Identification of a serotonin/glutamate receptor complex implicated in psychosis

Identification of a serotonin/glutamate receptor complex implicated in psychosis

The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception1, 2. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR)3, 4. Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia5, 6, 7. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR8, 9, 10 and resemble some of the core symptoms of schizophrenia10, 11, 12. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR–mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR–mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.

Letter
Nature 452, 93-97 (6 March 2008) | doi:10.1038/nature06612; Received 2 November 2007; Accepted 20 December 2007; Published online 24 February 2008