| Summary: | Previous studies in humans and animals have shown that withdrawal from high
doses of psychostimulant drugs can lead to a number of aversive psychological
symptoms. One of the more prominent symptoms is anhedonia, a core symptom of major
depression, manifested behaviourally as decreased interest in normally rewarding stimuli.
Several preclinical studies have shown that withdrawal from a chronic schedule of
psychostimulant administration can produce discrete disturbances in psychological and
affective processes, such as decreases in rodents' responding for rewarding electrical
brain stimulation, and disruption in responding for natural rewarding stimuli (i.e. a
sucrose solution, or a sexually receptive rat). These effects are likely due to a long-lasting
reduction in the efflux of dopamine (DA) in limbic nuclei, such as the nucleus accumbens
(NAc), a brain area that is involved in mediating reward processes.
The main purpose of this thesis was to furthur investigate the relationship between
psychostimulant withdrawal and anhedonia in the rat. In the first series of experiments
the brain microdialysis technique, coupled with HPLC, was used to evaluate in freelymoving
rats the effect of withdrawal on stimulus-induced changes in DA efflux in the
NAc following a 4-day escalating-dose schedule of D-amphetamine administration (1-10
mg/kg, i.p., at ~8 hr intervals). In drug-withdrawn rats, the DA efflux in the NAc was
significantly blunted in response to both pharmacological (a 5 mg/kg D-amphetamine
injection i.p.), and natural rewards (4% sucrose), compared to vehicle-treated rats. The
second series of experiments, investigated whether the negative affective state of drugwithdrawn
rats could affect their response to the positive contrast paradigm, in which rats
shifted from a 4% to 32% sucrose condition respond significantly more than rats always
maintained on 32% sucrose. Drug-withdrawn rats failed to display successive positive
contrast, suggesting that incentive contrast is a particularly sensitive measure to detect
changes in motivation and emotion. These data are consistent with many previous reports
that withdrawal from a binge-like regimen of psychostimulant drug administration
disrupts responding for natural reward stimuli, and provide important support for the
hypothesis that withdrawal following exposure to escalating doses of psychostimulant
drugs produces depressive-like symptoms, and that this model of psychostimulant drug
withdrawal may be used as an animal model of depression. === Medicine, Faculty of === Graduate
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