Conditioned stress prevents cue-primed cocaine reinstatement only in stress-responsive rats

Abstract

Neurobiological mechanisms underlying comorbid posttraumatic stress disorder (PTSD) and cocaine use disorder (CUD) are unknown. We aimed to develop an animal model of PTSD + CUD to examine the neurobiology underlying cocaine-seeking in the presence of PTSD comorbidity. Rats were exposed to cat urine once for 10-minutes and tested for anxiety-like behaviors one week later. Subsequently, rats underwent long-access (LgA) cocaine self-administration and extinction training. Rats were re-exposed to the trauma context and then immediately tested for cue-primed reinstatement of cocaine-seeking. Plasma and brains were collected afterwards for corticosterone assays and real-time qPCR analysis. Urine-exposed (UE; n = 23) and controls not exposed to urine (Ctrl; n = 11) did not differ in elevated plus maze behavior, but UE rats displayed significantly reduced habituation of the acoustic startle response (ASR) relative to Ctrl rats. A median split of ASR habituation scores was used to classify stress-responsive rats. UE rats (n = 10) self-administered more cocaine on Day 1 of LgA than control rats (Ctrl + Coc; n = 8). Re-exposure to the trauma context prevented cocaine reinstatement only in stress-responsive rats. Ctrl + Coc rats had lower plasma corticosterone concentrations than Ctrls, and decreased gene expression of corticotropin releasing hormone (CRH) and Glcci1 in the hippocampus. Rats that self-administered cocaine displayed greater CRH expression in the amygdala that was independent of urine exposure. While we did not find that cat urine exposure induced a PTSD-like phenotype in our rats, the present study underscores the need to separate stressed rats into cohorts based on anxiety-like behavior in order to study individual vulnerability to PTSD + CUD.

Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine

“…However, different approaches for segregating populations have been employed across studies using the predator odor exposure model (Cohen et al, 2012; Edwards et al, 2013; Hadad et al, 2016). We first sought to characterize this model in our laboratory, and then to define a segregation procedure that is appropriate based on this characterization.…”

“…In these studies, we used a single intense and inescapable stressor because this procedure has been used previously to produce a spectrum of PTSD-like behaviors (Cohen et al, 2012; Edwards et al, 2013; Endres and Fendt, 2007; Hacquemand et al, 2013; Hadad et al, 2016; Koresh et al, 2016). We established and validated a segregation model based on data obtained in our own laboratory that relies on the expression of both context avoidance and anxiety like behavior.…”

Lessons from regular gathering of experts in stress research: focus on pathophysiological consequences of stress exposure

“…As can be appreciated from this issue, the symposium highlighted recent evolution and innovation in the area of stress, including expanded consideration of stress as a complicating factor in a variety of somatic disease states, such as cancer (Krizanova et al, 2016) and obesity (Vargovic et al, 2016). In addition, important new insight was offered into the role of stress in neurodegenerative processes (Chomova & Zitnanova, 2016;Kvetnansky et al, 2016), addiction (Hadad et al, 2016) and first episode schizophrenia (Havelka et al, 2016). Human clinical and rodent studies shed new light on possible biomarkers of stress-related disease (Strac et al, 2016;Tseilikman et al, 2016) and on understanding the role of experiential factors in determining stress coping.…”

“…Preclinical studies highlighted clear and important theoretical advances in understanding mechanisms of stress responses. Numerous presentations noted the importance of prior stress experience in determining the impact of new stressors on sensitive outcomes, such as drug reinstatement (Hadad et al, 2016), highlighting the need to incorporate consideration of context in interpretation of the impact of stress on the brain. Another resonating theme was the ability of stress-effector molecules to coordinate a diversity of stress responses via independent mechanisms, e.g., different control mechanisms for body weight and HPA axis stress responses by pituitary adenylate cyclase activating polypeptide (PACAP) (Jiang & Eiden, 2016), parallel activation of anxiety, and emotional responses by vasopressin (Csikota et al, 2016).…”

Berberine alleviates symptoms of anxiety by enhancing dopamine expression in rats with post-traumatic stress disorder

“…The onset of PTSD often precedes and increases the risk for subsequent development of anxiety disorders, and PTSD enhances the susceptibility to anxiety [ 5 ]. Although the neurobiology of PTSD is not fully understood, preclinical and clinical studies have implicated altered dopamine (DA) activity in the disorder [ 6 ].…”