Effect of the dopaminergic neurotoxin MPTP on cocaine-induced locomotor sensitization

The blockade of dopamine (DA) uptake via the dopamine transporter (DAT) in the nucleus accumbens (NAC) and striatum by cocaine has a major role in the reinforcing and psychomotor stimulating effects of the drug. Here we inves tigated the effect of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine (MPTP) on the expression and induction of sensitization to the locomotor stimulating effect of cocaine. MPTP (20 mg/kg x 4) caused 72 and 76% depletion of DAT sites in the NAC and striatum, respectively, i n C57BL/6 mice. The magnitude of this depletion 3 and 19 days after MPTP ad ministration was the same. To determine the effect of MPTP on the expressio n of the sensitized response to cocaine, cocaine-experienced mice (20 mg/kg for 5 days) received MPTP 3 days before a challenge cocaine injection was given on day 15. Cocaine/MPTP mice were significantly more sensitive to the challenge cocaine injection than the cocaine/saline-pretreated mice. To de termine whether depletion of NAC and striatal DAT affects the induction of sensitization to cocaine, mice were pretreated with MPTP 3 days before the administration of cocaine (20 mg/kg for 5 days). The magnitude of the sensi tized response of MPTP/cocaine-pretreated mice to cocaine challenge was the same as the sensitized response of mice treated with saline/cocaine, while the number of DAT binding sites in the MPTP/cocaine group was significantl y lower than the saline/cocaine group. The present study indicates that MPT P exacerbates the expression of locomotor sensitization to cocaine, but it had no effect on the induction of sensitization. We conclude that the expre ssion, but not the induction, of locomotor sensitization to cocaine may be dependent on the level of DAT binding sites. (C) 1999 Elsevier Science Inc.