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

Marcia J. Ramaker, Moriah N. Strong-Kaufman, Matthew Ford, Tamara Phillips, Deborah (Deb) Finn

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1415-1426
Number of pages12
JournalPsychopharmacology
Volume232
Issue number8
DOIs
StatePublished - Apr 1 2015

Fingerprint

Nucleus Accumbens
Ethanol
GABA-A Receptors
Pregnanolone
Steroids
Alcohols
gaboxadol
ganaxolone
Pharmaceutical Preparations
GABA-A Receptor Agonists
Lateral Ventricles
Hypnotics and Sedatives
Injections
Water

Keywords

  • Alcohol
  • Allopregnanolone
  • Extrasynaptic
  • GABA<inf>A</inf> receptor
  • Locomotor
  • Neurosteroids
  • THIP
  • Tonic

ASJC Scopus subject areas

  • Pharmacology

Cite this

Effect of nucleus accumbens shell infusions of ganaxolone or gaboxadol on ethanol consumption in mice. / Ramaker, Marcia J.; Strong-Kaufman, Moriah N.; Ford, Matthew; Phillips, Tamara; Finn, Deborah (Deb).

In: Psychopharmacology, Vol. 232, No. 8, 01.04.2015, p. 1415-1426.

Research output: Contribution to journalArticle

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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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