Interactive influences of catecholamines and corticotropin-releasing factor in anxiety responses and the reinstatement of cocaine seeking in rats: role of withdrawal duration

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Significant advances have been made toward characterizing the basic neurobiological substrates underlying renewed drug seeking in rats. Central to this effort are studies based on an animal model of relapse, known as the reinstatement procedure. In this procedure, an animal is trained to perform a behavioural response for drug infusions. Subsequently, the behaviour is extinguished by withholding drug, at which time the reinstatement of drug seeking is triggered by exposure to an event, such as a priming injection of drug, exposure to drug-associated cues, or exposure to a stressor. An important factor to consider in the study of reinstatement is withdrawal duration. Indeed, the motivational and corresponding neurobiological factors affecting the propensity for reinstatement at one time following termination of drug taking may be very different than at another time. The proposed experiments are designed to provide a systematic investigation of the relationship between anxiety responses and reinstatement of cocaine seeking as a function of withdrawal duration, and the corresponding neuronal processes. The general hypothesis of the proposal is that the balance of activity within specific stress-responsive brain circuits, including those containing the neurochemicals corticotropin-releasing factor, noradrenaline, and dopamine, changes depending on time lapsed since the termination of cocaine self-administration, and these changes are reflected in behaviour, including the expression of anxiety-like behaviour and stress-induced reinstatement of cocaine seeking. Furthermore, it is hypothesized that there is a lack of correspondence between conditions that elicit anxiety-like responses and the stress-induced reinstatement of cocaine seeking. This work is important toward understanding the motivational factors that influence reinstatement responding at different times following the termination of drug self-administration and, more generally, toward clarifying the mechanisms mediating addiction, reinstatement, and drug seeking.