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

Abstract

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 selfadministration 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. KEYWORDSalcohol dependence, matrix metalloproteinase, negative reinforcement

Phenotypic and gene expression features associated with variation in chronic ethanol consumption in heterogeneous stock collaborative cross mice

“…Some key findings include: (1) Chronic broad spectrum MMP inhibition during ethanol dependence induction and withdrawal prevented escalated ethanol self-administration in rats; moreover, acute MMP inhibition after induction of ethanol dependence prevented expression of escalated ethanol intake [65]. (2) Go et al [66] focused on the role(s) of the MMPs in withdrawal-induced escalation of ethanol self-administration and observed that MMP-9 activity was increased in the CeA and NAc as a function of escalation. Further, they observed that site-specific inhibition of MMP-9 blocked the withdrawal-induced escalation.…”

Alteration of Ethanol Reward by Prior Mephedrone Exposure: The Role of Age and Matrix Metalloproteinase-9 (MMP-9)

“…On the other hand, the acquisition of CPP for abuse drugs is a learning process [71]. Still, while MMP-9 is increased during drug-induced learning processes, when learning/plasticity is posited to have been completed, MMP-9 expression returns to pharmacological control levels in some brain structures, including the NAc [35,69,[72][73][74]. Thus, we hypothesize that transient changes in MMP-9 could have occurred in the vSTR during the active phase (rising phase of the acquisition curve when performance is improving) of learning and memory consolidation of ethanol-induced CPP in rats.…”

Alcohol Dependence in Rats Is Associated with Global Changes in Gene Expression in the Central Amygdala

“…Many of these genes are expressed in a cell type-specific manner and many of the functional groups represent known functions of specific brain cells, providing a more focused interpretation of the data. The CeA is a key brain region implicated in the regulation of escalated alcohol drinking in alcohol-dependent subjects [ 32 , 64 , 65 , 66 , 67 , 68 ]. It is the major output nucleus of the amygdala, and is connected to other parts of the extended amygdala, as well as other key brain regions involved in the regulation of alcohol effects.…”

“…MMPs are Zn +2 dependent endoproteinase that are important for the cleavage of extracellular proteins and inactivation of certain chemokines and cytokines (i.e., cleavage of TNF-α, glycoproteins, and collagen) [ 84 , 85 , 86 ]. MMPs have been linked to several biological functions within the brain such as synaptic plasticity [ 65 , 72 , 87 ], upregulation in gliomas [ 88 ], chronic inflammatory diseases [ 89 ], AUD [ 72 , 87 ], and neuron/CNS repair mechanisms [ 83 ]. Similar to MMPs, ADAMs are membrane anchored enzymes that are regulated by Zn +2 and play a similar role to MMPs.…”