Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems.

Diagram of the experimental design for the acute and chronic FN-439 treatment regimens following the acquisition of operant ethanol self-administration, dependence induction and post-dependence induction self-administration sessions during acute withdrawal. aCSF = artificial cerebrospinal fluid, ICV = intracerebroventricular and PDI = post-dependence induction.

Intermittent ethanol vapor induces escalated responding during acute withdrawal in dependent animals. Representative of the typical dependence-like phenotype during acute withdrawal, there is a significant Exposure × Session interaction (*= p≤0.05) for operant ethanol self-administration following one month of intermittent ethanol vapor exposure for testing that occurred 6 hrs into acute withdrawal. The dashed line indicates one month of chronic intermittent ethanol vapor exposure, with pre-vapor exposure sessions on the left and post-dependence induction sessions during acute withdrawal (AW) on the right (n=5 / grp for the air- and vapor-exposed animals).

Chronic MMP inhibition prevents escalated responding for ethanol. Mean (+S.E.M) ethanol consumption during baseline and post-vapor self-administration sessions for animals that had chronic intracerebroventricular FN-439 (n = 7) or artificial cerebrospinal fluid (aCSF, n= 5) treatment via osmotic minipumps during the one month of intermittent vapor exposure and subsequent post-vapor testing. A significant Drug Treatment × Session interaction was found (*= p≤0.05) indicating that the escalation of ethanol self-administration differed over the sessions depending on whether the animals were aCSF-treated or had received FN-439. PVI = initial post-vapor sessions and PVE = escalated post-vapor session.

Acute MMP inhibition, restricted to post-dependence induction acute withdrawal test days, prevents escalated responding for ethanol. Mean (+S.E.M) ethanol consumption during baseline and post-vapor sessions for animals receiving acute intracerebroventricular FN-439 (n = 6) or artificial cerebrospinal fluid (n = 5) infusions following one-month of intermittent vapor exposure. A significant Drug Treatment × Session interaction was found (*= p≤0.05) indicating that acute exposure to FN-439 attenuated the negative reinforcement learning associated with the development of the dependence-like phenotype of excessive ethanol self-administration. PVI = initial post-vapor sessions and PVE = escalated post-vapor session.

Control conditions required for a learning-based explanation of dependence-induced escalation. Left panel: Mean (+S.E.M) ethanol consumption during the session in which the artificial cerebrospinal fluid (aCSF) – treated animals escalated (PVE) compared to those same animals receiving subsequent acute intracerebroventricular FN-439 infusion. The lack of an acute FN-439 effect shows that once negative reinforcement learning has occurred and the animals show escalated response patterns, inhibition of matrix metalloproteinases has no impact. Right Panel: Mean (+S.E.M) ethanol consumption following acute aCSF infusions in animals initially treated with FN-439 that did not display negative reinforcement learning (i.e., did not show escalated responding)–demonstrates that those animals are capable of learning and display a normal dependence-like phenotype in the absence of FN-439. A significant main effect of session (†= p≤0.05) was observed for the three aCSF-treated sessions.