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Titolo:
RODENT DATA AND GENERAL HYPOTHESIS - ANTIPSYCHOTIC ACTION EXERTED THROUGH 5-HT2A RECEPTOR ANTAGONISM IS DEPENDENT ON INCREASED SEROTONERGICTONE
Autore:
MARTIN P; WATERS N; SCHMIDT CJ; CARLSSON A; CARLSSON ML;
Indirizzi:
GOTHENBURG UNIV,DEPT PHARMACOL,BOX 431 SE-40530 GOTHENBURG SWEDEN HOECHST MAR ROUSSEL INC BRIDGEWATER NJ 00000
Titolo Testata:
Journal of neural transmission
fascicolo: 4-5, volume: 105, anno: 1998,
pagine: 365 - 396
SICI:
0300-9564(1998)105:4-5<365:RDAGH->2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
NONCOMPETITIVE NMDA ANTAGONIST; D-ASPARTATE ANTAGONIST; RAT-BRAIN; REUPTAKE INHIBITORS; CLOZAPINE TREATMENT; DOPAMINE RELEASE; EXTRAPYRAMIDAL SYMPTOMS; SCHIZOPHRENIC-PATIENTS; LOCOMOTOR STIMULATION; BASAL GANGLIA;
Keywords:
MDL100907; M100907; MK-801; LOCOMOTION; SCHIZOPHRENIA; SEROTONIN; MOUSE; PSYCHOSIS; MONOAMINERGIC BIOCHEMISTRY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
117
Recensione:
Indirizzi per estratti:
Citazione:
P. Martin et al., "RODENT DATA AND GENERAL HYPOTHESIS - ANTIPSYCHOTIC ACTION EXERTED THROUGH 5-HT2A RECEPTOR ANTAGONISM IS DEPENDENT ON INCREASED SEROTONERGICTONE", Journal of neural transmission, 105(4-5), 1998, pp. 365-396

Abstract

The locomotor stimulation induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) in mice was regarded as a model of at least some aspects of schizophrenia. The serotonin synthesis inhibitor dl-p-chlorophenylalanine (PCPA) was used to evaluate the involvement of endogenous serotonin in (a) the induction of MK-801-induced hyperlocomotion in NMRI mice, and (b) the inhibition of MK-801-induced hyperlocomotion by each of five monoaminergic antagonists (M100907,clozapine, olanzapine, raclopride, SCH23390). Further, brain monoaminergic biochemistry was characterised in rats and mice after various drug treatments. PCPA pretreatment did not significantly reduce MK-801-induced hyperlocomotion in any of the experiments performed; however ina 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 inhibition of MK-801-induced hyperlocomotion. This effect was abolished in mice pretreated with PCPA, but could be restored in a dose-dependent manner by restitution of endogenous 5-HT by means of 5-hydroxytryptophan (5-HTP). On the other hand, the inhibition of MK-801-induced hyperlocomotion exerted by the selective dopamine D-2 receptor antagonist raclopride or the dopamine D-1 receptor antagonist SCH23390 was unaffected by PCPA pretreatment. The antipsychotics clozapine and olanzapine displayed a split profile. Hence, the inhibitory effect on MK-801-induced hyperlocomotion exerted by low doses of these compounds was diminished after PCPA pretreatment, while inhibition exerted by higher doses was unaffected by PCPA. These results suggest that (1) MK-801-induced hyperlocomotion is accompanied by an activation of, but is not fully dependent upon, brain serotonergic systems. (2) In the hypoglutamatergic state induced by MK-801, endogenous serotonin exerts a stimulatory effect on locomotion through an action at 5-HT2A receptors, an effect that is almost completely counterbalanced by a concomitant inhibitory impact on locomotion, mediated through stimulation of serotonin receptors other than 5-HT2A receptors. M100907, by blocking 5-HT2A receptors, unveils the inhibitory effect exerted on locomotion by these other serotonin receptors. (3) Dopamine D-2 receptor antagonistic properties of antipsychotic compounds, when they come into play, override 5-HT2A receptor antagonism. Possible implications for the treatment of schizophrenia with 5-HT2A receptor antagonists are discussed. It is hypothesized that treatment response to such agents is dependent on increased serotonergic tone.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 21:44:07