Differences in the reinstatement of ethanol seeking with ganaxolone and gaboxadol

Abstract

The endogenous neuroactive steroid allopregnanolone (ALLO) has previously been shown to induce reinstatement of ethanol seeking in rodents. ALLO is a positive allosteric modulator at both synaptic and extrasynaptic GABAA receptors. The contribution of each class of GABAA receptors in mediating reinstatement of ethanol seeking is unknown. The first aim of the present study was to determine whether ganaxolone (GAN), a longer-acting synthetic analog of ALLO, also promotes reinstatement of ethanol seeking. The second aim was to examine whether preferentially activating extrasynaptic GABAA receptors with the selective agonist gaboxadol (THIP) was sufficient to reinstate responding for ethanol in mice. Male C57BL/6J mice were trained to lever press for access to a 10% ethanol (v/v) solution (10E), using a sucrose fading procedure. Following extinction of the lever pressing behavior, systemic THIP (0, 4 and 6 mg/kg) and GAN (0, 10, and 15 mg/kg) were tested for their ability to reinstate ethanol-appropriate responding in the absence of 10E access. GAN significantly increased lever pressing on the previously active lever, while THIP did not alter lever pressing behavior. The results of this study suggest that direct activation of extrasynaptic GABAA receptors at the GABA site is not sufficient to induce ethanol seeking in the reinstatement procedure. Future studies are necessary to elucidate the mechanisms and brain areas by which differences in the pharmacological activity of GAN and THIP at the GABAA receptor contribute to the dissimilarity in their effect on the reinstatement of ethanol seeking. Nonetheless, based on the increased use of these drugs in clinical trials across multiple disease states, the effects of GAN or THIP on alcohol seeking may be an important consideration if these drugs are to be used clinically in a population with a co-occurring alcohol use disorder.

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).…”

Involvement of the GABAA Receptor in Age‐Dependent Differences in Binge‐Like Ethanol Intake

“…The magnitude of this effect was surprising and requires further investigation. Nonetheless, other studies have previously shown that a moderate dose of THIP may result in higher locomotor activity by itself (Ramaker et al, 2012(Ramaker et al, , 2014 or in combination with EtOH (Broadbent and Harless, 1999). In contrast, THIP had a considerable depressant action in adolescent mice.…”

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

“…An initial increase in ethanol intake following GAN treatment is consistent with previous work using systemic ALLO or GAN, whereas an initial increase in intake was absent following THIP injection (Ford et al, 2005, 2007; Ramaker et al, 2011). Although it is not clear if the initial increase in ethanol intake following intra-NAc GAN reflects ethanol seeking, previous data have shown an increase in ethanol seeking following systemic ALLO or GAN, but not THIP injection (Janak and Gill, 2003; Finn et al, 2008; Ramaker et al, 2012, 2014). Together these studies suggest that differences in receptor pharmacology or GABA A R targets between the synthetic neuroactive steroid and direct extrasynaptic agonist may differentially alter ethanol seeking or initial ethanol intake.…”