Antagonizing the GABA_A receptor during behavioral training improves spatial memory at different doses in control and chronically stressed rats

Chronic stress leads to a dysregulated inhibitory tone that could impact hippocampal-dependent spatial learning and memory. The present study examined whether spatial memory deficits resulting from chronic stress could be overcome by antagonizing the GABA_A receptor, a prominent inhibitory receptor of GABA in the hippocampus. Young adult male Sprague-Dawley rats were chronically stressed (STR, wire mesh restraint, 6 h/d/21 d) or placed in a no-stress control group (CON). When chronic restraint ended, rats were tested on a 2-trial object placement (OP) task at a delay (3 h) that would result in chance performance without intervention and then on novel object recognition (NOR) and the elevated plus maze (EPM) to assess non-spatial memory and anxiety profile. In CON rats, Bicuculline (BIC, 0, 0.25, 0.5 mg/kg), a GABA_A antagonist, injected 30 min prior to training led to facilitated OP performance with 0.25 and 0.5 mg/kg doses. In contrast, STR rats required BIC at the highest dose (0.5 mg/kg) to improve OP performance. While overall object exploration was decreased by chronic stress, motivation or anxiety profile were unlikely to explain these results. These findings reveal two different dose response functions for BIC in control and chronically stressed rats, with the dose response function of BIC being shifted to the right for chronically stressed rats compared to controls in order to improve spatial memory. While the literature demonstrates that chronic stress disrupts hippocampal inhibitory tone, the current study reveals that a single injection to antagonize the GABA_A receptor can restore hippocampal-dependent spatial memory in chronically stressed subjects.