Typical and Atypical Antipsychotic Drugs Increase Extracellular Histamine Levels in the Rat Medial Prefrontal Cortex: Contribution of Histamine H1 Receptor Blockade

Matthew J. Fell,Alexander Nikolayev,Kjell A. Svensson,Kenneth W. Perry,Ming-Shang Kuo,David L. G. Nelson,Jason S. Katner,Kurt Rasmussen

doi:10.3389/fpsyt.2012.00049

Abstract

Atypical antipsychotics such as clozapine and olanzapine have been shown to enhance histamine turnover and this effect has been hypothesized to contribute to their improved therapeutic profile compared to typical antipsychotics. In the present study, we examined the effects of antipsychotic drugs on histamine (HA) efflux in the mPFC of the rat by means of in vivo microdialysis and sought to differentiate the receptor mechanisms which underlie such effects. Olanzapine and clozapine increased mPFC HA efflux in a dose related manner. Increased HA efflux was also observed after quetiapine, chlorpromazine, and perphenazine treatment. We found no effect of the selective 5-HT2A antagonist MDL100907, 5-HT2c antagonist SB242084, or the 5-HT6 antagonist Ro 04-6790 on mPFC HA efflux. HA efflux was increased following treatment with selective H1 receptor antagonists pyrilamine, diphenhydramine, and triprolidine, the H3 receptor antagonist ciproxifan and the mixed 5-HT2A/H1 receptor antagonist ketanserin. The potential novel antipsychotic drug FMPD, which has a lower affinity at H1 receptors than olanzapine, did not affect HA efflux. Similarly, other antipsychotics with lower H1 receptor affinity (risperidone, aripiprazole, and haloperidol) were also without effect on HA efflux. Finally, HA efflux after antipsychotic treatment was significantly correlated with affinity at H1 receptors whereas nine other receptors, including 5-HT2A, were not. These results demonstrate that both typical and atypical antipsychotics increase mPFC histamine efflux and this effect may be mediated via antagonism of histamine H1 receptors.

Highlights

The introduction of typical antipsychotic drugs in the 1950s revolutionized the treatment of schizophrenia, their use has been impeded by a number of side effects such as extrapyramidal symptoms (EPS), tardive dyskinesia, and their failure to adequately treat the negative and cognitive symptoms in schizophrenia
The present study was undertaken to investigate the effects of atypical antipsychotic drugs on histamine release in the medial prefrontal cortex (mPFC) and to determine the role of individual monoamine receptor subtypes in mediating these effects
The major findings of the present study are: (1) clozapine olanzapine, quetiapine (20 mg/kg), perphenazine (3 mg/kg), and chlorpromazine (10 mg/kg) significantly increased mPFC histamine efflux (2) selective antagonism of H1 and H3 receptors but not 5-HT2A, 5-HT2C, or 5-HT6 receptors markedly increased histamine efflux in the mPFC; (3) the potential novel antipsychotic drug FMPD, which has a similar binding profile to that of olanzapine but with lower affinity for H1 receptors, does not increase histamine efflux in the mPFC (4) for the nine antipsychotic drugs examined, affinity at histamine H1 receptors was significantly correlated with histamine efflux in the mPFC, whereas affinity at most other monoaminergic receptors examined, including 5-HT2A, were not

Summary

Introduction

The introduction of typical antipsychotic drugs in the 1950s revolutionized the treatment of schizophrenia, their use has been impeded by a number of side effects such as extrapyramidal symptoms (EPS), tardive dyskinesia, and their failure to adequately treat the negative and cognitive symptoms in schizophrenia. Previous preclinical studies have shown that atypical antipsychotic drugs but not typical antipsychotic drugs such as haloperidol or chlorpromazine, preferentially enhance dopamine (DA), norepinephrine, and acetylcholine efflux in the rat medial prefrontal cortex (mPFC) and hippocampus compared with the nucleus accumbens (Li et al, 1998; Kuroki et al, 1999; Zhang et al, 2000; Assié et al, 2005) These effects have been hypothesized to contribute to the enhanced ability of atypical antipsychotic drugs to improve cognitive function and negative symptoms in patients with schizophrenia (Morisset et al, 1999; Huang et al, 2008)

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Conclusion