Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity.

January 1, 2019

de la Fuente Revenga M, Ibi D, Cuddy T, Toneatti R, Kurita M, Ijaz MK, Miles MF, Wolstenholme JT, González-Maeso J.
Neuropsychopharmacology. 2019 Jan;44(2):443-454. doi: 10.1038/s41386-018-0143-4. Epub 2018 Jul 7. PMCID: PMC6300555

Preclinical findings in rodent models pointed toward activation of metabotropic glutamate 2/3 (mGlu2/3) receptors as a new pharmacological approach to treat psychosis. However, more recent studies failed to show clinical efficacy of mGlu2/3 receptor agonism in schizophrenia patients. We previously proposed that long-term antipsychotic medication restricted the therapeutic effects of these glutamatergic agents. However, little is known about the molecular mechanism underlying the potential repercussion of previous antipsychotic exposure on the therapeutic performance of mGlu2/3 receptor agonists. Here we show that this maladaptive effect of antipsychotic treatment is mediated mostly via histone deacetylase 2 (HDAC2). Chronic treatment with the antipsychotic clozapine led to  a decrease in mouse frontal cortex mGlu2 mRNA, an effect that required expression of both HDAC2 and the serotonin 5-HT2A receptor. This transcriptional alteration  occurred in association with HDAC2-dependent repressive histone modifications at  the mGlu2 promoter. We found that chronic clozapine treatment decreased via HDAC2 the capabilities of the mGlu2/3 receptor agonist LY379268 to activate G-proteins  in the frontal cortex of mice. Chronic clozapine treatment blunted the antipsychotic-related behavioral effects of LY379268, an effect that was not observed in HDAC2 knockout mice. More importantly, co-administration of the class I and II HDAC inhibitor SAHA (vorinostat) preserved the antipsychotic profile of  LY379268 and frontal cortex mGlu2/3 receptor density in wild-type mice. These findings raise concerns on the design of previous clinical studies with mGlu2/3 agonists, providing the rationale for the development of HDAC2 inhibitors as a new epigenetic-based approach to improve the currently limited response to treatment with glutamatergic antipsychotics.