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Polymorphism in the corticotropin-releasing factor receptor 1 (CRF1-R) gene plays a role in shaping the high anxious phenotype of Marchigian Sardinian alcohol-preferring (msP) rats

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Abstract

Introduction

Marchigian Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol along with anxious phenotype. In these animals, two single-nucleotide polymorphisms in position −1,836 and −2,097 from the first start codon of the CRF1-R transcript have been found.

Materials and Methods

Here, we examined whether these point mutations account for the heightened anxiety-like behavior and stress responsiveness of msP rats. We rederived the msP rats to obtain two distinct lines carrying the wild-type (GG) and point mutations (AA), respectively.

Results

CRF1-R gene expression analysis revealed significant dysregulation of the system in the extended amygdala of AA rats. At the behavioral level, using the elevated plus maze, we found that both AA and GG lines had higher basal anxiety compared to Wistar rats. In the defensive burying test, AA rats showed decreased burying behavior compared to the GG and the unselected Wistar lines. Freezing/immobility did not differ among AA and GG but was higher than that of Wistars. The selective CRF1-R antagonist antalarmin (0, 10, and 20 mg/kg) reduced burying behavior in Wistar animals. However, antalarmin (10 mg/kg) tended to increase rather than reducing this behavior when tested in the msP lines, an effect that appeared more marked in the GG as compared to the AA line.

Conclusion

The present data suggest that rats with msP genetic background are more anxious and show different sensitivity to stress and CRF1-R blockade than Wistars. The point mutations occurring in the CRF1-R gene do not seem to influence basal anxiety while they appear to affect active responses to stress.

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Acknowledgments

We are thankful to Rina Righi and Mariangela Fiorelli for animal care and Marino Cucculelli and Alfredo Fiorelli for technical support. This work was supported by the National Institutes of Health, grant RO1 AA017447, and RO1 AA014351 from the National Institute on Alcohol Abuse and Alcoholism.

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Pharmacology Unit, School of Pharmacy, University of Camerino, Building of Experimental Medicine, Via Madonna delle Carceri, Camerino, MC, 62032, Italy

    Andrea Cippitelli, Lydia O. Ayanwuyi, Esi Domi, Jose M. Lerma-Cabrera, Francisca Carvajal, Giulia Scuppa, Hongwu Li, Massimo Ubaldi & Roberto Ciccocioppo

  2. Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, 20892, USA

    Estelle Barbier & Markus Heilig

  3. Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, SP30-1150, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Marisa Roberto

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  1. Andrea Cippitelli
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  2. Lydia O. Ayanwuyi
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Correspondence to Roberto Ciccocioppo.

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Andrea Cippitelli and Lydia O. Ayanwuyi contributed equally to the work.

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Cippitelli, A., Ayanwuyi, L.O., Barbier, E. et al. Polymorphism in the corticotropin-releasing factor receptor 1 (CRF1-R) gene plays a role in shaping the high anxious phenotype of Marchigian Sardinian alcohol-preferring (msP) rats. Psychopharmacology 232, 1083–1093 (2015). https://doi.org/10.1007/s00213-014-3743-7

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