PT  - JOURNAL ARTICLE
AU  - Francesco Fornai
AU  - Maria Grazia Alessandrì
AU  - Maria Tilde Torracca
AU  - Lucia Bassi
AU  - Giovanni Umberto Corsini
TI  - Effects of Noradrenergic Lesions on MPTP/MPP<sup>+</sup>Kinetics and MPTP-Induced Nigrostriatal Dopamine Depletions
DP  - 1997 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 100--107
VI  - 283
IP  - 1
4099  - http://jpet.aspetjournals.org/content/283/1/100.short
4100  - http://jpet.aspetjournals.org/content/283/1/100.full
SO  - J Pharmacol Exp Ther1997 Oct 01; 283
AB  - Norepinephrine (NE) depletion caused by damage to locus ceruleus neurons was shown to worsen experimental Parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys and in rodents. However, it is not clear whether the lesion to the NE system enhances neurotoxicity in the nigrostriatal dopaminergic (DA) pathway and/or impairs the recovery of DA neurons once the neurotoxic insult is generated. In this study, we provide evidence that the lesion of NE terminals, induced by the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg), must occur before MPTP (30 mg/kg) administration in order to enhance MPTP toxicity. As a second step, we evaluated the acute effects of MPTP on the nigrostriatal DA pathway in NE-lesioned animals compared with intact animals. We observed a more marked acute DA depletion, persisting at 12 h, in DSP-4 + MPTP-treated mice compared with MPTP-injected controls. These findings, combined with the lack of an MPTP enhancement when NE depletion was induced 12 h after MPTP administration, suggest that in NE-depleted animals, a more pronounced acute neuronal sensitivity to MPTP occurs. In line with the hypothesis of an acute protective effect by NE axons, we evaluated whether the enhancement of MPTP toxicity in NE-lesioned animals is achieved through alterations to the kinetics of MPTP and its metabolite. Our findings indicate that despite the pivotal role of NE terminals in taking up and storing 1-methyl-4-phenylpyridinium (MPP+), MPTP enhancement does not depend on modifications in the striatal kinetics of MPTP/MPP+ measured at seven different time intervals after MPTP administration. The American Society for Pharmacology and Experimental Therapeutics