|Ten years ago, the rediscovery of the atypical antipsychotic drug clozapine represented a breakthrough for the treatment of schizophrenia. Clozapine, among several other actions, potently antagonises serotonin (5-HT)2 receptors, and thus, it has been suggested that a truly selective 5-HT2 receptor antagonist may exert antipsychotic efficacy on its own. However, ritanserin, a selective 5-HT2 receptor antagonist, appeared active mainly against the negative (and depressive) symptoms of schizophrenia, with less effect on the positive symptom cluster. Clozapine and ritanserin block all three 5-HT2 receptor subtypes, ie the 5-HT2A, 5-HT2B and 5-HT2C receptors; the relative contribution to the therapeutic effect of antagonism at each subtype is not well-known. To address this issue we studied M100907, the first highly selective and potent antagonist at 5-HT2A receptors, in a hypoglutamatergia rodent model of schizophrenia. Based on the prevailing hypothesis that a glutamatergic deficiency is involved in the pathophysiology of schizophrenia, mice or rats were rendered hypoglutamatergic by means of acute systemic injections of MK-801, an un-competitive antagonist of the glutamatergic NMDA receptor. We argue that the hyperlocomotion induced by MK-801 is related to positive symptoms/acute episodes of schizophrenia. Effects on spontaneous locomotion of drug-naive rodents were measured to detect non-specific interactions with locomotor activity. Postmortem brain tissue or perfusates from in vivo microdialysis were analysed for monoamine levels. M100907 potently abolished MK-801-induced hyperlocomotion with no or minor reductions of spontaneous locomotion. Although ritanserin and M100907 have equal in vitro and in vivo potencies as 5-HT2A receptor antagonists, ritanserin displayed a 100-fold lower potency with regard to inhibition of MK-801-induced hyperlocomotion. This enigma was resolved by experiments where ritanserin was found to markedly counteract M100907 s inhibitory effect on MK-801-treated hyperlocomotion. This effect of ritanserin was probably mediated by antagonism at 5-HT2B/C receptors since similar, albeit weaker, effects were obtained with the selective 5-HT2B/C receptor antagonist SB206553. Further, in rats, spontaneous locomotion was significantly enhanced by ritanserin, accompanied by elevations in 3-MT in the striatum and limbic regions. MK-801 increased brain serotonin metabolism in rats and mice, and the levels of cortical 5-HIAA in MK-801-treated mice were positively correlated to locomotor activity. However, neurochemically verified depletion of serotonin by means of pretreatment with the 5-HT synthesis inhibitor PCPA, did only reduce MK-801 induced hyperlocomotion slightly (on average 17 %). At the same time, the inhibitory effect of M100907 (as well as low doses of clozapine or olanzapine) on MK-801-induced hyperlocomotion was abolished by PCPA pretreatment; the effect of M100907 was reinstated by acute administration of the 5-HT precursor 5-HTP or the 5-HT2A/B/C receptor agonist DOI. Taken together, the data suggest that endogenous 5-HT exerts a dual action on psychotic-like behaviour, ie promotes locomotion through stimulation of 5-HT2A receptors, and reduces locomotion through stimulation of other 5-HT (possibly 5-HT2C) receptors. Further, the antipsychotic-like effect of 5-HT2A receptor antagonists is dependent on increased serotonergic tone. Possible implications for the treatment of schizophrenia are discussed.