Reduction of dopamine release and synthesis by repeated amphetamine treatment: role in behavioral sensitization.
Changes in extracellular dopamine concentration in the ventral striatum during repeated amphetamine administration and over the first 7 days of withdrawal were studied by transversal microdialysis in freely moving rats. 2 days after fiber implantation rats were treated with either amphetamine (1.5 mg/kg i.p.) or saline every 12 h for 14 days. In amphetamine-treated rats, the baseline extracellular dopamine concentration, preceding the morning treatment, increased from 0.43 +/- 0.01 on day 1 up to 0.59 +/- 0.02 pmol/40 microliters sample on day 3 of treatment. Thereafter, dopamine fell rapidly on day 5(0.16 +/- 0.01 pmol/40 microliters) and remained at approximately the level reached on day 7(0.11 +/- 0.01 pmol/40 microliters) throughout the treatment and also over the 7 days of withdrawal. In contrast, in control rats, the extracellular dopamine concentration (0.40 +/- 0.01 pmol/40 microliters, on day 1) decreased progressively during the first days of treatment to reach a fairly stable value on day 4 (0.25 +/- 0.01 pmol/40 microliters sample). Thereafter, dopamine remained stable at this level throughout the remaining period of experimentation. Challenge with amphetamine (1.5 mg/kg i.p.) of animals treated with amphetamine for 10 days or withdrawn for 7 days produced a potentiated motor response compared to that in control rats but much less marked dopamine releasing effects. Dopamine synthesis in the ventral striatum, measured as L-dihydroxyphenylalanine formation after blockade of dihydroxyphenylalanine decarboxylase, was found to be reduced by approximately 60% after 2 weeks of amphetamine treatment and in animals withdrawn for 1 day or 7 days. These results indicate that repeated amphetamine treatment causes persistent inhibition of dopamine synthesis and release in the ventral striatum. Such inhibition may be a compensatory response to the repeated stimulation of postsynaptic dopamine receptors by the endogenously released dopamine and also the cause of postsynaptic sensitization to dopamine action.
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Department of Neuroscience Bernard B. Brodie, University of Cagliari, Italy.
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D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D007980:Levodopa; D000661:Amphetamine; D004298:Dopamine