The Divergent Effects of CDPPB and Cannabidiol on Fear Extinction and Anxiety in a Predator Scent Stress Model of PTSD in Rats

Abstract

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.

Increased mGlu5 mRNA expression in BLA glutamate neurons facilitates resilience to the long-term effects of a single predator scent stress exposure

“…Anxiety-like and fear behavior EPM and ASR data from the entire population of TMT-exposed rats have been published previously (Shallcross et al, 2019). There were no differences in time spent in the OA or percent habituation in the ASR between Resilient and Control rats used in the present experiment (Fig.…”

“…Startle habituation was calculated as the percent change in startle amplitude from the average of the first six trials to the average of the last six trials as in our previous publications (Schwendt et al 2018;Shallcross et al 2019). A double median split was conducted on EPM (time spent in the OA) and ASR (% habituation of initial startle).…”

“…In addition to finding increased mGlu5 and CB1 mRNA expression in stress-Resilient rats, our prior work finds that Susceptible but not Resilient outbred Sprague-Dawley rats display contextual fear that does not extinguish (Schwendt et al 2018;Shallcross et al 2019) We also found that systemic administration of the mGlu5 positive allosteric modulator CDPPB reduces contextual fear, but not anxiety, in Susceptible rats, further supporting a role for mGlu5 in mediating PSS conditioned fear (Shallcross et al 2019). The current study seeks to further explore the potential role for mGlu5 expression in resistance to contextual fear.…”

“…The startle habituation program consisted of 5 min acclimation followed by thirty 110 dB white noise pulses (ITI: 30 -45 sec). Following EPM/ASR tests, rats were phenotyped as stress-Susceptible, Resilient, or Intermediate (see below and (Schwendt et al 2018;Shallcross et al 2019). Only Control rats and TMT-exposed rats meeting the criteria for stress-Resilience were assigned to Experiment 1 or Experiment 2.…”

“…Rats that scored below the median time spent in the OA and above the median ASR habituation were phenotyped as Susceptible; those scoring above-median OA time and below ASR habituation were phenotyped as Resilient (Resil) as in our previous report (Schwendt et al 2018). All Susceptible and some Resilient rats were used in a previous publication (Shallcross et al, 2019) whereas a subset of Resilient rats was used for the present set of experiments (n=31) along with a new cohort of unstressed Control rats (n=11).…”