Stimuli that have been paired with reward can potentiate behavior aimed at obtaining the reward. This potentiating effect of Pavlovian conditioned cues on reward seeking, termed Pavlovian-instrumental transfer, generally is adaptive; however, it can become maladaptive when the reward is pursued in excess or induces damage, as is the case in drug addiction and obesity. The goal of the present proposal is to shed light on the neurobiological mechanisms underlying Pavlovian-instrumental transfer. We recently found that exposure to a reward-paired cue induces a transient increase in the activation of extracellular signal-regulated kinase (ERK) in the nucleus accumbens (NAc) of adult rats, and that this activation is required for the ability of the conditioned cue to potentiate reward seeking (Shiflett et al., 2008). These observations suggest an important role for NAc ERK in the mediation of the incentive-motivational properties of conditioned cues. The goal of the present proposal is to determine the receptors and cell types within the NAc involved in the cue-driven ERK activation (Specific Aim 1), the output targets of the NAc impacted by the cue-driven ERK activation (Specific Aim 2), and ERK-mediated intracellular events through which the cue-driven activation of this enzyme may facilitate reward seeking (Specific Aim 3). For each of these aims, our working hypotheses are as follows. The CS-driven ERK activation results from activation of D1 dopamine and NMDA glutamate receptors on NAc cells. The cell type that expresses CS-driven ERK activation are D1 receptor-expressing projection neurons that are part of direct, disinhibitory output pathways from the core and the shell of the NAc. CS-driven ERK activation within these projection neurons transiently raises their excitability, thereby facilitating output from these neurons onto their targets. The disinhibitory effect, in turn, promotes enhanced reward seeking. We will test these hypotheses using a powerful and innovative combination of behavioral, pharmacological, peroxidase- and double-flouresence immunohistochemical, retrograde tracing, and molecular techniques. The findings from the proposed work will advance our understanding of a fundamental aspect of behavior control by reward- predictive cues. The findings also will have implications for our understanding of the neural processes that contribute to costly behavioral aberrations, such as addiction and obesity, and the development of strategies for the treatment of these behavioral aberrations.