RODENT DATA AND GENERAL HYPOTHESIS - ANTIPSYCHOTIC ACTION EXERTED THROUGH 5-HT2A RECEPTOR ANTAGONISM IS DEPENDENT ON INCREASED SEROTONERGICTONE

The locomotor stimulation induced by the N-methyl-D-aspartate (NMDA) r eceptor antagonist MK-801 (dizocilpine) in mice was regarded as a mode l of at least some aspects of schizophrenia. The serotonin synthesis i nhibitor dl-p-chlorophenylalanine (PCPA) was used to evaluate the invo lvement of endogenous serotonin in (a) the induction of MK-801-induced hyperlocomotion in NMRI mice, and (b) the inhibition of MK-801-induce d hyperlocomotion by each of five monoaminergic antagonists (M100907, clozapine, olanzapine, raclopride, SCH23390). Further, brain monoamine rgic biochemistry was characterised in rats and mice after various dru g treatments. PCPA pretreatment did not significantly reduce MK-801-in duced hyperlocomotion in any of the experiments performed; however in a metaanalysis of six experiments, the locomotion displayed by MK-801- treated animals was diminished 17% by PCPA pretreatment. The selective 5-HT2A receptor antagonist M100907 exerted a dose-dependent inhibitio n of MK-801-induced hyperlocomotion. This effect was abolished in mice pretreated with PCPA, but could be restored in a dose-dependent manne r by restitution of endogenous 5-HT by means of 5-hydroxytryptophan (5 -HTP). On the other hand, the inhibition of MK-801-induced hyperlocomo tion exerted by the selective dopamine D-2 receptor antagonist raclopr ide or the dopamine D-1 receptor antagonist SCH23390 was unaffected by PCPA pretreatment. The antipsychotics clozapine and olanzapine displa yed a split profile. Hence, the inhibitory effect on MK-801-induced hy perlocomotion exerted by low doses of these compounds was diminished a fter PCPA pretreatment, while inhibition exerted by higher doses was u naffected by PCPA. These results suggest that (1) MK-801-induced hyper locomotion is accompanied by an activation of, but is not fully depend ent upon, brain serotonergic systems. (2) In the hypoglutamatergic sta te induced by MK-801, endogenous serotonin exerts a stimulatory effect on locomotion through an action at 5-HT2A receptors, an effect that i s almost completely counterbalanced by a concomitant inhibitory impact on locomotion, mediated through stimulation of serotonin receptors ot her than 5-HT2A receptors. M100907, by blocking 5-HT2A receptors, unve ils the inhibitory effect exerted on locomotion by these other seroton in receptors. (3) Dopamine D-2 receptor antagonistic properties of ant ipsychotic compounds, when they come into play, override 5-HT2A recept or antagonism. Possible implications for the treatment of schizophreni a with 5-HT2A receptor antagonists are discussed. It is hypothesized t hat treatment response to such agents is dependent on increased seroto nergic tone.