NeuroAIDS, the neurological manifestations associated with HIV infection, has been associated with increases in drug abuse. It has been proposed that HIV viral proteins may be responsible for the central nervous system pathology associated with NeuroAIDS. We hypothesized that HIV-Tat protein potentiates the rewarding effects of drugs of abuse through a MAP kinase sensitive mechanism. Using a transgenic mouse model with inducible and brain-selective Tat expression, we tested the effects of Tat on drug reward using the conditioned place preference (CPP) assay. Mice induced to express Tat demonstrated a preference for cocaine and morphine that was significantly potentiated compared to the response of their uninduced littermates. To determine a mechanism by which Tat might alter the rewarding properties of drugs of abuse, we examined the activity of signal transduction cascades known to be influenced by Tat expression. Data indicated a significant increase in activated ERK1/2 MAP kinase and pretreatment with the ERK1/2 MAP kinase inhibitor SL-327 attenuated the potentiated cocaine-CPP response in Tat-induced mice. Overall, these data may offer insight into the mechanism by which HIV affects drug reward and suggests that HIV-Tat protein may be necessary and sufficient to induce these behavioral changes.