Selective dopamine D3 receptor antagonism significantly attenuates stress-induced immobility in a rat model of post-traumatic stress disorder.

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric syndrome that occurs in individuals exposed to extremely threatening or traumatic events. In both animals and humans, dopamine (DA) function appears to be dysregulated in brain areas involved in the conditioned fear response(s) that underlie PTSD. In this study, we determined the effect of the selective DA D3 receptor antagonists YQA14A (6.25, 12.5 and 25 mg/kg i.p.) and SB-277011A (6 mg/kg i.p.) on tone-induced fear (assessed by measuring freeze time) in a modified version of the single-prolonged stress (SPS) model of PTSD in adult male Sprague-Dawley rats. Rats pretreated with vehicle and then subjected to restraint stress, forced swim and random foot shock (SPS) in the presence of a distinctive tone, displayed a significantly increased tone-induced contextual freeze time and fecal pellet mass following re-exposure to the tone. Rats pretreated with a single i.p. injection of 6.25 or 12.5 mg/kg of YQA14 or 6 mg/kg of SB-277011A showed significantly attenuated contextual freeze time in the presence of the tone when tested 14 days after exposure to SPS. Overall, our results indicate that selectively antagonizing DA D3 receptors significantly decreases freezing time caused by an environment previously associated with stress. If our findings can be extrapolated to humans with PTSD, they suggest that DA D3 receptors may play a role in the pathophysiology of PTSD, and may have therapeutic utility for the clinical management of PTSD.