Reinstatement of cocaine-seeking behavior induced by discrete sensory cues and the associated immediate early gene expression

Drug addiction is a serious problem for modern societies worldwide. There are remarkable costs associated with this problem, from the direct costs of the substance abuse treatment and prevention healthcare infrastructure to the less direct implications for the criminal justice system and social welfare programs. For individuals there is a loss of health, livelihood, interpersonal relationships, freedom, and ultimately life. The hallmark behavioral feature of addiction is a pattern of intermittent relapse lasting for decades after initial substance abuse. The research community has made a substantial investment of time and resources to better understand the etiology and fundamental features underlying addiction and relapse. Modern theories posit that addiction involves a recurring compulsion by an individual to engage in drug-seeking and drug-taking behaviors despite significant negative consequences. In humans, exposure to drug-associated stimuli and environmental contexts is known to induce an intense state of craving, independent of the length of time since acute drug exposure. Furthermore, neuroimaging studies of humans have suggested that basal ganglia structures may be involved in craving. Progress in the study of basal ganglia-mediated learning and memory has begun to outline a neuroanatomical substrate for the transition of egocentric, selfinitiated goal-directed behavior, to allocentric or externally driven behavior arising from exposure to environmental contexts or particular stimuli. While many elegant experiments have addressed the ability of drug-associated environmental contexts to affect behavior, the ability of discrete drug-associated sensory cues to affect behavior has been less thoroughly addressed. Discrete cues can become associated with drug use by two major operant learning mechanisms that vary in their temporal relationship to the subjective perception of primary reinforcement. The experiments described in this dissertation were designed to identify the extent to which discriminative stimuli and conditioned reinforcers activate the same or different populations of neurons in the dorsal striatum, the main input nucleus of the mammalian basal ganglia. This work has examined, in a novel experimental model of relapse, the capability of discrete sensory cues to elicit reinstatement of drug-seeking behavior and the expression of learning and memory related genes associated with this behavior.