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 D 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 D 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 D receptors may play a role in the pathophysiology of PTSD, and may have therapeutic utility for the clinical management of PTSD.

Emphasizing the Crosstalk Between Inflammatory and Neural Signaling in Post-traumatic Stress Disorder (PTSD)

“…3) (Yang et al 2020). Furthermore, deletion or antagonism of D 3 R resulted in anxiolytic effects in the rodent SPS model of PTSD, implying that D 3 receptor antagonism was effective in reducing PTSD symptoms and also could decrease the risk of drug abuse and addiction (Rice et al 2018;Song et al 2018).…”

Emotion Processing Dysfunction in Alzheimer’s Disease: An Overview of Behavioral Findings, Systems Neural Correlates, and Underlying Neural Biology

“…316 Stress elevated DA signals in the MPFC 317 and administration of dopamine D3 receptor antagonist-YQA14A and SB-277011A reduced stress-like behavior in rats. 318 Thus, preclinical studies point to dopamine's complex roles in emotional and motivational behavior. How DA system and behavior supported by the DA system are impacted by aging and AD models associating changes in DA functions to emotional behavior remain to be investigated.…”

Frequency of the Dopamine Receptor D3 (rs6280) vs. Opioid Receptor µ1 (rs1799971) Polymorphic Risk Alleles in Patients with Opioid Use Disorder: A Preponderance of Dopaminergic Mechanisms?

“…This expression is particularly conspicuous in the basolateral nucleus of the amygdala (BLA), an essential region for processing of opioid-related reward and withdrawal aversion-related memories [40,41] as assessed with conditioned place preference and aversion (in conjunction with molecular analyses of BLA protein expression) [42]. Using genetic manipulation of individual dopamine receptors in animals, our understanding of some molecular and cellular mechanisms inherent in addictive behaviors have improved [42][43][44][45][46][47][48][49][50][51][52][53]. Most of what is known about blocking, activating, gain-of-function studies were through animal studies.…”