In situ hybridization histochemistry as a method to assess GABA(A) receptor subunit mRNA expression following chronic alprazolam administration.
Previous work in our laboratory has demonstrated region-specific 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 alpha1 and gamma2 subunits of the GABA(A) receptor. Specific hybridization was clearly demonstrated and alpha1 subunit mRNA expression in frontoparietal cortex (layers II-IV) 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 alpha1 subunit mRNA in the frontoparietal cortex, hippocampus or dentate gyrus. Expression of gamma2 subunit 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-specific. This makes a definitive conclusion regarding benzodiazepines and their interactions with GABA(A) receptors difficult at best.
Fahey
J M
JM
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and the Division of Clinical Pharmacology, New England Medical Center, Boston, MA, USA.
Pritchard
G A
GA
Grassi
J M
JM
Pratt
J S
JS
Shader
R I
RI
Greenblatt
D J
DJ
D000525:Alprazolam / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D015152:Blotting, Northern; D018757:GABA Modulators / Q000494:pharmacology*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015345:Oligonucleotide Probes; D012333:RNA, Messenger / Q000096:biosynthesis*; D011963:Receptors, GABA-A / Q000096:biosynthesis*
D018757:GABA Modulators; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D000525:Alprazolam