GABA receptor subunit mRNA expression in brain of conflict, yoked control and control rats

Animal conflict models have been used for years as a preclinical screen for predicting anxiolytic therapeutic efficacy. Anxiolytics, including benzodiazepines, increase punished responding. This suggests that the punished behavior may be mediated by the GABA receptor. To evaluate this hypothesis, we performed in situ hybridization histochemistry studies of GABA receptor subunits (α1-α4) and synthetic enzymes glutamic acid decarboxylase (GAD₆₅ and GAD₆₇) in four groups of rats: conflict (punishment), yoked controls (rats shocked without conflict training history), fixed interval only controls (rats that worked for food but were not shocked) and untreated controls. With conflict behavioral training, bilateral reduction of mRNA for the GABA(A) α1 subunit was seen relative to controls in the cortex, thalamus and hippocampus. In contrast, alteration of α2 mRNA levels appeared only in the yoked control group, with increased levels seen in the thalamus and cortex and decreased levels in the hippocampus. There were no differences in the α2 mRNA level between the control and the conflict behavioral trained animals. Further, no significant differences were found between groups in the mRNA levels for the α3 subunit, α4 subunit, GAD₆₅, and GAD₆₇. These results suggest that the behaviors related to conflict and uncontrollable aversive stimuli (yoked control group) are accompanied and perhaps mediated by selective changes in the GABA(A) α1 or α2 subunits, respectively. These findings highlight the potential usefulness of the conflict model as a means of elucidating the biological underpinnings of anxiety disorder.