Publications by authors named "John Shallcross"

4 Publications

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

Front Behav Neurosci 2019 10;13:91. Epub 2019 May 10.

Department of Psychology, University of Florida, Gainesville, FL, United States.

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.
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http://dx.doi.org/10.3389/fnbeh.2019.00091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523014PMC
May 2019

Neurobiological substrates of persistent working memory deficits and cocaine-seeking in the prelimbic cortex of rats with a history of extended access to cocaine self-administration.

Neurobiol Learn Mem 2019 05 1;161:92-105. Epub 2019 Apr 1.

Psychology Department, University of Florida, Gainesville, FL 32611, USA; Center for Addiction Research and Education (CARE) at University of Florida, USA. Electronic address:

Cocaine use disorder (CUD) is associated with prefrontal cortex dysfunction and cognitive deficits that may contribute to persistent relapse susceptibility. As the relationship between cognitive deficits, cortical abnormalities and drug seeking is poorly understood, development of relevant animal models is of high clinical importance. Here, we used an animal model to characterize working memory and reversal learning in rats with a history of extended access cocaine self-administration and prolonged abstinence. We also investigated immediate and long-term functional changes within the prelimbic cortex (PrL) in relation to cognitive performance and drug-seeking. Adult male rats underwent 6 days of short-access (1 h/day) followed by 12 days of long-access (6 h/day) cocaine self-administration, or received passive saline infusions. Next, rats were tested in delayed match-to-sample (DMS) and (non)match-to-sample (NMS) tasks, and finally in a single context + cue relapse test on day 90 of abstinence. We found that a history of chronic cocaine self-administration impaired working memory, though sparing reversal learning, and that the components of these cognitive measures correlated with later drug-seeking. Further, we found that dysregulated metabolic activity and mGlu5 receptor signaling in the PrL of cocaine rats correlated with past working memory performance and/or drug-seeking, as indicated by the analysis of cytochrome oxidase reactivity, mGlu5 and Homer 1b/c protein expression, as well as Arc mRNA expression in mGlu5-positive cells. These findings advocate for a persistent post-cocaine PrL dysfunction, rooted in ineffective compensatory changes and manifested as impaired working memory performance and hyperreactivity to cocaine cues. Considering the possible interplay between the neural correlates underlying post-cocaine cognitive deficits and drug-seeking, cognitive function should be evaluated and considered when developing neurobiologically-based treatments of cocaine relapse.
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http://dx.doi.org/10.1016/j.nlm.2019.03.007DOI Listing
May 2019

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

Transl Psychiatry 2018 10 5;8(1):209. Epub 2018 Oct 5.

Psychology Department, University of Florida, Gainesville, FL, 32611, USA.

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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http://dx.doi.org/10.1038/s41398-018-0265-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173705PMC
October 2018

The many facets of meaning making: comparing multiple measures of meaning making and their relations to psychological distress.

Memory 2013 Jan 17;21(1):111-24. Epub 2012 Aug 17.

Department of Psychology, Emory University, 36 Eagle Row, Atlanta, GA 30322, USA.

The goals of the present study were to (1) provide a first examination of the potential overlap/independence of three meaning making constructs emerging from distinct literatures, (2) examine those meaning making constructs in relation to psychological distress and (3) assess the extent to which these constructs relate to unique variance regarding psychological distress. Multiple measures of meaning making, including narrative coherence, cognitive mechanisms, narrative theme and post-traumatic growth, and their relations to psychological distress, measured as PTSD and depression, were compared in narratives written by university undergraduates regarding their most traumatic events. Results show that growth, elements of narrative coherence and narrative theme independently relate to PTSD, but not to depression. Stepwise multiple regression analyses and partial correlations suggest that the inclusion of multiple measures of meaning making account for additional variance within psychological distress. These findings suggest that meaning making is multifaceted.
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http://dx.doi.org/10.1080/09658211.2012.705300DOI Listing
January 2013