Behavioral Domain-Specific Effects of Positive Modulation of α5 and α6 GABAA Receptors in a Rat Double-Hit Stress Model.

Abstract

Impulsivity is an understudied area of post-traumatic stress disorder, a debilitating disorder specifically associated with stress. We examined reward-related impulsive behavior, anxiety-like behavior, locomotor activity and social behavior in the absence and presence of protracted pharmacological positive modulation of α5- and α6-GABA_A receptors (GL-II-73 and DK-I-56-1, respectively) in male Sprague-Dawley rats exposed to a combination of maternal deprivation (MD) and single prolonged stress (SPS). While locomotor and anxiety-like behavior were not affected in the SPS and MD+SPS groups, the double-hit group treated with DK-I-56-1 exhibited a higher locomotor distance compared with MD+SPS and a higher percentage of open-arm time in the elevated plus maze compared with the control group. In the variable delay-to-signal task of impulsivity, the total number of successful trials and premature responses (PR) in the first stage of the test day were reduced in all groups exposed to stress compared with the controls. Based on PR rates in the first and second set of trials, motor impulsivity was apparently suppressed in all stressed groups, while delay intolerance was suppressed only in the MD+SPS+GL-II-73 group, respectively. In the three-chamber test, social interaction was completely normal, while social recognition was preserved in the MD+SPS+GL-II-73 group. In the resident-intruder test, social play was reduced only in the SPS group. The evaluation of impulsive behavior in the used complex task was hindered by the lack of motivation of stressed rats, which in the case of omission percentage was ameliorated by positive modulation of α5 and α6 GABA_A receptors.