Region-specific dysregulation of allopregnanolone brain content in the olfactory bulbectomized rat model of depression.

Allopregnanolone (ALLO) is one of the most potent positive endogenous allosteric modulators of the type A gamma-aminobutyric acid (GABA(A)) receptors. While the robust anxiolytic profile of ALLO has been extensively characterized in rodents and its antidepressant-like effect was recently demonstrated in mice, there have been only few reports on alterations of brain ALLO levels in putative animal models of depression and anxiety. Removal of the olfactory bulbs of rats produces one of the most predictive animal models with which to screen for drugs with potential antidepressant activity following repeated treatment. We therefore investigated whether the olfactory bulbectomized (OB) rat model of depression may be associated with alterations of ALLO levels in whole brain tissue and in different brain regions. We determined ALLO levels in whole brain, amygdala, frontal cortex, hippocampus, and whole cerebral cortex of OB or sham-operated rats at 7, 14, or 28 days following bulbectomy or sham surgery. We observed a significant increase of whole brain ALLO content at 7 and 28 days post-surgery in the OB rats. At days 7 and 14 following olfactory bulb removal, ALLO levels were significantly decreased in amygdala and frontal cortex and significantly increased in whole cerebral cortex. In the hippocampus we observed only a tendency for decreased ALLO levels at day 14. Our data indicates a strong region-specific dysregulation of ALLO homeostasis in brains of OB rats which may contribute to the formation of the bulbectomy syndrome via a sustained reduction in physiological GABA-ergic tone in amygdala and frontal cortex.