instrucfions): Addiction to drugs of abuse produces pathological changes in synaptic physiology that impair the capacity of the prefrontal cortex (PFC) to communicate with the basal ganglia and impedes the successful regulation of compulsive drug-seeking. The primary portal of entry by the PFC into the basal ganglia is through the nucleus accumbens, and withdrawal from self-administered cocaine is associated with enduring adaptations at PFC synapses in the accumbens. As part of the current Project 1 (2008-13), we characterized differences in accumbens adaptations depending on whether or not rats were withdrawn with or without extinction training. We recently discovered a rapid, transient synaptic potentiation in the accumbens core (NAcore) but not in the shell (NAshell) that correlated with the intensity of cue-reinstated cocaine seeking. Conversely, a similar synaptic potentiation occurs in the NAshell, not NAcore, when rats are placed into an extinguished context. Aim 1 will characterize this rapid accumbens synaptic plasticity using different behavioral protocols. Aim 2 uses optogenetics to test the hypotheses that giutamatergic afferents from the PFC and dopaminergic inputs from the ventral tegmental area (VTA) are necessary forthe rapid, transient synaptic potentiation in excitatory transmission to be characterized in Aim 1. A variety of proteins and signaling mechanisms are purported to account for the cocaine-induced changes in synaptic plasticity at PFC-accumbens synapses. We present preliminary data showing a potential role for matrix metalloproteases (MMPs) in reinstated cocaine seeking and the plasticity being characterized in Aims 1 & 2. MMP activity known to be is necessary for shaping the extracellular matrix and for expressing many forms of plasticity, and in Aim 3 we propose to determine: 1) if inhibiting MMP signaling reduces cocaine seeking and extinction responding, and 2) if this is accomplished by preventing the rapid, transient synaptic potentiation being characterized in Aims 1 & 2. Project 1 synergizes with other NARC projects and cores by sharing animal and optogenetic use through the Animal Core, and through scientific synergisms based on all projects examining different aspects of PFC and VTA regulation ofthe nucleus accumbens. RELEVANCE (See instrucfions): Project 1 describes a new form of morphological and physiological synaptic plasticity that is correlated with cocaine seeking. This synaptic plasticity will be evaluated for its importance in cocaine seeking, as well as in the ability to inhibit cocaine seeking. A set of enzymes, the MMPs, are known to regulate synaptic plasticity and have been shown to regulate cocaine seeking. These enzymes will be examined as a possible target for therapeutic intfirvention in animal models of cocaine relaose.