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The infralimbic cortex and mGlu5 mediate the effects of chronic intermittent ethanol exposure on fear learning and memory

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Abstract

Rationale and objectives

Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) often occur comorbidly. While the incidence of these disorders is increasing, there is little investigation into the interacting neural mechanisms between these disorders. These studies aim to identify cognitive deficits that occur as a consequence of fear and ethanol exposure, implement a novel pharmaceutical intervention, and determine relevant underlying neurocircuitry. Additionally, due to clinical sex differences in PTSD prevalence and alcohol abuse, these studies examine the nature of this relationship in rodent models.

Methods

Animals were exposed to a model of PTSD+AUD using auditory fear conditioning followed by chronic intermittent ethanol exposure (CIE). Then, rats received extinction training consisting of multiple conditioned stimulus presentations in absence of the shock. Extinction recall and context-induced freezing were measured in subsequent tests. CDPPB, a metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulator, was used to treat these deficits, and region-specific effects were determined using microinjections.

Results

These studies determined that CIE exposure led to deficits in fear extinction learning and heightened context-induced freezing while sex differences emerged in fear conditioning and extinction cue recall tests. Furthermore, using CDPPB, these studies found that enhancement of infralimbic (IfL) mGlu5 activity was able to recover CIE-induced deficits in both males and females.

Conclusions

These studies show that CIE induces deficits in fear-related behaviors and that enhancement of IfL glutamatergic activity can facilitate learning during extinction. Additionally, we identify novel pharmacological targets for the treatment of individuals who suffer from PTSD and AUD.

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Acknowledgments

The authors would like to acknowledge Katherine Nimchuk, Heyam Saleh, and Nicholas Baker for their assistance in proof-reading this manuscript.

Funding

This work was supported by the National Institutes of Health (grant numbers R00AA020537 and R01AA024526) and the National Institute on Alcohol Abuse and Alcoholism (grant number 5T32AA007474).

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  1. Department of Neuroscience, Medical University of South Carolina, Basic Science Building, 173 Ashley Avenue, Room 403, Charleston, SC, 29425, USA

    C. E. Smiley, J. T. McGonigal, T. Valvano, R. J. Newsom & J. T. Gass

  2. Department of Behavioral Sciences, University of Arkansas – Fort Smith, 5210 Grand Ave, Fort Smith, AR, 72904, USA

    N. Otero

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  1. C. E. Smiley
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  2. J. T. McGonigal
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Smiley, C.E., McGonigal, J.T., Valvano, T. et al. The infralimbic cortex and mGlu5 mediate the effects of chronic intermittent ethanol exposure on fear learning and memory. Psychopharmacology 237, 3417–3433 (2020). https://doi.org/10.1007/s00213-020-05622-9

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