As a result, the second experiment was conducted in which the animals were allowed to develop dependence and then received acute administration of FN-439 immediately before and after the acute withdrawal operant self-administration sessions. This assessed whether MMP inhibition, at the time point at which negative reinforcement learning would be hypothesized to occur, would be sufficient to attenuate escalated operant self-administration even though any neuroadaptations associated with dependence-induction had been allowed to occur. Rats which received acute ICV infusions of FN-439 before and after self-administering ethanol did not develop the escalated response pattern that typifies acute withdrawal and is hypothesized to reflect negative reinforcement learning (Walker and Koob, 2008; Koob and Le Moal, 1997; 2008; Walker et al., 2011; Nealey et al., 2011). Thus, MMP inhibition during acute withdrawal in dependent animals was sufficient to attenuate escalations in operant self-administration even though the animals had an intact dependence induction phase. These results are consistent with those established previously showing that MMP expression is necessary for the occurrence of plasticity associated with learning (Meighan et al., 2007; Meighan et al., 2006;
