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Changes in in vivo dopamine efflux associated with drug-seeking behaviour by rats Di Ciano, Patricia


The experiments in the present thesis was designed to allow changes in dopamine efflux to be monitored, using in vivo chronoamperometry with stearate-modified graphite paste electrodes, during various phases of the binge-abstinence-relapse cycle of damphetarnine use by rats. Given the importance of the prevention of relapse in the treatment of psychostimulant addiction, particular attention was paid to the changes in dopamine efflux associated with animal models of relapse. Craving and relapse in humans are commonly associated with two events, namely: 1) during drug abstinence, psychostimulant use reverses the negative subjective and physiological aspects of psychostimulant withdrawal; and 2) following exposure to environmental stimuli, such as needles, that were previously associated with drug use. Accordingly, these two situations were studied in rats in an effort to better understand the role of dopamine in craving and relapse. The first two experiments were designed to monitor extracellular dopamine in the nucleus accumbens during voluntary abstinence and relapse following binge use of damphetarnine by rats, d-Amphetamine self-administration was associated with an increase in DA efflux which showed evidence of a tolerance following prolonged J-amphetamine self-administration. During abstinence, dopamine efflux fell to its lowest levels. Together, these findings suggest that following psychostimulant withdrawal, DA efflux is decreased. The finding that experimenter administration of ^-amphetamine to rats during the abstinence did not increase dopamine efflux above the nadir supports the view that abstinence may be associated with an inability of the dopamine system to respond further drug use. Moreover, reinitiation of ^-amphetamine self-administration by rats was associated with increases in dopamine efflux. This lends support to the hypothesis that during drug relapse by humans DA efflux is increased. The purpose of Experiments III and IV was to monitor changes in dopamine efflux during animal models of craving and relapse following the presentation of a conditioned stimulus repeatedly paired with ^-amphetamine infusions. The finding that presentation of a conditioned stimulus to rats was associated with robust increases in dopamine levels ini the nucleus accumbens indicates that CS can induce increases in DA efflux. Relapse is often studied in rats by monitoring the ability of a conditioned drug-related stimulus, or drug infusions, to reinstate operant responding following extinction of this behaviour. In Experiment IV, presentation of a conditioned stimulus to rats two days after drug withdrawal and extinction induced small and transient increases in both responding for the stimulus, and associated increases in dopamine efflux. Administration of <i-amphetamine reinstated robust bar pressing for this stimulus. The confirmation that reinstatement of drug-seeking behaviour by both a conditioned stimulus and the single administration of damphetamine was associated with increases in dopamine efflux supports the hypothesis that dopamine efflux in increased during behaviours maintained by a CS. The results of the present experiments are discussed in relation to a common role for dopamine in drugseeking behaviour during craving and relapse. Several treatment strategies also are discussed, with respect to the hypothesized role of dopamine in relapse.

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