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

Psychopharmacology (Berl). 2015 Apr;232(8):1415-26. doi: 10.1007/s00213-014-3777-x. Epub 2014 Oct 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alcohol Drinking / metabolism*
  • Alcohol Drinking / prevention & control*
  • Animals
  • Ethanol / administration & dosage
  • GABA-A Receptor Agonists / administration & dosage
  • Infusions, Intraventricular
  • Isoxazoles / administration & dosage*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism*
  • Pregnanolone / administration & dosage
  • Pregnanolone / analogs & derivatives*
  • Receptors, GABA-A / metabolism
  • Treatment Outcome

Substances

  • GABA-A Receptor Agonists
  • Isoxazoles
  • Receptors, GABA-A
  • Ethanol
  • ganaxolone
  • Pregnanolone
  • gaboxadol