GABA RECEPTOR SUBUNIT MESSENGER-RNA EXPRESSION IN BRAIN OF CONFLICT, YOKED CONTROL AND CONTROL RATS

Animal conflict models have been used for years as a preclinical scree n for predicting anxiolytic therapeutic efficacy. Anxiolytics, includi ng benzodiazepines, increase punished responding. This suggests that t he punished behavior may be mediated by the GABA receptor. To evaluate this hypothesis, we performed in situ hybridization histochemistry st udies of GABA receptor subunits (alpha 1-alpha 4) and synthetic enzyme s glutamic acid decarboxylase (GAD(65) and GAD(67)) in four groups of rats: conflict (punishment), yoked controls (rats shocked without conf lict 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) alpha 1 subunit was seen relative to controls in the cortex, thalamus and h ippocampus. In contrast, alteration of alpha 2 mRNA levels appeared on ly in the yoked control group, with increased levels seen in the thala mus and cortex and decreased levels in the hippocampus. There were no differences in the alpha 2 mRNA level between the control and the conf lict behavioral trained animals. Further, no significant differences w ere found between groups in the mRNA levels for the alpha 3 subunit, a lpha 4 subunit, GAD(65), and GAD(67). These results suggest that the b ehaviors related to conflict and uncontrollable aversive stimuli (yoke d control group) are accompanied and perhaps mediated by selective cha nges in the GABA(A) alpha(1) or alpha 2 subunits, respectively. These findings highlight the potential usefulness of the conflict model as a means of elucidating the biological underpinnings of anxiety disorder . Published by Elsevier Science B.V. All rights reserved.