EVIDENCE FOR A PROTECTIVE ACTION OF THE VIGILANCE PROMOTING DRUG MODAFINIL ON THE MPTP-INDUCED DEGENERATION OF THE NIGROSTRIATAL DOPAMINE NEURONS IN THE BLACK MOUSE - AN IMMUNOCYTOCHEMICAL AND BIOCHEMICAL-ANALYSIS

Based on the observations that the psycho-stimulant drug amphetamine in combination with physiotherapy can promote recovery of brain function after brain injury, we have studied the ability of the vigilance promoting drug Modafinil to counteract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP)-induced degeneration of the nigrostriatal dopamine (DA) neurons of the black mouse. MPTP was given s.c. in a dose of 40 mg/kg and the mice were sacrificed 2 weeks later. The effects of acute and chronic treatment with Modafinil were studied on MPTP-induced DA neurotoxicity. The substantia nigra and neostriatum were taken to both biochemical and histochemical analysis of presynaptic parameters of the nigrostriatal DA neurons, the latter in combination with image analysis. In separate experiments in rats in vivo tests for DA uptake blocking activity were made using intrastriatal microdialysis to study superfusate levels of DA and its metabolites and the 4-alpha-dimethylmetatyramine (H77/77) model to test for a possible ability of Modafinil to protect against H77/77-induced depletion of forebrain DA stores. Chronic treatment with Modafinil in doses of 10 to 100 mg/kg counteracted the MPTP-induced disappearance of nigral TH IR nerve cell body profiles and neostriatal TH IR nerve terminal profiles as evaluated after 2 weeks with image analysis. Chronic treatment with Modafinil (10-100 mg/kg) also dose-dependently counteracted the MPTP-induced disappearance of striatal DA uptake binding sites as evaluated at the same time interval. Also in the dose range 10-100 mg/kg Modafinil counteracts the MPTP-induced depletion of DA stores both in the neostriatum and the substantia nigra. In the acute experiments Modafinil (30 mg/kg) protected against the MPTP-induced depletion of striatal DA, dihydrophenyl-acetic acid (DOPAC) and homovanillic acid (HVA) levels both when given 15 min before, at the same time and 3 h following the MPTP injection. In the substantia nigra, however, these protective actions of Modafinil were only observed when the drug was coadministered with MPTP. Experiments with microdialysis in intact rats failed to demonstrate any increases of superfusate DA levels in neostriatum with 30 mg/kg of Modafinil. Modafinil in high doses of 2 x 50 mg/kg, however, significantly counteracted the H77/77 induced DA depletion of striatal DA stores. Thus, morphological and biochemical evidence has been obtained that Modafinil in the dose range 10-100 mg/kg protects against MPTP-induced degeneration of the nigrostriatal DA neurons of the black mouse. The results also indicate that the protective action of Modafinil is not caused by monoamine oxidase inhibition or by DA uptake inhibition, although the latter action may contribute in the highest dose used (100 mg/kg). Instead, it is hypothesized that its protective action may be related to actions on GABAergic mechanisms as evidenced by reduced cortical GABA outflow in doses of 3-30 mg/kg (Tanganelli et al. 1991) and/or to other unknown mechanisms.