| Abstract
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Humans and animals learn to avoid pain and to seek pleasure. In fact, actions that are essential to the survival of the organism such as mating, eating, and drinking, are invariably pleasurable. The subjective experience of pleasure is typically perceived when engaging the sensory systems, but may even begin in anticipation of consumption of a given reward. These sensory systems send neural projections to areas of the brain that, when activated, produce euphoria in humans and reinforce behavior that is instrumental in obtaining rewards. To protect from over consumption, organisms also have evolved the capacity to stop seeking and consuming rewards. These feedback mechanisms reduce the sensation of pleasure with continued consumption. This is why turkey tastes far better at the beginning of Thanksgiving dinner than at the end. Such is not the case with the consumption of drugs of abuse. Drugs of abuse directly and potently activate brain reward systems and they do not rely, at least initially, on the senses to produce their pleasurable effects. In fact, this potent activation turns ordinary sights, sounds, places, smells, and tastes into profound emotional experiences and coveted goals in and of themselves by mere association. In this way, abused drugs ‘hijack’ brain reward systems by eroding self-control and redirecting attention and motivated behaviors toward the drug and its associated cues. Furthermore, as drug taking escalates, brain reward substrates are repeatedly overstimulated and become hypersensitive in the presence of drug while becoming hyporesponsive in its absence. This hyposensitivity increases negative affect, and reduces the sensitivity to the relative value of less powerful natural rewards and increases drug craving and seeking. The result is a compulsive preoccupation with drug seeking and consumption, and a reduced motivation to pursue natural rewards (e.g., employment, child care, nutritional needs, sex). Despite the pervasive nature of this debilitating aspect of drug addiction there are no animal models that target it. Therefore, the basic research contained within this dissertation is organized under one theme: To create a rodent model of drug-induced devaluation of natural rewards and cue induced craving. To that end, rats were given access to a saccharin cue that always predicted access to either passively delivered or self-administered drug (usually cocaine). Upon repeated pairings with the drug of abuse, the value of the saccharin cue decreased similar to when it predicts access to a much sweeter sucrose solution. In the first set of experiments, the parameters under which devaluation of a palatable taste cue occurs were determined, individual differences in the phenomenon were characterized, and this variation was compared to cocaine seeking and self-administration. Principally, it was found that the more sensitive a rat was to the reinforcing properties of the drug the less of the saccharin cue they consumed. The next set of experiments tested manipulations that might protect against the acquisition of cocaine self-administration. Interestingly, relative to active administration, the unpredictable, uncontrollable yoked delivery of cocaine enhanced saccharin avoidance, reduced the motivation to work for cocaine, and reduced the preference for contextual cues associated with drug delivery. Additionally, it was found that a sudden unexpected loss or gain of sucrose reward had no effect on the motivation to self-administer cocaine; however, daily experience with a consistently high sucrose reward, relative to a low one, greatly reduced the motivation to work for cocaine. The last two chapters investigated the role of the VTA and NAc, two brain regions critical for drug reward, in modulating the devaluation of saccharin by drugs of abuse. It was found that dopaminergic lesions of the VTA had little effect on the phenomenon. Nevertheless, the electrophysiological experiment showed that the activity of single neurons in the NAc (the target for VTA dopamine release) tracked thi devaluation. The degree of devaluation was associated with a shift toward negative affect, and this shift predicted the rapidity with which rats would seek and take drug. Together, these data integrate several distinct theories of drug addiction, provide a behavioral model for the investigation of novel drug therapeutics to combat addiction, and reveal new insight on the solution to a nearly 40 year old paradox.
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