A novel rat model of comorbid PTSD and addiction reveals intersections between stress susceptibility and enhanced cocaine seeking with a role for mGlu5 receptors

Abstract

PTSD is highly comorbid with cocaine use disorder (CUD), and cocaine users with PTSD + CUD are more resistant to treatment. Here we sought to develop a rat model of PTSD + CUD in order to identify the neurobiological changes underlying such comorbidity and screen potential medications for reducing cocaine seeking in the PTSD population. We utilized a predator scent stress model of PTSD, wherein rats received a single exposure to the fox pheromone 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). One week after TMT exposure, stress-susceptible (susceptible), intermediate, and resilient phenotypes were detected and were consistent with behavioral, corticosterone, and gene expression profiles 3 weeks post TMT. We assessed phenotypic differences in cocaine self-administration, extinction, and cue-primed reinstatement. Susceptible rats exhibited deficits in extinction learning and increased cue-primed reinstatement that was not prevented by Ceftriaxone, an antibiotic that consistently attenuates the reinstatement of cocaine seeking. TMT-exposed resilient rats displayed increased mGlu5 gene expression in the amygdala and medial prefrontal cortex and did not display the enhanced cocaine seeking observed in susceptible rats. Combined treatment with the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1 H-pyrazol-5-yl)benzamide (CDPPB), fear extinction, and ceftriaxone prevented the reinstatement of cocaine seeking in susceptible rats with fear extinction an important mediating condition. These results highlight the need for animal models of PTSD to consider stress-responsivity, as only a subset of trauma-exposed individuals develop PTSD and these individuals likely exhibit distinct neurobiological changes compared with trauma-exposed populations who are resilient to stress. This work further identifies glutamate homeostasis and mGlu5 as a target for treating relapse in comorbid PTSD-cocaine addiction.

The divergent effects of CDPPB and cannabidiol on fear extinction and anxiety in a predator scent stress model of PTSD in rats.

“…Notably, we found that only stress "Susceptible" rats displayed increased freezing upon re-exposure to the stress/trauma context whereas "Resilient" rats did not, indicating that inter-subject phenotypic heterogeneity influences the observed outcomes across entire populations of stressed animals. Furthermore, we also demonstrated that Susceptible rats do not decrease freezing over the course of 5 days of extinction to the stress context (Schwendt et al, 2018). Taken together, this data indicates that knowledge gained from classic footshock conditioning experiments may not apply to models that consider differential stress vulnerability.…”

“…2, 3, 5-Trimethyl-3-thiazoline (TMT, 5 µl; BioSRQ) was presented undiluted (97% purity). The amount of TMT used for predator odor exposures was based on previous studies by our laboratory and others (Day et al, 2004;Tanapat et al, 2001;Schwendt et al, 2018).…”

“…Power analyses (G power) indicated the number of animals needed was 7-8/ treatment group with a significance level of 0.05. We have previously shown that the incidence of the Susceptible phenotype amongst TMT-exposed rats ranges from 14-21.8% (Schwendt et al, 2018). Thus, with a target of 8 rats/group for a total of 16 Susceptible rats needed for Experiment 1 and 32 needed for Experiment 2, we initially exposed 307 rats to TMT.…”

“…freezing; Wallace & Rosen, 2000), and supports contextual fear conditioning (Endres & Fendt, 2007). Predator threat exposure has also been demonstrated to more closely resemble a PTSD-like profile in that the persistent manifestations of anxiety and hyperarousal following exposure to threat are observed only in a subset of "Susceptible" exposed rats and not in "Resilient rats" (Cohen & Zohar, 2004;Schwendt et al, 2018). Despite these advantages, little is understood about the neural mechanisms involved in the extinction of innate predator fears, or the benefits of extinction-enhancing agents under these conditions.…”

“…Despite these advantages, little is understood about the neural mechanisms involved in the extinction of innate predator fears, or the benefits of extinction-enhancing agents under these conditions. We have previously demonstrated that a single 10-minute exposure to the fox odor 2, 3, 5-Trimethyl-3-thiazoline (TMT) gives rise to distinct stress-Susceptible and Resilient rat phenotypes, each with distinct behavioral, hormonal, and molecular signatures (Schwendt et al, 2018). Notably, we found that only stress "Susceptible" rats displayed increased freezing upon re-exposure to the stress/trauma context whereas "Resilient" rats did not, indicating that inter-subject phenotypic heterogeneity influences the observed outcomes across entire populations of stressed animals.…”