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GABAA receptor subunit mRNA levels are differentially influenced by chronic FG 7142 and diazepam exposure
1Department of Psychiatry, Yale University, New Haven, CT 06508.
Abstract:
Levels of mRNA for the alpha 1, gamma 2 and beta 1 subunits of the GABAA receptor complex were examined in rats maintained on a chronic, continuous schedule of exposure to the benzodiazepine inverse agonist FG 7142. The effect of chronic exposure to the benzodiazepine agonist diazepam was also examined on levels of gamma 2 subunit mRNA. FG 7142 (2 mg/ml of 100% dimethyl sulfoxide (DMSO) or vehicle (100% DMSO) was administered continuously for 8 days in the right ventricle via an osmotic minipump. At the end of the eighth day of exposure, the brain was removed and cerebral cortex, cerebellum and hippocampus were dissected and mRNA prepared from each region. Levels of GABAA alpha 1 and gamma 2 subunit mRNA were examined by Northern blot analysis with cDNA probes specific for these subunits. A significant increase in alpha 1 mRNA was measured in both cortex and hippocampus, but not in cerebellum, of rats chronically exposed to FG 7142 relative to vehicle-treated rats. A significant increase in gamma 2 subunit mRNA in cortex was also evident in drug-treated rats; however, no change in gamma 2 subunit mRNA was observed in either the hippocampus or cerebellum. Examination of GABAA beta 1 subunit mRNA by solution hybridization using a beta 1 riboprobe revealed no effect of chronic FG 7142 treatment on this subunit in either cortex, hippocampus or cerebellum. In rats chronically exposed to diazepam (21 days via silastic implants), levels of gamma 2 subunit mRNA were significantly decreased in cortex, but not changed in either hippocampus or cerebellum.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Chronic exposure to FG 7142 increased GABAA receptor alpha 1 and gamma 2 subunit mRNA in rat brains. Diazepam, however, decreased gamma 2 subunit mRNA in the cortex.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- The GABAA receptor is a key inhibitory neurotransmitter receptor in the brain.
- Benzodiazepines modulate GABAA receptor activity, affecting neuronal excitability.
- Understanding how different benzodiazepine ligands alter GABAA receptor subunit expression is crucial for neuroscience research.
Purpose of the Study:
- To investigate the effects of chronic FG 7142, a benzodiazepine inverse agonist, on GABAA receptor subunit mRNA levels in specific rat brain regions.
- To examine the impact of chronic diazepam, a benzodiazepine agonist, on GABAA receptor gamma 2 subunit mRNA expression.
Main Methods:
- Rats received continuous administration of FG 7142 or vehicle via osmotic minipumps for 8 days.
- Brain regions (cortex, cerebellum, hippocampus) were dissected, and mRNA was extracted.
- Northern blot analysis and solution hybridization were used to quantify GABAA receptor alpha 1, gamma 2, and beta 1 subunit mRNA levels.
Main Results:
- FG 7142 treatment significantly increased alpha 1 mRNA in the cortex and hippocampus, but not cerebellum.
- FG 7142 also significantly increased gamma 2 subunit mRNA in the cortex, with no changes in hippocampus or cerebellum.
- No significant effects of FG 7142 were observed on beta 1 subunit mRNA in any brain region.
- Chronic diazepam administration led to a significant decrease in gamma 2 subunit mRNA in the cortex, but not hippocampus or cerebellum.
Conclusions:
- Chronic administration of the GABAA receptor inverse agonist FG 7142 upregulates specific GABAA receptor subunit mRNAs in a region-dependent manner.
- The benzodiazepine agonist diazepam downregulates gamma 2 subunit mRNA in the cortex.
- These findings highlight differential regulation of GABAA receptor subunits by agonists and inverse agonists, with implications for understanding benzodiazepine pharmacology.