The role of matrix metalloproteinase-9 in negative reinforcement learning and plasticity in alcohol dependence

A role for matrix metalloproteinases (MMPs) in plasticity-dependent learning has been established. MMPs degrade the extracellular matrix (ECM) when synaptic reorganization is warranted. Previously, we showed that escalation of alcohol self-administration is a learned plasticity-dependent process that requires an intact MMP system. To identify the MMP subtypes within specific brain regions that are associated with plasticity underlying the negative reinforcing effects of alcohol (as measured by escalated alcohol self-administration) during acute withdrawal in alcohol dependence, male Wistar rats were trained to self-administer alcohol in an operant paradigm, subjected to one month of intermittent alcohol vapor exposure to induce alcohol dependence and then allowed to self-administer alcohol during repeated acute withdrawal self-administration sessions. Subsequently, rat brains were extracted after initial or stable escalated alcohol self-administration phases of acute withdrawal and analyzed by immunoblot to detect MMP-2, -3, and -9 levels in the anterior cingulate cortex (ACC), bed nucleus of the stria terminalis, central amygdala (CeA), hippocampus, and nucleus accumbens (NAc). The results showed that MMP-9 expression in the CeA and NAc of alcohol-dependent rats was increased, however, MMP-9 expression in the ACC was decreased during negative reinforcement learning. Subsequently, the importance of plasticity mediated by MMP-9 in escalated alcohol self-administration during acute withdrawal was functionally assessed through site-specific intra-CeA MMP-9 inhibition during repeated acute withdrawal self-administration sessions. MMP-9 inhibition prevented acute withdrawal-induced escalation of alcohol self-administration in a manner that was not confounded by locomotor effects or a permanent inability to learn about the negative reinforcing effects of alcohol.