BOSTON UNIVERSITY SCHOOL OF MEDICINE Dissertation THE ACQUISITION AND EXTINCTION OF MORPHINE CONDITIONED PLACE PREFERENCE HAVE OPPOSITE EFFECTS ON THE MORPHOLOGY OF NEURONS IN THE NUCLEUS ACCUMBENS by KENDRA

Drug-associated stimuli trigger craving and relapse in addiction. Murine morphine conditioned place preference (CPP) was used to model learning of opioid associations. We examined how morphine and learning interact to alter neuron morphology in the nucleus accumbens (NAc) core and shell after acquisition and extinction of CPP. Conditioning with morphine dose-dependently increased place preference compared to saline. In comparison to those from saline conditioned and morphine non-conditioned controls, neurons from the NAc core of morphine conditioned mice had increased dendritic complexity, as defined by increased dendritic length, number, and Sholl intersections. This effect is due to the combination of morphine and learning, which is different from effects of morphine or conditioning alone. Morphine administration without conditioning was associated with increased spine density in the core, which was reversed by CPP acquisition. Control ix conditioning with saline produced no morphology changes. Morphine CPP extinction was associated with decreased dendritic complexity, reversing the increased complexity seen after acquisition. Mice that extinguished CPP had similar dendritic complexity to saline conditioned mice, in terms of dendritic count and intersections, but less dendritic complexity than non-extinguished mice that retained CPP. Since dopamine release imbues salience to stimuli that coincide with drug use, and the dopamine D1 receptor mediates CPP acquisition, we tested the effect of SKF81297 D1 receptor agonist on CPP extinction and associated accumbal neuron morphology. SKF81297 (0.8 mg/kg) injected after each extinction training session impeded extinction, and produced increased dendritic complexity compared to controls. SKF81297 may have sustained conditioned associations, disrupted consolidation of extinction, and/or disrupted the decline in dopamine levels that may occur throughout extinction sessions. We hypothesize that changes occurred in the NAc core because this region mediates how stimuli and drug effects direct motor action. Since D1 receptors oppose extinction of drug-cue-induced behavior, they play a role in reinforcing opioid addiction. Acquisition and extinction may be opposite processes in the brain, as in behavior. Extinction may include some reversal of acquisition learning as well as being new learning with its own pathway. Interventions that target D1 receptors or that selectively reduce NAc core dendritic complexity may contribute to opioid addiction treatment.