Reinstatement of ethanol and sucrose seeking by the neurosteroid allopregnanolone in C57BL/6 mice - PubMed (original) (raw)

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

Deborah A Finn et al. Psychopharmacology (Berl). 2008 Dec.

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 nonreinforced 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 the reinstatement of extinguished ethanol-seeking behavior and compared this effect to the reinstatement of responding for sucrose reward.

Materials and 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 preextinction baseline, mice received an intraperitoneal 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 nonreinforced 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 nonreinforced 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.

PubMed Disclaimer

Conflict of interest statement

No author has a conflict of interest with the funding institute that sponsored the research.

Figures

FIGURE 1. Time Course of Responding During Extinction

Responses on the previously active (panel A) and inactive (panel B) levers are shown for 5S-trained (open squares; n = 14) and 10E-trained (black circles; n = 10) mice. Baseline responding prior to extinction onset was 16 presses on the active lever for all mice and averaged 0.37 ± 0.13 and 1.18 ± 0.22 inactive lever presses for the 5S and 10E groups, respectively. Responding in both groups dropped below the extinction criterion (< 16 responses on the previously active lever) by the 10th extinction session. #P < 0.05, ##P < 0.02, ###P < 0.001; between group differences within a given session ***P < 0.001; versus within-group extinction session 1 values for both 5S and 10E groups

FIGURE 2. ALLO reinstates extinguished ethanol- and sucrose-reinforced responding

Responses on the previously active (panel A) and inactive (panel B) levers are shown for the 5S (left side of each panel; n = 14) and 10E (right side of each panel; n = 10) groups of animals that were pretreated with ALLO (3.2, 5.6, 10 and 17 mg/kg, IP) at 15 min prior to extinction session onset. Baseline (0 mg/kg, VEH) responding represents the collapsed average of the extinction sessions following VEH injection that immediately preceded each test session with ALLO. *P < 0.05, **P < 0.01 versus within-subject baseline

FIGURE 3. Ethanol priming does not reinstate extinguished ethanol- and sucrose-reinforced responding

Responses on the previously active (panel A) and inactive (panel B) levers are shown for the 5S (left side of each panel; n = 14) and 10E (right side of each panel; n = 10) groups of animals that were pretreated with ethanol (0.5, 1.0 and 2.0 g/kg, IP) at 15 min prior to extinction session onset. Baseline (0 mg/kg, VEH) responding represents the collapsed average of the extinction sessions following VEH injection that immediately preceded each test session with ethanol. *P < 0.05, **P < 0.01, ***P < 0.001 versus within-subject baseline

FIGURE 4. Cue-induced reinstatement of extinguished ethanol- and sucrose-reinforced responding

Responses on the previously active (panels A & C) and inactive (panels B & D) levers are shown for the 5S (left side of each panel; n = 14) and 10E (right side of each panel; n = 10) groups of mice following presentation of a stimulus light cue (panels A & B) or a compound cue consisting of the light+lever retraction (panels C & D). *P < 0.05, **P < 0.01, ***P < 0.001 versus within-subject baseline

References

1. Ator NA, Grant KA, Purdy RH, Paul SM, Griffiths RR. Drug discrimination analysis of endogenous neuroactive steroids in rats. Eur J Pharmacol. 1993;241:237–243. - PubMed
1. Bäckström P, Hyytiä P. Ionotropic glutamate receptor antagonists modulate cue-induced reinstatement of ethanol-seeking behavior. Alcohol Clin Exp Res. 2004;28:558–565. - PubMed
1. Becker HC. Animal models of alcohol withdrawal. Alcohol Res Health. 2000;24:105–113. - PMC - PubMed
1. Belelli D, Lambert JJ. Neurosteroids: endogenous regulators of the GABAA receptor. Nature Rev Neurosci. 2005;6:565–575. - PubMed
1. Bell RL, Zodd RA, Lumeng L, Murphy JM, McBride WJ. The alcohol-preferring P rat and animal models of excessive alcohol drinking. Addiction Biol. 2006;11:270–288. - PubMed

Reinstatement of ethanol and sucrose seeking by the neurosteroid allopregnanolone in C57BL/6 mice - PubMed (original) (raw)