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April 19, 2026Pharmacology Research & Perspectives0 citationsOpen Access

Behavioral Domain‐Specific Effects of Positive Modulation of α5 and α6 GABA A Receptors in a Rat Double‐Hit Stress Model

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ĐĐĐorđe ĐorovićJAJovana AranđelovićJIJana Ivanović

Key Points

  • This research aims to investigate how positive modulation of α5 and α6 GABA receptors affects impulsivity and behavior in a rat model of stress.
  • Utilized a double-hit stress model involving maternal deprivation and single prolonged stress in male Sprague-Dawley rats.
  • Administered pharmacological agents GL-II-73 and DK-I-56-1 to modulate GABA receptors.
  • Assessed behaviors related to locomotion, anxiety, impulsivity, and social interaction using various behavioral tests.
  • The double-hit group treated with DK-I-56-1 showed increased locomotor distance compared to control and MD+SPS groups.
  • In impulsivity tasks, all stressed groups exhibited reduced successful trials and premature responses compared to controls.
  • Delay intolerance was specifically reduced in the MD+SPS+GL-II-73 group, while social interaction remained normal in stressed rats.

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-GABAA 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 GABAA receptors.

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Cite This Study

Đorović et al. (2026) studied this question.

synapsesocial.com/papers/69e473de010ef96374d8fa40https://doi.org/10.1002/prp2.70245
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