CONICET | Buscador de Institutos y Recursos Humanos

Schizophrenia is a chronic mental illness affecting nearly 1% of the population. The causes of schizophrenia and the mechanism of action of antipsychotics are unknown. The neurotransmitters glutamate and serotonin both have been the target of considerable attention regarding psychosis and antipsychotic drug development. Thus clozapine and other atypical antipsychotics have high affinity for 5-HT2A receptors (2AR), and metabotropic receptors 2/3 (mGluR2/3) agonists have recently shown efficacy in treating schizophrenia. We have identified a novel functional 2AR/mGluR2 complex that may be responsible for some of the molecular mechanisms responsible for psychosis. Psychotomimetic drugs such as phencyclidine (PCP) and lysergic acid diethylamide (LSD) induce schizophrenia-like psychosis in humans, and represent in mouse a behavioral model of schizophrenia and psychosis. We have previously demonstrated that head-twitch is reliably and robustly elicited by LSD-like drugs, and is absent in 2AR null-mutant mice. Interestingly, the head-twitch response induced by the hallucinogenic 2AR agonist DOI was significantly lower in mGluR2 null-mutant mice. Activation of mGluR2, but not mGluR3, has been found to reduce the behavioral stereotypy and hyperlocomotion produced by PCP-like drugs. We found that the mGluR2 agonist LY379268 failed to abolish the effects on horizontal activity induced by the PCP-like drug MK801. Based on these results, we propose that the psychedelic effects of 2AR agonists, as well as the antipsychotic properties of mGluR2 agonists, may be due, in part, to the signaling crosstalk resulting from their activity at the 2AR/mGluR2 complex in cortical neurons. Supported by: NIH and NARSAD