Substance use disorder is a chronic, often relapsing disease that can include a loss of behavioral inhibition and compulsive drug-seeking. Acquisition of a reward seeking behavior often begins when cues are paired with rewards. These cues are thought to influence subsequent extinction (animal model of exposure-based therapy) and relapse-like behavior, both in humans and animals. My work found that acquisition and extinction of cocaine-induced conditioned place preference (CPP) were sensitive to the configuration of the apparatus (Chapter 2) and that the dorsal hippocampus (DH) regulated expression of CPP after acquisition and extinction (Chapter 3). At the molecular level, the epigenetic enzyme histone deacetylase 3 (HDAC3), is a negative regulator of cocaine-associated learning and spatial memory. I determined that inhibition of HDAC3 activity enhanced this hippocampus-based extinction after operant self-administration. Extended extinction did not eliminate contextual or cue-induced reinstatement, but the systemic injection of RGFP966 (HDAC3 inhibitor) caused persistent extinction and weakened context and cue-induced reinstatement (Chapter 4). The generality of these findings was examined by assessing overexpression of a wildtype or point mutant version of HDAC3 in the dorsal hippocampus during acquisition and extinction of responding for natural rewards (food pellets). In this experiment, the HDAC3 point mutant led to faster acquisition and faster extinction, similar to prior effects with the systemic HDAC3 inhibitor (Chapter 5). Together, this dissertation presents novel findings on xii interactions between the context, dorsal hippocampus, and HDAC3 regulating acquisition and extinction of Pavlovian (Chapters 2-3) or instrumental reward-seeking behaviors (Chapters 4-5). Further research on these factors and associated brain activity may be used to design novel prevention and treatment for problematic and context-dependent reward behavior.