The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist than dopamine agonist induced hyperactivity in mice

The purpose of the present study was to compare the effectiveness of the se lective 5-HT2A antagonist M100907 in different psychosis models. The classi cal neuroleptic haloperidol was used as reference compound. Two hyperdopami nergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GB R 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M1 00907 was found to counteract the locomotor stimulant effects of the NMDA r eceptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amph etamine- and GBR-12909-induced hyperactivity were not significantly affecte d. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the hi ghest dose used. Based on the present and previous results we draw the conc lusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5- HT2A receptor antagonist, due to i a the low side effect liability, could b e the preferable treatment strategy in various disorders associated with hy poglutamatergia; such conditions might include schizophrenia. childhood aut ism and dementia disorders.