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.

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Post-traumatic stress disorder (PTSD) currently has no FDA-approved treatments that reduce symptoms in the majority of patients. The ability to extinguish fear memory associations is impaired in PTSD individuals. As such, the development of extinction-enhancing pharmacological agents to be used in combination with exposure therapies may benefit the treatment of PTSD. Both mGlu5 and CB1 receptors have been implicated in contextual fear extinction. Thus, here we tested the ability of the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and cannabidiol (CBD) to reduce both conditioned and unconditioned fear. We used a predator-threat animal model of PTSD which we and others have previously shown to capture the heterogeneity of anxiety responses observed in humans exposed to trauma. Here, 1 week following a 10-min exposure to predator scent stress, rats were classified into stress-Susceptible and stress-Resilient phenotypes using behavioral criteria for elevated plus maze and acoustic startle response performance. Two weeks after classification, rats underwent 3 days of contextual fear extinction and were treated with vehicle, CDPPB or CBD prior to each session. Finally, the light-dark box test was employed to assess phenotypic differences and the effects of CDPPB and CBD on unconditioned anxiety. CDPBB but not CBD, reduced freezing in Susceptible rats relative to vehicle. In the light-dark box test for unconditioned anxiety, CBD, but not CDPPB, reduced anxiety in Susceptible rats. Resilient rats displayed reduced anxiety in the light-dark box relative to Susceptible rats. Taken together, the present data indicate that enhancement of mGlu5 receptor signaling in populations vulnerable to stress may serve to offset a resistance to fear memory extinction without producing anxiogenic effects. Furthermore, in a susceptible population, CBD attenuates unconditioned but not conditioned fear. Taken together, these findings support the use of predator-threat stress exposure in combination with stress-susceptibility phenotype classification as a model for examining the unique drug response profiles and altered neuronal function that emerge as a consequence of the heterogeneity of psychophysiological response to stress.

Post-traumatic stress disorder (PTSD) is a disorder with no clear FDA-approved treatments that reduce symptoms in the majority of patients. PTSD individuals possess an impaired capacity for extinguishing fear memory associations. As such, considerable focus has been given to the development of extinction-enhancing pharmacological agents to be used in combination with PTSD treatments. Here we use a predator-threat animal model of PTSD to test the ability of two compounds to enhance contextual fear extinction and reduce anxiety. Mirroring the heterogeneity observed in human response to trauma, an exposure to predator threat, including the fox odor TMT, have been shown to induce long-term changes in anxiety behavior in only subsets of "susceptible" rats. Here, two weeks following a ten-minute exposure to a predator odor, rats were classified into stress-Susceptible (Sus) and stress-Resilient (Res) phenotypes using cut-off behavioral criteria for elevated plus maze and acoustic startle response performance. One week following classification, Sus rats underwent three days of context fear extinction. We found that Sus rats increased freezing from day one to day two. Treatment with the mGlu5 positive allosteric modulator CDPPB, but not the phytocannabinoid cannabidiol (CBD), prior to sessions resulted in reduced freezing. CDPPB administration resulted in an increase of Fos immunoreactive cells in the medial prefrontal cortex, indicative of increased neuronal activity. Finally, we used the light-dark box test to measure phenotypic differences and the effects of CDPPB and CBD on unconditioned anxiety two weeks after classification. We found that Res rats showed less anxiety compared to Sus rats, and that CBD, but not CDPPB, administered prior to testing was anxiolytic in Sus rats. Taken together, the present data indicate that mGlu5 PAMs such as CDPPB hold promise for treating human PTSD patients as they enhance extinction of fear without increasing general anxiety. Polytherapy with medications such as CBD may be necessary in order to attenuate general anxiety and future directions will explore this hypothesis.

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