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

ABSTRACT: 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-HT_2A 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.

SUBMITTER: de la Fuente Revenga M

PROVIDER: S-EPMC6300555 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

de la Fuente Revenga Mario M Ibi Daisuke D Cuddy Travis T Toneatti Rudy R Kurita Mitsumasa M Ijaz Maryum K MK Miles Michael F MF Wolstenholme Jennifer T JT González-Maeso Javier J

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20180707 2

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 reperc ...[more]

PMID: 30038413

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Project description:Although clozapine treatment is often discontinued due to limited efficacy or low tolerability, there is a lack of guidelines and evidence on treatment options after discontinuation of clozapine in patients with schizophrenia. Persistence has proven to be an adequate indicator for treatment effectiveness in patients with schizophrenia. The aim of this study was, therefore, to compare persistence of antipsychotic use between antipsychotic treatment options in patients after stopping clozapine treatment. Registry data from a prescription database representative of the Dutch population (1996-2017) was collected to investigate persistence in patients with schizophrenia who had been using clozapine for ? 90 days. Persistence with antipsychotics after clozapine discontinuation was analyzed using Cox-proportional hazard regression models. Our study population consisted of 321 participants, of whom 138 re-initiated clozapine and 183 started some other antipsychotic in the year after clozapine discontinuation (N = 518 antipsychotic use periods, N = 9,178 months). Second-generation antipsychotics (SGAs) as a group were associated with better persistence compared to first-generation antipsychotics (adjusted hazard ratio (aHR), 0.73; 95% confidence interval (CI) 0.57-0.93; P = 0.011). Compared with other antipsychotics, the following oral monotherapy antipsychotics were associated with significantly better persistence: restarting clozapine (aHR 0.48; 95% CI 0.32-0.71; P < 0.001) and switching to risperidone (aHR 0.52; 95% CI 0.32-0.84; P = 0.008) or olanzapine (aHR 0.55; 95% CI 0.35-0.87; P = 0.010). Sensitivity analyses confirmed the results. In conclusion, oral SGAs are associated with better persistence than alternative antipsychotic treatment options in patients discontinuing clozapine for undefined reasons. Especially clozapine (except in those with previous serious adverse reactions to clozapine), olanzapine and risperidone should be considered as oral monotherapy for these patients.

Project description:G-protein-coupled receptor (GPCR) agonists are known to induce both cellular adaptations resulting in tolerance to therapeutic effects and withdrawal symptoms upon treatment discontinuation. Glutamate neurotransmission is an integral part of sleep-wake mechanisms, which processes have translational relevance for central activity and target engagement. Here, we investigated the efficacy and tolerance potential of the metabotropic glutamate receptors (mGluR2/3) agonist LY354740 versus mGluR2 positive allosteric modulator (PAM) JNJ-42153605 on sleep-wake organisation in rats. In vitro, the selectivity and potency of JNJ-42153605 were characterized. In vivo, effects on sleep measures were investigated in rats after once daily oral repeated treatment for 7 days, withdrawal and consecutive re-administration of LY354740 (1-10 mg/kg) and JNJ-42153605 (3-30 mg/kg). JNJ-42153605 showed high affinity, potency and selectivity at mGluR2. Binding site analyses and knowledge-based docking confirmed the specificity of JNJ-42153605 at the mGluR2 allosteric binding site. Acute LY354740 and JNJ-42153605 dose-dependently decreased rapid eye movement (REM) sleep time and prolonged its onset latency. Sub chronic effects of LY354740 on REM sleep measures disappeared from day 3 onwards, whereas those of JNJ-42153605 were maintained after repeated exposure. LY354740 attenuated REM sleep homeostatic recovery, while this was preserved after JNJ-42153605 administration. JNJ-42153605 enhanced sleep continuity and efficiency, suggesting its potential as an add-on medication for impaired sleep quality during early stages of treatment. Abrupt cessation of JNJ-42153605 did not induce withdrawal phenomena and sleep disturbances, while the initial drug effect was fully reinstated after re-administration. Collectively, long-term treatment with JNJ-42153605 did not induce tolerance phenomena to its primary functional effects on sleep measures, nor adverse effects at withdrawal, while it promoted homeostatic recovery sleep. From the translational perspective, the present rodent findings suggest that mGluR2 positive allosteric modulation has therapeutic potential based on its superior long term efficacy over agonists in psychiatric disorders, particularly of those commonly occurring with REM sleep overdrive.

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

Publications

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

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