Anhedonia, Reduced Cocaine Reward, and Dopamine Dysfunction in a Rat Model of Posttraumatic Stress Disorder

Abstract

Background Posttraumatic stress disorder (PTSD) co-occurs with substance use disorders (SUD) at high rates, but the neurobiological basis of this relationship is largely unknown. PTSD and drug addiction each involve dysregulation of brain reward circuitry, therefore the identification of pathology of the mesolimbic dopamine system may aid in understanding their functional relationship. Dopamine reward dysfunction also may be relevant to the mechanisms underlying the PTSD symptoms of anhedonia and emotional numbing. Methods Single-prolonged stress (SPS) was used as a rat model of PTSD, and a series of behavioral and neuropharmacological assays were applied to assess the impact of SPS on reward, cocaine intake, and components of the striatal dopamine system. Results Exposure to SPS increased anhedonia-like behaviors and decreased the rewarding properties of cocaine compared to control handling. Altered cocaine intake during extended-access self-administration sessions was observed in rats exposed to SPS, further suggesting a difference in the reinforcing properties of cocaine following severe stress. SPS reduced tissue content of dopamine and its metabolites in the striatum, as well as altered striatal dopamine transporter and D2, but not D1, receptor densities. Conclusions These results support a role for altered dopaminergic transmission in reduced reward function in PTSD. Pathology of the dopamine system and the degradation of reward processes may contribute to PTSD symptomology and have implications for co-occurring psychiatric disorders such as substance abuse or depression.

The polymethoxylated flavone, Tangeretin improves cognitive memory in rats experiencing a single episode of prolonged post-traumatic stress

“…severe stressors support the notion that neurobiological events trigger dysregulation of the DA system (Enman et al 2015). We hypothesize that TAN-mediated modulation of SPS-induced memory impairment-like symptoms reflects improvement in central DA and 5-HT status.…”

“…PTSD patients exhibit reduction in hippocampal volume that is evident on imaging and appears to be correlated with disease severity and the extent of cognitive impairment (Li et al 2010). It is widely accepted that catecholamine dysfunction in general, and dopamine (DA) dysfunction in particular, play important roles in the pathophysiology of PTSD (Enman et al 2015). DAergic neurotransmission in the mesolimbic pathway is important in terms of arousal and memory; changes in DA levels may contribute to the hyperarousal and re-experiencing symptoms associated with PTSD (Wilson et al 2014).…”

Capturing Individual Differences: Challenges in Animal Models of Posttraumatic Stress Disorder and Drug Abuse

“…However, despite this evidence and diagnostic requirement for substantial temporal separation from trauma to PTSD manifestation, many preclinical researchers do not wait an adequate amount of time from stress exposure to behavioral tests assessing for PTSD-like symptoms. Although the one week isolation period in the Enman et al (3) study was informative, face and translational validity would be improved, and perhaps the results would be different, with a more disease-relevant spacing from stress exposure to behavioral and neurochemical evaluation.…”

“…Although Enman et al (3) did not investigate individual differences in their SPS model of PTSD, a beautifully designed study by Toledano and Gisquet-Verrier (6) demonstrated that SPS can indeed engender phenotypes of susceptible and resilient rats long after stress exposure. In this study, rats were first tested for baseline anxiety-like and novelty reactivity behavior, after which the rats were exposed to SPS or control handling.…”

“…In this issue of Biological Psychiatry , Enman and colleagues (3) investigated anhedonia-like symptoms and cocaine self-administration in an animal model of PTSD. Rats were exposed to single prolonged stress (SPS), a putative animal model for PTSD, or handling as control, and assessed one week later for sucrose preference, spontaneous locomotor activity, conditioned place preference for cocaine, cocaine self-administration, and dopamine receptor density within the striatum.…”