The Roles of Mineralocorticoid and GABA A Receptors in Anxiety and Fear Memory

The purpose of this dissertation was to examine the roles of brain mineralocorticosteroid (MR) and γ-aminobutyric acid (GABAA) receptors in mediating unconditioned fear and fear memory. The first set of experiments explored the role of hippocampal and medial prefrontal cortex mineralocorticosteroid receptors (MRs) in anxiety and fear memory. The MR antagonist RU28318 was microinfused into the dorsal hippocampus (DH), ventral hippocampus (VH) or medial prefrontal cortex (mPFC) ten minutes prior to testing in two rodent models of unconditioned anxiety, the elevated plus-maze and shock-probe burying test. Fear memory was then assessed in the shock-probe apparatus 24 hours later by re-exposing non-drugged rats to a non-electrified probe. RU28318 infusions into the VH reduced anxiety in the elevated plus-maze while RU28318 in the DH or mPFC did not. In contrast, RU28318 infusions into the DH, VH and mPFC all reduced anxiety in the shock-probe burying test. Fear memory was not affected by infusions into any of the three brain regions. The second and third set of experiments examined the role of hippocampal GABAA receptors and GABAA receptor sub-units in mediating anxiety and fear memory. α2 GABAA receptor sub-units are thought to mediate the anxiolytic effects of benzodiazepines and α5 sub-units are thought to mediate the amnesic effects of benzodiazepines. The DH and VH both contain GABAA receptors having these sub-units. Rats were given intra-hippocampal microinfusions of either TPA023 (an α2 agonist) or TB-21007 (an α5 inverse agonist) and tested in the plus-maze and shock-probe tests. Twenty-four hours later, rats were tested for fear memory with the non-electrified shock-probe. The α2 agonist (TPA023) reduced anxiety when it was infused into the VH but had no effect when infused into the DH. Conversely, the inverse α5 agonist (TB-21007) impaired fear memory when it was infused into the DH, but not when it was infused into the VH. Overall, these results suggest that mineralocorticoid and GABAA receptors in the ventral hippocampus mediate anxiety. In addition, these results suggest that ventral hippocampal GABAA α2 sub-units mediate anxiety and dorsal hippocampal GABAA α5 sub-units mediate fear memory.