REDUCTION OF DOPAMINE RELEASE AND SYNTHESIS BY REPEATED AMPHETAMINE TREATMENT - ROLE IN BEHAVIORAL SENSITIZATION

Changes in extracellular dopamine concentration in the ventral striatu m during repeated amphetamine administration and over the first 7 days of withdrawal were studied by transversal microdialysis in freely mov ing rats. 2 days after fiber implantation rats were treated with eithe r amphetamine (1.5 mg/kg i.p.) or saline every 12 h for 14 days. In am phetamine-treated rats, the baseline extracellular dopamine concentrat ion, preceding the morning treatment, increased from 0.43 +/- 0.01 on day 1 up to 0.59 +/- 0.02 pmol/40 mu l sample on day 3 of treatment. T hereafter, dopamine fell rapidly on day 5 (0.16 +/- 0.01 pmol/40 mu l) and remained at approximately the level reached on day 7 (0.11 +/- 0. 01 pmol/40 mu l) throughout the treatment and also over the 7 days of withdrawal. In contrast, in control rats, the extracellular dopamine c oncentration (0.40 +/- 0.01 pmol/40 mu l, on day 1) decreased progress ively during the first days of treatment to reach a fairly stable valu e on day 4 (0.25 +/- 0.01 pmol/40 mu l sample). Thereafter, dopamine r emained stable at this level throughout the remaining period of experi mentation. Challenge with amphetamine (1.5 mg/kg i.p.) of animals trea ted with amphetamine for 10 days or withdrawn for 7 days produced a po tentiated motor response compared to that in control rats but much les s marked dopamine releasing effects. Dopamine synthesis in the ventral striatum, measured as L-dihydroxyphenylalanine formation after blocka de of dihydroxyphenylalanine decarboxylase, was found to be reduced by approximately 60% after 2 weeks of amphetamine treatment and in anima ls withdrawn for 1 day or 7 days. These results indicate that repeated amphetamine treatment causes persistent inhibition of dopamine synthe sis and release in the ventral striatum. Such inhibition may be a comp ensatory response to the repeated stimulation of postsynaptic dopamine receptors by the endogenously released dopamine and also the cause of postsynaptic sensitization to dopamine action.