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In situ hybridization histochemistry as a method to assess GABAAreceptor subunit mRNA expression following chronic alprazolam administration

Gary A. Pritchard

Jeffrey M. Grassi

John S. Pratt

Richard I. Shader

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and the Division of Clinical Pharmacology, New England Medical Center, Boston, MA, USA

David J. Greenblatt

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and the Division of Clinical Pharmacology, New England Medical Center, Boston, MA, USA; DGreenblatt{at}Infonet.tufts.edu

Previous work in our laboratory has demonstrated region-specic effects for chronic alprazolam on binding and function at the GABA_A receptor. The present study evaluated regional changes in mRNA expression of several subunits of the GABA_A receptor following chronic alprazolam administration that might underlie these effects. Mice received alprazolam (2 mg/kg/day) or vehicle via subcutaneously implanted osmotic pumps for 1, 7, 14 or 28 days. In situ hybridization histochemistry was performed on tissue sections using [³⁵S]dATP oligonucleotide probes corresponding to the a₁ and g₂ subunits of the GABA_A receptor. Specic hybridization was clearly demonstrated and a₁ subunit mRNA expression in frontoparietal cortex (layers IIIV) on day 1 of infusion was reduced in animals receiving alprazolam compared to vehicle. On subsequent days, there were no alterations in the levels of a₁ subunit mRNA in the frontoparietal cortex, hippocampus or dentate gyrus. Expression of g₂subunit mRNA was increased on day 1 in the frontoparietal cortex (layer VI), hippocampus and dentate gyrus. mRNA expression was also increased in the dentate gyrus on day 28 of infusion. Comparison of the present study with the results of chronic treatment with other benzodiazepines clearly demonstrates that the pattern of mRNA subunit alterations obtained is both treatment- and region-specic. This makes a de¢nitive conclusion regarding benzodiazepines and their interactions with GABA_A receptors di¤cult at best.

Key Words: alprazolam • benzodiazepine • GABA • in situ hybridization histochemistry • mRNA

Journal of Psychopharmacology, Vol. 13, No. 3, 211-218 (1999)
DOI: 10.1177/026988119901300301


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