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Effects of Repeated Administration of Baclofen to Rats on GABAB Receptor Binding Sites and Subunit Expression in the Brain

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Abstract

Repeated stimulation of the GABAB receptor with baclofen frequently produces tolerance, the underlying mechanisms of which are poorly understood. The purpose of the present work was to determine whether repeated administration of baclofen to rats is accompanied by changes in cerebral GABAB receptor binding sites, mRNA for the subunits GABAB(1) and GABAB(2), and protein levels for these subunits. Rats were injected with placebo or baclofen (20 μmmol/kg subcutaneously) once daily for 14 days. Decreases in body temperature were measured as an index of pharmacological effects of baclofen. Binding of radiolabeled GABA to GABAB receptors was quantitated in brain membranes, mRNA levels were determined using quantitative real-time PCR, and GABAB receptor protein levels were assessed with Western blot analysis. Baclofen caused a decline in temperature amounting to approximately 2.5 °C after the first dose. This effect was partly lost after the fifth and abolished after the seventh injection. Despite the complete development of tolerance, there were no significant alterations in GABAB receptor binding sites (number or affinity) or mRNA levels for the subtypes GABAB(1a), GABAB(1b), or GABAB(2). Receptor protein levels were also unchanged. It is concluded that baclofen induces tolerance through mechanisms other than down-regulation of GABAB receptor transcription or translation.

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Authors and Affiliations

  1. Integrative Pharmacology, AstraZeneca R&D Mölndal, Mölndal, Sweden

    Anders Lehmann

  2. Cell Biology and Biochemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden

    Jan P. Mattsson

  3. Molecular Biology, AstraZeneca R&D Mölndal, Mölndal, Sweden

    Anders Edlund, Thore Johansson & A. Jonas Ekstrand

  4. Department of Public Health and Clinical Medicine, Umeå University, S-901 87, Umeå, Sweden

    Anders Edlund

  5. UmanGenomics AB, Umestan, S-903 47, Umeå, Sweden

    Thore Johansson

  6. Department of Biology and Molecular Sciences, Medivir AB, Lunastigen 7, S-141 44, Huddinge, Sweden

    A. Jonas Ekstrand

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  1. Anders Lehmann
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Correspondence to Anders Lehmann.

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Lehmann, A., Mattsson, J.P., Edlund, A. et al. Effects of Repeated Administration of Baclofen to Rats on GABAB Receptor Binding Sites and Subunit Expression in the Brain. Neurochem Res 28, 387–393 (2003). https://doi.org/10.1023/A:1022353923578

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