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Rats in a vehicle treated control condition when shifted from 4% to 32% sucrose displayed successive positive contrast by responding at a significantly higher lick rate in a 5 min trial than rats maintained on 32% sucrose throughout the experiment. In contrast, rats treated with an escalating dose regimen of D-amphetamine (1-10 mg/kg) over a 4 day interval failed to display successive positive contrast. Withdrawal from drug treatment had no effect on lick rate or response latency in rats maintained on 32% sucrose. 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. These findings support the use of psychostimulant withdrawal as a model of drug-induced dysphoria and suggest that incentive contrast is a particularly sensitive measure of these changes in motivation and emotion.

Abstinence from high doses of psychostimulant drugs, in both humans and rodents, is linked to adverse psychological effects including anhedonia, a core symptom of major depression, manifested behaviorally as decreased responding for rewarding stimuli. The present study used brain microdialysis in freely moving rats to examine the effect of D-amphetamine (D-amph) withdrawal on changes in extracellular dopamine (DA) levels in the nucleus accumbens (NAc) evoked by D-amph or behavior related to sucrose consumption. D-amph was administered intraperitoneally (i.p.) according to an escalating dose (ED) schedule (from 1 to 10 mg/kg, 3 doses/day). We first confirmed the development of tolerance by monitoring DA efflux in the NAc in response to 5 and 10 mg/kg doses of D-amph administered during the ED schedule of drug administration and again in response to the 5 mg/kg dose of D-amph 72 h following the last 10 mg/kg D-amph injection. In a separate study, DA efflux in the NAc was first shown to be increased significantly during both preparatory and consummatory phases of responding for a 4% sucrose solution. Withdrawal from the ED schedule of D-amph caused a selective attenuation of DA efflux only during the preparatory phase of the sucrose test. These results provided convincing evidence of neurochemical adaptation within the mesocorticolimbic DA pathway during and following the administration of an ED schedule of D-amph as well as suppressed neurochemical responses to a psychostimulant drug and cues associated with a natural reward after withdrawal from drug treatment. Accordingly, these findings support the hypothesis that downregulation of mesocorticolimbic DA function maintained during D-amph withdrawal may account for the selective disruption of motivated behavior reported in studies employing psychostimulant drug withdrawal as a model of depression in rodents.Neuropsychopharmacology (2007) 32, 932–939. doi:10.1038/sj.npp.1301173; published online 2 August 2006 [ABSTRACT FROM AUTHOR]