SUMMARY G protein-coupled receptors form hetero-dimers and higher order hetero-oligomers, yet the significance of receptor heteromerization in cellular and behavioral responses is poorly understood. Atypical antipsychotic drugs, such as clozapine and risperidone all have in common a high affinity for the serotonin 5-HT2A receptor (2AR). However, closely related nonantipsychotic drugs, such as ritanserin and methysergide, while blocking 2AR function, lack comparable neuropsychological effects. Why some but not all drugs that inhibit 2AR-dependent signaling exhibit antipsychotic properties remains unresolved. We found that a heteromeric complex formed between the metabotropic glutamate 2 receptor (mGluR2) and the 2AR critically integrates the action of drugs affecting signaling and behavioral outcomes. Acting through the mGluR2/2AR heterocomplex, both glutamatergic and serotonergic drugs achieve a balance between Gi- and Gq-dependent signaling that predicts their psychoactive behavioral effects. These observations provide a novel mechanistic insight into antipsychotic action that may advance therapeutic strategies for schizophrenia.

Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we show that chronic atypical antipsychotics down-regulate the expression of mGlu2, an effect that is associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurs in concert with a 5-HT2A receptor-dependent up-regulation and increased binding of HDAC2 to the mGlu2 promoter. Viral-mediated over-expression of HDAC2 in frontal cortex decreases mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevent the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augment their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target to improve schizophrenia treatment.

Background:The 5-HT 2A ⅐mGlu2 receptor heterocomplex is involved in psychosis.

It has been suggested that severe adverse life events during pregnancy increase the risk of schizophrenia in the offspring. The serotonin 5-HT2A and the metabotropic glutamate 2 (mGlu2) receptors both have been the target of considerable attention regarding schizophrenia and antipsychotic drug development. We tested the effects of maternal variable stress during pregnancy on expression and behavioral function of these two receptors in mice. Prenatal stress increased 5-HT2A and decreased mGlu2 expression in frontal cortex, a brain region involved in perception, cognition and mood. This pattern of expression of 5-HT2A and mGlu2 receptors was consistent with behavioral alterations, including increased head-twitch response to the hallucinogenic 5-HT2A agonist DOI, and decreased mGlu2-dependent antipsychotic-like effect of the mGlu2/3 agonist LY379268 in adult, but not prepubertal, mice born to stressed mothers during pregnancy. Cross-fostering studies determined that these alterations were not due to effects of prenatal stress on maternal care. Additionally, a similar pattern of biochemical and behavioral changes were observed in mice born to mothers injected with poly-(I:C) during pregnancy as a model of prenatal immune activation. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for schizophrenia and other psychiatric disorders.

Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT2A receptor (5-HT2AR) binding associated with the pathophysiology of schizophrenia. These studies were performed with ligands, such as ketanserin, altanserin and LSD, that may bind with high-affinity to different structural or functional conformations of the 5-HT2AR. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT2AR density by radioligand binding assays in postmortem prefrontal cortex of antipsychotic-free (n=29) and antipsychotic-treated (n=16) schizophrenics, suicide victims with other psychiatric diagnoses (n=13), and individually matched controls. [3H]Ketanserin binding, and its displacement by altanserin or the LSD-like agonist DOI, was assayed. Results indicate that the number of [3H]ketanserin binding sites to the 5-HT2AR was increased in antipsychotic-free (128±11%), but not in antipsychotic-treated (92±12%), schizophrenic subjects. In suicide victims, [3H]ketanserin binding did not differ as compared to controls. Aging correlated negatively with [3H]ketanserin binding in schizophrenia, suicide victims and controls. The fraction of high-affinity sites of DOI displacing [3H]ketanserin binding to the 5-HT2AR was increased in antipsychotic-free schizophrenic subjects. Functional uncoupling of heterotrimeric G proteins led to increased fraction of high-affinity sites of altanserin displacing [3H]ketanserin binding to the 5-HT2AR in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT2AR is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained.

Rationale In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity. Objective This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT2A receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis. Method Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [3H]Ketanserin binding and 5-HT2A mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT2A agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed. Results Head-twitch response was decreased and [3H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT2A mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day). Conclusion Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT2A receptor as a potential mechanism involved in these persistent therapeutic-like effects.

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