Selective impact of lateral orbitofrontal cortex inactivation on reinstatement of alcohol seeking in male Long-Evans rats

Abstract

The orbitofrontal cortex (OFC) plays a fundamental role in motivated behavior and decision-making. In humans, OFC structure and function is significantly disrupted in drug using and dependent individuals, including those exhibiting chronic alcohol use and alcoholism. In animal models, the OFC has been shown to significantly influence the seeking of non-alcohol drugs of abuse. However direct investigations of the OFC during alcohol seeking and use have been more limited. In the studies reported here, we inactivated lateral (lOFC) or medial OFC (mOFC) subregions in rats during multiple stages of alcohol seeking. After one month of intermittent access to homecage 20% ethanol (EtOH), rats were trained to self-administer EtOH under an FR3 schedule and implanted with cannulae directed to lOFC or mOFC. We inactivated OFC subregions with baclofen/muscimol during EtOH self-administration, extinction, cue-induced reinstatement, and progressive ratio testing to broadly characterize the influence of these subregions on alcohol seeking. There were no significant effects of mOFC or lOFC inactivation during FR3 self-administration, extinction, or progressive ratio self-administration. However, lOFC, and not mOFC, inactivation significantly decreased cue-induced reinstatement of EtOH seeking. These findings contribute new information to the specific impact of OFC manipulation on operant alcohol seeking, support previous studies investigating the role of OFC in seeking and consumption of alcohol and other drugs of abuse, and indicate a specific role for lOFC vs. mOFC in reinstatement.

Keywords: Addiction; Alcohol use disorder; Motivation; Orbital; Prefrontal.

Fig. 1.

(A) Rats increased drinking over the course of homecage intermittent access. Mean ± SE EtOH in-take in g/kg on each drinking day over the course of 4 weeks of homecage drinking (pre-cannula implant) for mOFC implanted rats (n = 16, top) and lOFC implanted rats (n = 16, bottom). Significant effects observed across all animals (F(11, 341) = 5.97, p < 0.0001, mixed-effects model with Geisser-Greenhouse correction, main effect of drinking session) and within each group (mOFC (F(11, 165) = 4.00, p = 0.007) and lOFC (F(11, 165) = 2.84, p = 0.027, repeated-measures ANOVAs). See main text for additional analyses. (B) Cannula placements based on damage caused by injector cannulae. Gray ovals = mOFC placements. Black rectangles = lOFC placements. One rat was removed due to missed cannula placements. *p < 0.05, **p < 0.01.

Fig. 2.

OFC inactivation did not significantly influence EtOH self-administration. There were no significant decreases (as measured by paired t-tests) in active nosepokes, infusions, or inactive nosepokes after inactivation of either (A) mOFC (n = 14) or (B) lOFC (n = 16).

Fig. 3.

lOFC (n = 16), but not mOFC (n = 14) inactivation significantly decreased cue-induced reinstatement of EtOH seeking. (A) Extinction curve for mOFC-implanted rats. (B) Extinction curve for lOFC-implanted rats. (C) mOFC inactivation did not significantly alter active nosepokes or ethanol-cues received. Inactive nosepokes were slightly, but significantly decreased after mOFC inactivation (t(13) = 2.69, p = 0.02, paired t-test). (D) lOFC inactivation significantly decreased active nosepokes (t(15) = 3.31, p = 0.0048, paired t-test), and “infusions” received, i.e., cues elicited (t(15) = 3.25, p = 0.0054)., but not inactive nosepokes. See main text for additional analyses. *p < 0.05, **p < 0.01, ***p < 0.005.

Fig. 4.

OFC inactivation did not significantly affect extinction of EtOH seeking. There were no significant effects of inactivation of (A) mOFC (n = 14) or (B) lOFC (n = 8) on active or inactive nosepokes.

Fig. 5.

OFC inactivation did not significantly affect EtOH seeking under a progressive ratio schedule. (A) mOFC inactivation (n = 14) did not influence nosepokes or infusions. (B) lOFC inactivation (n = 8) decreased active nose-pokes and infusions, but the effect was not significant (nosepokes: (t(7) = 2.16, p = 0.068; infusions: (t(7) = 2.00, p = 0.09, paired t-test).