In summary, the present experiment confirmed that chronic intermittent ethanol vapor exposure induces the dependence-like phenotype of escalated ethanol self-administration that is hypothesized to represent negative reinforcement learning. Importantly, it was shown for the first time that inhibition of MMPs by FN-439 exclusively during acute withdrawal can disrupt the development of the dependence-like phenotype. This confirmed that escalated responding for ethanol during acute withdrawal in dependent animals is a learned response and that an intact MMP system is required for the plasticity that underlies such escalations in operant ethanol self-administration produced by dependence.
