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Effect of nucleus accumbens shell infusions of ganaxolone or gaboxadol on ethanol consumption in mice

Abstract

Rationale

Allopregnanolone (ALLO) is an endogenous neuroactive steroid thought to alter the reinforcement value of alcohol (ethanol) due to its actions as a positive modulator of the GABAA receptor (GABAAR). Extrasynaptic GABAARs may be a particularly sensitive target of ethanol and neuroactive steroids. Previous work showed that systemic injections of an ALLO analog, ganaxolone (GAN), or an extrasynaptic GABAAR agonist (gaboxadol; THIP) decreased ethanol intake in male mice with limited access to ethanol.

Objectives

The present studies tested whether activation of GABAARs in the nucleus accumbens (NAc) shell by GAN or THIP was sufficient to reduce ethanol intake. C57BL/6J male mice had 2-h access to 10 % ethanol (10E) and water, and 10E intake was measured following site-specific infusions of GAN or THIP.

Results

Decreases in limited-access 10E consumption were observed following site-specific bilateral infusions of either drug into the NAc shell. Significant changes in intake were absent when the drugs were infused in a region dorsal to the target site (GAN) or into the lateral ventricle (THIP). Locomotor data confirmed that the decreases in intake were not due to a sedative effect of the drugs.

Conclusions

These data demonstrate the sufficiency of GABAAR activation by a positive allosteric modulator or an agonist with selectivity for extrasynaptic GABAARs to decrease ethanol consumption in mice. Importantly, more refined GABAAR-active targets that decrease ethanol intake may enhance our understanding and ability to treat alcohol use disorders.

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Acknowledgments

We thank Michelle Tanchuck-Nipper, Dr. Debra Cozzoli, and Chris Snelling for assistance. Funding was provided by grants R01 AA16981 and R01 AA12439 and the Department of Veterans Affairs (DAF). MJR was supported by F31 AA020716, MMF was supported by KO1 AA16849 and P51 OD011092, and TJP was supported by P60 AA010760 and the Department of Veterans Affairs.

Funding was provided by grants R01 AA16981 and R01 AA12439 and the Department of Veterans Affairs (DAF). MJR was supported by F31 AA020716, MMF was supported by KO1 AA16849 and P51 OD011092, and TJP was supported by P60 AA010760 and the Department of Veterans Affairs.

Conflict of interest

There are no conflicts of interest or competing financial interests in relation to the work described.

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Correspondence to Marcia J. Ramaker.

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Ramaker, M.J., Strong-Kaufman, M.N., Ford, M.M. et al. Effect of nucleus accumbens shell infusions of ganaxolone or gaboxadol on ethanol consumption in mice. Psychopharmacology 232, 1415–1426 (2015). https://doi.org/10.1007/s00213-014-3777-x

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  • DOI: https://doi.org/10.1007/s00213-014-3777-x

Keywords

  • Alcohol
  • Allopregnanolone
  • Extrasynaptic
  • GABAA receptor
  • Locomotor
  • Neurosteroids
  • THIP
  • Tonic