Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice

Abstract

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.

Preclinical models of antipsychotic drug action

“…Another approach to determine the therapeutic-like effects of chronic treatment with antipsychotic drugs is based on the use of LSD as a mouse model of psychosis (Gonzalez-Maeso et al, 2008; Kurita et al, 2012; Moreno et al, 2013a, b). Administration of psychedelic 5-HT 2A receptor agonists induces expression of the immediate early genes c-fos, egr-1 and egr-2 in mouse somatosensory cortex (Gonzalez-Maeso et al, 2003,2007; Moreno et al, 2013a, b).…”

“…Administration of psychedelic 5-HT 2A receptor agonists induces expression of the immediate early genes c-fos, egr-1 and egr-2 in mouse somatosensory cortex (Gonzalez-Maeso et al, 2003,2007; Moreno et al, 2013a, b). The authors found that chronic (21 d), but not sub-chronic (2 d), treatment with clozapine eliminates the induction of c-fos, egr-1 and egr-2 by LSD 1 d after the final injection (Moreno et al, 2013b). The induction of c-fos, egr-1 and egr-2 by LSD was not affected with chronic treatment with haloperidol.…”

“…These findings correlate with the effect of chronic clozapine, but not chronic haloperidol, on 5-HT 2A receptor binding in mouse somatosensory cortex. Thus, chronic, but not sub-chronic, treatment with clozapine down-regulated [ 3 H]ketanserin binding, an effect that was not observed after chronic treatment with haloperidol (Moreno et al, 2013b). These findings suggest that down-regulation of 5-HT 2A receptor is one of the mechanisms underlying the therapeutic effects of chronic treatment with antipsychotic drugs.…”

Repressive Epigenetic Changes at themGlu2Promoter in Frontal Cortex of 5-HT2AKnockout Mice

“…In patients with schizophrenia, optimal treatment with antipsychotic drugs requires weeks to months of sustained drug therapy (Agid et al, 2003;Lieberman et al, 2008;Nestler and Hyman, 2010). It has been recently shown that chronic treatment with the atypical antipsychotics clozapine or risperidone, but not with the typical antipsychotic haloperidol, decreases the density of 5-HT 2A receptor in mouse frontal cortex (Gonzalez-Maeso et al, 2008;Kurita et al, 2012;Moreno et al, 2013b). Similar effects of chronic antipsychotic treatment have been reported in postmortem human brain of schizophrenic subjects.…”

Epigenetic Mechanisms of Serotonin Signaling

“…For chronic treatment with typical and atypical antipsychotic drugs in mouse models, it has been demonstrated that chronic treatment with atypical antipsychotics markedly decreases the density of 5-HT 2A receptors in frontal cortex. 82–84 Considering that the density of 5-HT 2A receptors is increased in post-mortem frontal cortex of antipsychotic-free schizophrenic subjects, and reduced to control levels in postmortem frontal cortex of antipsychotic-treated schizophrenic subjects, 84,85 these findings suggest that down-regulation of 5-HT 2A receptor density by chronic atypical antipsychotic treatment may be one of the molecular mechanisms involved in their therapeutic effects (see refs 86 and 87 for review articles discussing the level of expression of 5-HT 2A receptor in the schizophrenia brain). However, it was also demonstrated that this down-regulation of 5-HT 2A receptor density in mouse frontal cortex by chronic treatment with atypical antipsychotic drugs leads to down-regulation of the transcription of mGlu2 , an effect that was associated with repressive histone modifications at the promoter region of the mGlu2 gene in mouse and human frontal cortex.…”