The benzodiaepines (BZs) are widely prescribed for the treatment of anxiety-related disorders, although these compounds also have anticonvulsant, hypnotic, and sedative actions. The BZs act at specific receptor sites in the brain to potentiate the actions of the neurotransmitter gamma-aminobutyric acid (GABA). Evidence suggests that the GABA/BZ system in the amygdala may play a critical role in mediating the anxiety-reducing aspects of BZ agonists. Further evidence suggests that the endogenous opioid system also modulates the amygdalar GABAergic system underlying anxiety responses. The proposed studies employ herpes- mediated gene transfer techniques to alter expression of opioid peptides in the rat amygdala. The anxiety levels and the anxiety-reducing effects of BZs will be determined using the elevated plus maze and social interaction tests. Pilot studies using herpes virus vectors encoding either the bacterial protein Beta-galactosidase (virus SHZ.1) or human preproenkephalin (virus SHPE) in the amygdala have demonstrated that 1) we can induce high level expression of the transgenes encoded in these viral vectors in defined brain areas, 2) that viral expression in the amygdala does not have deleterious effects on the animal, 3) that overexpression of enkephalin in the amygdala enhances the anxiolytic effects of the BZs examined using the plus maze, and 4) that we can demonstrate viral expression of the encoded proteins.
AIMS 1 and 2 will further characterize the ability of enkephalin overexpression in the amygdala to enhance the anxiety-reducing effects of BZ agonists (diazepam). This includes determining if enkephalin overexpression in amygdala enhances sensitivity to the anxiolytic actions of BZ agonists in another model of anxiety and insuring these effects are mediated through a BZ receptor-dependent mechanism (AIM 1).
AIM 2 begins to address the mechanism through which enkephalin overexpression enhances the anxiolytic effects of BZs. Studies examine the opioid receptor subtype involved in this effect of enkephalin, begin to assess which neuronal population is affected in amygdala, and determine if changes in GABA/ BZ receptor sites are observed. Overall, this technique could provide a powerful tool to examine the role of neuropeptides in anxiety- related behaviors, and the anxiolytic action of the BZs. This approach has the marked advantage of altering neurotransmitter or receptor expression in defined brain regions of adult animals. It will thus help to elucidate the role(s) of specific, localized neurotransmitter functions in complex behaviors such as anxiety.
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