component of neuroleptic receptors”.
Nature. 1978;272(5649):168-71.
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Abstract
The serotoninergic component of neuroleptic receptors was studied. Methods Rat striatum or frontal cortex was incubated for 10 min with 3H-spiperone,3H-haloperidol or 3H-LSD. The inhibition of specific binding of these drugs by amine agonists or serotonin antagonists was recorded. Also, rats (240+20 g) pretreated with the drugs had 1.25 mg/kg, i.v. apomorphine, and 40 mg/kg, i.v. tryptamine, t hr later. Results 3H-Spiperone and 3H-LSD binding in the frontal cortex was inhibited more effectively by rnianserin, cinanserin, methysergide, pizatifen and cyproheptadine than by bufotenin, serotonin, LSD, tryptamine, apomorphine, dopamine, and 2-(N,N dipropyl)amino-5,6-dihydroxy tetralin, while in vitro binding of 3H-haloperidol and 3H-spiperone in the striatum was inhibited more effectively by the latter group of drugs than by the former. Also, their efficacy in inhibiting tryptamine seizures correlated with their binding activity in the frontal cortex, and the ratio of their inhibition of 3H-haloperidol binding in the striatum to 3H spiperone binding in the frontal cortex paralleled the ratio of the efficacy of their antagonism of apomorphine stereotypy to that of tryptamine seizures. There was also a highly significant correlation between potency of binding inhibition in the frontal cortex and in vivo inhibition of tryptamine seizures, and between potency of binding inhibition in the striatum and antagonism of apomorphine stereotypy for pipamperone, clozapine, azaperone, chlorprothix ene, clothiapine, chlorpromazine, methithepine, propericiazine, flupenthixol, thior idaz ine, fluspiper one, fluphenazine, droperidol, spiperone, (+)-butaclamol, trifluperidol, benperidol, pimozide, clopimozide, haloperidol, oxiperomide, metoclopramide and sulpiride. In vivo displacement of 3H-spiperone by pipamperone and LSD occurred at low doses (both 0.63 mg/kg) in the frontal cortex but not in brain dopaminergic areas, while labeling in these fatter regions was reduced by high doses of LSD (10 mg/kg) but only significantly after 2 hr. Haloperidol displaced 3H spiperone in both dopaminergic regions and frontal cortex. Conclusions Both serotoninergic and dopaminergic receptors are involved in the mechanism of action of neuroleptic drugs.
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