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d-Amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice

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Abstract

Rationale

We have earlier found that 1) COMT inhibitors did not enhance amphetamine-induced dopamine efflux into striatal extracellular, that 2) they did not increase dopamine levels in striatal tissue and that 3) they did not potentiate amphetamine-induced turning behavior of hemiparkinsonian rats. Further, when COMT knockout mice were challenged with l-dopa or a dopamine transporter (DAT) inhibitor, an accumulation of dopamine occurred and the neurochemical and locomotor effects of l-dopa and GBR 12909 were modified accordingly.

Objective

Since DAT inhibitors and amphetamine apparently have different mechanisms of action, we were interested to see how COMT knockout mice would react to d-amphetamine treatment.

Methods

We measured the effects of d-amphetamine on locomotor activity and on the levels of catecholamines and their metabolites in striatal microdialysis fluid and in striatal, hypothalamic and cortical brain regions of COMT gene disrupted mice. Striatal dopamine receptor binding was also determined.

Results

After d-amphetamine administration, the DOPAC content in homozygous mice was 3-fold in the striatum, 17- to 18-fold in the cortex and 7- to 8-fold in the hypothalamus higher than in wild-type control mice, and there were no indications of genotype×sex interactions. However, the lack of COMT did not potentiate d-amphetamine-induced dopamine levels in brain tissue or in striatal extracellular fluid. d-Amphetamine-induced (10 mg/kg) hyperlocomotion was less suppressed in male COMT knockout mice than in their wild-type counterparts. Striatal dopamine D1 and D2 receptor levels in male mice were not altered by COMT gene disruption.

Conclusions

Changes in COMT activity modulates dopamine metabolism but the behavioral effects of d-amphetamine in male mice only to a small extent, and this action does not seem to depend on the actual extracellular dopamine concentration. Nor is it mediated through compensatory changes in dopamine D1 and D2 receptor levels. In dopaminergic neurons, the contribution of intracellular COMT remains secondary in conditions when dopamine is released by d-amphetamine.

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Acknowledgements

The skilful technical assistance of Pirjo Hänninen and Kati Puputti is gratefully acknowledged. We are grateful to Dr Ewen MacDonald for linguistic advice. Support for this work was provided in part by Academy of Finland (no. 50324), The National Technology Agency (TEKES, no. 40160/99), the Whitehall Foundation (M.K.) and the Patterson Trust (M.K.).

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Authors and Affiliations

  1. University of Kuopio, Department of Pharmacology and Toxicology, PO Box 1627, 70211, Kuopio, Finland

    Marko Huotari, J. Arturo García-Horsman & Pekka T. Männistö

  2. Laboratory of Human Neurogenetics, The Rockefeller University, New York, NY 10021, USA

    Maria Karayiorgou

  3. Department of Physiology and Cellular Biophysics and Center for Neurobiology and Behaviour, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA

    Joseph A. Gogos

Authors
  1. Marko Huotari
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  2. J. Arturo García-Horsman
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  3. Maria Karayiorgou
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  4. Joseph A. Gogos
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  5. Pekka T. Männistö
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Correspondence to Pekka T. Männistö.

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Huotari, M., García-Horsman, J.A., Karayiorgou, M. et al. d-Amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice. Psychopharmacology 172, 1–10 (2004). https://doi.org/10.1007/s00213-003-1627-3

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  • DOI: https://doi.org/10.1007/s00213-003-1627-3

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