al., 2008). Furthermore, MMP-9 levels are increased following cocaine-primes in a reinstatement paradigm (Brown, Forquer, Harding, Wright, & Sorg, 2008), have been shown to be altered in the hippocampus by chronic cocaine exposure (Mash et al., 2007) and are increased in mice displaying behavioral sensitization to methamphetamine (Mizoguchi et al., 2007). Interestingly, a functional polymorphism in the MMP-9 gene is associated with alcohol dependence in humans (Samochowiec et al., 2010) and, although it relates to peripheral rather than brain MMPs, serum MMP-9 concentrations are increased alcoholics compared to controls (Sillanaukee, Kalela, Seppa, Hoyhtya, & Nikkari, 2002). In addition, MMP-3 is required for spatial learning (Meighan et al., 2006), as well as passive avoidance conditioning (Olson et al., 2008) and habituation (Wright et al., 2009). Future studies will need to be conducted in order to identify the precise involvement of the different MMPs, as well as specific brain nuclei in which synaptic remodeling is occurring as the basis of escalated operant self-administration.
