Behavioural and neurochemical coorelates of psychostimulant withdrawal as an animal model of depression

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 In drug-withdrawn rats, the DA efflux in the NAc was significantly blunted in response to both pharmacological (a 5 mg/kg D-amphetamine injection i.p.), and natural rewards (4%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 Drug-withdrawn rats failed to display successive positive contrast, suggesting that incentive contrast is a particularly sensitive measure to detect changes in motivation and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 ofGraduat