Reinstatement of ethanol and sucrose seeking by the neurosteroid allopregnanolone in C57BL/6 mice

Abstract

Rationale Recent work in our laboratory documented that the “sipper” method of operant ethanol self-administration produced high ethanol intake and blood ethanol concentrations as well as the typical extinction “burst” in responding under non-reinforced conditions in male C57BL/6 mice. However, the neurochemical basis for reinstatement of responding following extinction has not been examined in mice with this model. Objectives Based on findings that the GABAergic neurosteroid allopregnanolone (ALLO) significantly increased the consummatory phase of ethanol self-administration, the present study determined the effect of ALLO on reinstatement of extinguished ethanol-seeking behavior and compared this effect to reinstatement of responding for sucrose reward. Methods Separate groups of male C57BL/6 mice were trained to lever press for access to a 10% ethanol (10E) or a 5% sucrose (5S) solution. A single response requirement of 16 presses (RR16) on an active lever resulted in 30 min of continuous access to the 10E or 5S solution. After the animals responded on the RR16 schedule for 14 weeks, mice were exposed to 30 min extinction sessions where responding had no scheduled consequence. Once responding stabilized below the pre-extinction baseline, mice received an IP injection of ALLO (0, 3.2, 5.6, 10 or 17 mg/kg) 15 min prior to the extinction session in a within-subjects design. Results ALLO produced a dose-dependent increase in responding under non-reinforced conditions in both the 10E and 5S groups. Additional work documented the ability of a conditioned cue light or a compound cue (light+lever retraction) to reinstate non-reinforced responding on the previously active lever. Conclusions These findings definitively show that conditioned cues and priming with ALLO are potent stimuli for reinstating both ethanol and sucrose seeking behavior in C57BL/6 mice.

Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies

“…Moreover, GABAergic neuroactive steroids, like various drugs of abuse, exhibit rewarding properties in DBA/2J mice and Long-Evans rats (Finn et al 1997a; Sinnott et al 2002) and enhance brain stimulation reward in C57BL/6J mice, much like cocaine (Fish et al, this issue). 3α,5α-THP and other GABAergic neuroactive steroids exhibit biphasic modulation of ethanol intake in various rodent models of ethanol self-administration (Besheer et al 2010; Finn et al 2008; Ford et al 2007; Ford et al 2005; Janak et al 1998; Morrow et al 2001), suggesting complex actions on neuronal circuitry mediating these behaviors. The complexity of these behavioral responses in rodents points to the possibility that genetic variation may play an important role in neuroactive steroid actions across species.…”

“…It has been suggested that endogenous neuroactive steroids may play a role in ethanol sensitivity in these strains. In fact, 3α,5α-THP modulates ethanol intake (Ford et al 2007; Ford et al 2005), reinstates ethanol seeking behavior in C57BL/6J mice (Finn et al 2008) and affects ethanol withdrawal severity (Finn et al 2004a; Gililland and Finn 2007). …”

Operant ethanol self-administration in ethanol dependent mice

“…Studies also have shown mice responding for ethanol when ethanol reinforcement is continuously available (Risinger, Brown, Doan, & Oakes, 1998), when it is made available for extended periods (~16 h) (Besheer, Lepoutre, & Hodge, 2004; Hodge et al, 2006), and when access is limited for short periods of time (~30–60 min) (Chu et al, 2007; Lopez, Anderson, & Becker, 2008; Lopez & Becker, 2014; Ramaker, Strong, Ford, & Finn, 2012; Sparta et al, 2009; Tsiang & Janak, 2006). Using the ‘sipper’ model described above, mice were shown to reliably respond to gain access to drink ethanol from a bottle made available for 30 min once the response requirement was satisfied (Finn et al, 2008; Ford et al, 2007). In this latter case, manipulating the reinforcement schedule to further separate the appetitive and consummatory components of the procedure enhanced both the appetitive drive to gain access to ethanol (as indicated by reduced latency to fulfill the response requirement) and the consummatory component (increased amount of ethanol consumed).…”

Failure of Acute Ethanol Administration to Alter Cerebrocortical and Hippocampal Allopregnanolone Levels in C57BL/6J and DBA/2J Mice

“…However, previous studies have suggested that allopregnanolone may indeed play a role in EtOH's actions, independent from its steroidogenic effects. In fact, allopregnanolone administration to C57BL/6J mice modulates EtOH self-administration (Ford et al, 2005, 2007) and reinstates EtOH seeking behavior (Finn et al, 2008). Likewise, allopregnanolone administration modulates EtOH self-administration in rats (Janak et al, 1998).…”

“…Allopregnanolone modulates EtOH intake (Ford et al, 2005, 2007) and reinstates EtOH seeking behavior in C57BL/6J mice (Finn et al, 2008); it is also thought to modulate EtOH withdrawal severity across mouse strains (Finn et al, 2004a; Gililland and Finn, 2007). Acute EtOH administration increases whole brain allopregnanolone levels in male DBA/2J (Gabriel et al, 2004) and C57BL/6J mice, although in this strain, the effect did not reach statistical significance (Finn et al, 2004b).…”