Fig. 4.

VP inhibition reduces relapse-like behavior, especially in punishment-resistant rats. a Top panel: Example picture of a completed lever press. Bottom panel: CNO in VP-hM4Di rats modestly reduces active and inactive lever pressing for cocaine under threat of punishment on day 1 of punishment training. Control = vehicle-injected rats and CNO-injected VP misses. b Top panel: Example of an aborted press, in which the rat stretches its trunk toward the lever and extends its paw, without depressing the lever. Bottom panel: Active and inactive abortive lever pressing, quantified during safe (light/green shading) and punished (dark/red shading) intake sessions. CNO in VP-hM4Di rats reduced abortive lever pressing relative to control rats, returning abortive pressing to unpunished self-administration levels. Control = vehicle-injected rats and CNO-injected VP misses. c–f Within-subject comparisons of reinstatement for VP-hM4Di rats (top panels) in safe (light/green shading) and punishment (dark/red shading) contexts. CNO in VP-hM4Di rats reduced reinstatement in the safe context with cues (c), without cues (d), and with cocaine and no cues (e) but not in the punishment context with cues (f). CNO in control rats did not affect reinstatement under any condition (bottom panels). Control = eGFP-only rats and rats with hM4Di expression primarily outside VP. g CNO in VP-hM4Di punishment-resistant rats (dark/red bars) elicited a greater decrease in cued reinstatement, relative to VP inhibition in punishment-sensitive rats (light/gray bars). Data presented as change from vehicle test baseline. *p < 0.05, **p < 0.01, ***p < 0.001