| Summary: | 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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