Identification of a serotonin/glutamate receptor complex implicated in psychosis

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Abstract
New-generation antipsychotic drugs such as olanzapine and risperidone act by blocking neurotransmission by serotonin 2AR receptors; hallucinogens such as LSD also act via these receptors. And drugs that mimic the excitatory neurotransmitter glutamate at its mGluR2 receptor are also powerful antipsychotics. These and other lines of evidence suggest that the serotonin and glutamate neurotransmitter systems function abnormally in the brain in schizophrenia. This would seem to be confirmed with the surprising discovery of a functional complex containing the serotonin 2AR and mGluR2 receptors that is involved in the unique effects of chemical hallucinogens in cultured cells and mice. The balance of these two receptors is disrupted in the brains of schizophrenic subjects, further implicating this complex as a promising potential target for the treatment of psychosis. Metabotropic glutamate receptors (downregulated in untreated schizophrenics) interact with the serotonin 2A receptor to form a functional complex in the brain; this complex triggers unique responses when activated by hallucinogenic drugs, and may represent a new target for the treatment of 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.