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Differential region-specific regulation of central α1-adrenoceptor binding following chronic haloperidol and clozapine administration in the rat

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Abstract

Rationale

Many antipsychotics exhibit potent anti-α1-adrenergic receptor activity, which has been suggested to contribute to typical and atypical antipsychotic effects and to the production of centrally mediated side effects.

Objectives

To assess the relative contribution of α1-adrenoceptors to the mechanism of action of haloperidol and clozapine and to identify possible sites of action.

Methods

We examined the effect of chronic haloperidol and clozapine treatment on α1-adrenoceptor characteristics in several rat brain regions. For comparison, D2-like dopamine receptor density in the striatum was also determined.

Results

Clozapine administration (25 mg/kg/day i.p., 21 days) significantly increased α1-adrenoceptor density in the frontal cortex (44%), remaining cortex (49%) and thalamus (93%) but binding levels in the hippocampus and spinal cord were unchanged relative to vehicle. Haloperidol treatment (1.5 mg/kg/day i.p., 21 days) also significantly increased the density of α1-adrenoceptor binding in the thalamus (73%), but had no effect on α1-adrenoceptor levels in any other region examined. α1-Adrenoceptor affinity in the cortex was not significantly altered by either antipsychotic treatment. Haloperidol, in contrast to clozapine, significantly upregulated dopamine D2-like binding in the striatum.

Conclusions

Central α1-adrenoceptors are differentially regulated after chronic haloperidol and clozapine treatment. It is suggested that thalamic α1-adrenoceptors may represent a common anatomical locus contributing to the antipsychotic activity and/or α1-adrenoceptor centrally mediated side effects of both drugs, whereas the selective upregulation of cortical α1-adrenoceptor density by clozapine may contribute, in part, to its superior atypical properties.

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Acknowledgements

We thank Novartis for the generous gift of clozapine and Professor Brian Leonard for helpful discussions. T.D.W. Mawhinney was sponsored by a grant from PPP Healthcare.

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Authors and Affiliations

  1. Department of Therapeutics and Pharmacology, Queen’s University of Belfast, Whitla Medical Building, 97 Lisburn Road, BT9 7BL, Belfast, Northern Ireland

    Marie Cahir, Tim Mawhinney & David J. King

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  1. Marie Cahir
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  2. Tim Mawhinney
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  3. David J. King
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Correspondence to Marie Cahir.

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Cahir, M., Mawhinney, T. & King, D.J. Differential region-specific regulation of central α1-adrenoceptor binding following chronic haloperidol and clozapine administration in the rat. Psychopharmacology 172, 196–201 (2004). https://doi.org/10.1007/s00213-003-1639-z

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  • DOI: https://doi.org/10.1007/s00213-003-1639-z

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