WAY 100135, an Antagonist of 5-HT1A Serotonin Receptors, Attenuates Psychotomimetic Effects of MK-801

Abstract

Non-competitive antagonists of NMDA receptors such as phencyclidine (PCP) or ketamine are known for their strong, frequently neuroleptic-resistant psychotomimetic effects in humans (Javitt and Zukin 1991). These clinical effects, as well as evidence suggesting the involvement of NMDA receptors in the pathophysiology of schizophrenia (Carlsson et al. 1999;Harrison 1999;Wachtel and Turski 1990), support the experimental modeling of psychoses by administration of non-competitive NMDA receptor antagonists (Jentsch and Roth 1999). In this respect, MK-801 seems to be of special interest in experimental pharmacology. It belongs to a class of non-competitive NMDA receptor antagonists (Seeburg 1993;Lodge and Johnson 1990; Willetts et al. 1990) and MK-801 seems to be highly specific to the PCP binding site located in the ion channel of the NMDA receptor complex (Lodge and Johnson 1990;Seeburg 1993 (Carlsson 1993;Maj et al. 1991), impairment of sensorimotor gating (Mansbach and Geyer 1989; W dzony et al. 1994), and detrimental effects on spatial working memory (Verma and Moghaddam 1996). Although it is generally agreed that the psychostimulant and psychotomimetic effects of PCP, ketamine, and MK-801 are initiated by blockade of the NMDA receptor ion channel complex, the neuronal pathways or neurotransmitter systems involved in the propagation of the psychotomimetic effects are not precisely known (Bakshi and Geyer 1998). Moreover, the apparent lack of chemical compounds which might directly abolish the pharmacological blockade of these NMDA receptors (Lodge and Johnson 1990; Willetts et al. 1990), and prevent impairments of their function during the course of schizophrenia (Harrison 1999) justifies attempts to define neuroanatomical/neurochemical systems responsible for the propagation of the effects of non-competitive NMDA receptors.Apart from the dopaminergic system (Jentsch and Roth 1999), traditionally linked with psychotomimetic effects of non-competitive antagonists of NMDA receptors, and the noradrenergic system [currently under investigation (Bakshi and Geyer 1998, 1999;Jentsch et al. 1998)], considerable interest has been focused on serotonin and its receptors (Geyer 1998). It has been shown, for example, that MK-801 increases serotonin release (Whitton et al. 1992) and influences serotonin turnover (Loscher et al. 1991;W dzony et al. 1997). Moreover, the psychostimulant and psychotomimetic effects of MK-801 and PCP are attenuated by specific antagonists of 5-HT2A receptors (Schmidt and Fadayel 1996;Varty et al. 1999;Varty and Higgins 1995).Apart from 5-HT2A receptors, a growing number of studies indicate that MK-801 may also influence other serotonin receptors; for example, it increases mRNA of 5-HT6 and 5-HT7 receptors (Healy and Meador-Woodruff 1999). Moreover, the increased density of 5-HT1A receptors after a single administration of MK-801 has been reported in one of our recent studies (W dzony et al. 1997). The possible involvement of 5-HT1A receptors in the psychotomimetic effects of NMDA receptor antagon...

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Modulation of anxiety through blockade of anandamide hydrolysis

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