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.

Activation of extrasynaptic δ-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion

“…Previous studies from our lab (Moore et al, 2007; Fritz and Boehm, 2014; Quoilin and Boehm, 2016) and others (Ramaker et al, 2011, 2012, 2014a, 2014b) have shown that THIP can significantly reduce voluntary ethanol consumption and operant responding for the drug. Given THIP’s high affinity for δ-GABA A Rs, these data support a possible role for these extrasynaptically located GABA A receptors in mediating this pattern of ethanol use.…”

“…A growing number of reports support inhibition mediated by extrasynaptic GABA A receptors as a target for the effects of binge alcohol intoxication and consumption (Nie et al, 2011; Ramaker et al, 2011, 2012, 2014a, 2014b; Fritz and Boehm, 2014). Unlike the classic synaptic subtype of GABA A receptors that mediate phasic inhibition following vesicular release of GABA, extrasynaptic GABA A receptors mediate a constant tonic inhibition, responding to the low to moderate concentrations of ambient GABA found in the extrasynaptic space (Wei et al, 2003).…”

Microstructural analysis of rat ethanol and water drinking patterns using a modified operant self-administration model

“…Thus a potential period of `indecisiveness' on initial lever selection may have contributed to response latency measure not reaching full significance. While these measures have been most highly validated in operant paradigms utilizing higher lever press requirements [17–20, 35, 36], the latency to first lick has been validated as a measure of ethanol seeking behavior even in non-operant forms of ethanol self-administration [18, 37]. A similar latency is further used in the study of dopamine regulation of non-operant behavior [59–61].…”

Rodent models and mechanisms of voluntary binge-like ethanol consumption: Examples, opportunities, and strategies for preclinical research

“…However, the 2-bottle choice paradigm also appears to be sensitive to limited-access procedures. If offered a choice between 10% or 20% (v/v) ethanol and water, B6 mice have been shown to consume ∼2-6.5 g/kg of ethanol and reach BECs ∼50-90 mg/dl in a 2-4 hr period as well as demonstrate an ethanol preference of ∼60-80% (Cozzoli et al, 2014c; Ramaker et al, 2014; Rhodes et al, 2007). Thus, although concurrent access to water does appear to reduce ethanol intake in a limited access paradigm to some degree relative to the standard DID paradigm described above, BECs at the ‘binge’ level (≥ 80 mg/dl) can still be observed.…”

“…This is particularly interesting in regard to the aforementioned hypothesis that a pharmacological component of ethanol reward/reinforcement may be GABAergic disinhibition of VTA DA neurons. A prominent projection target of the VTA, the nucleus accumbens shell also regulates 2-bottle DID ethanol intake though GABA A processes as local infusion of the GABA A receptor partial agonist THIP significantly reduced ethanol consumption (Ramaker et al, 2014). Finally, THIP infused into the infralimbic cortex, a region associated with behavioral flexibility and fear extinction (Morgan and LeDoux, 1995; Ragozzino et al, 1999), has been shown to promote ethanol intake in DID and associated BECs (Fritz and Boehm II, 2014).…”