Clonidine suppresses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced reductions of striatal dopamine and tyrosine hydroxylase activity in mice.
Recent findings have shown that excitatory amino acid may be involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. At the same time, evidence is accumulating that the endogenous noradrenergic system plays a protective role in MPTP-induced striatal dopamine (DA) depletion and nigral dopaminergic cell death. Recently, alpha 2-adrenoceptors located on glutamatergic axons have been shown to inhibit glutamate overflow. In this study, we evaluated the effects of an alpha 2-agonist (clonidine) and an alpha 2-antagonist (yohimbine) on MPTP-induced striatal DA depletion and tyrosine hydroxylase activity reduction. We show that clonidine is able to prevent the neurotoxicity of MPTP in mice. To exert this effect, clonidine (0.5 mg/kg) must be administered at least twice (30 min before and 30 min after MPTP). Administration of another alpha 2-agonist (detomidine, 0.3 mg/kg) attenuated the neurotoxicity induced by MPTP. We provide evidence that the protective effect obtained with clonidine was not due to decreased striatal content of 1-methyl-4-phenylpyridinium (MPP+). We also show that yohimbine, which is a classic alpha 2-adrenoceptor antagonist with low affinity for imidazoline receptors, produced by itself an enhancement of MPTP toxicity and was able to block the protective effect of clonidine. These data raise the possibility that alpha 2-adrenoceptor may modulate the susceptibility of the nitrostriatal dopaminergic pathway to neurotoxicity.
Fornai
F
F
Institute of Pharmacology, School of Medicine, University of Pisa, Italy.
Alessandrì
M G
MG
Fascetti
F
F
Vaglini
F
F
Corsini
G U
GU
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors*; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D018492:Dopamine Antagonists; D007093:Imidazoles; D015016:Yohimbine; C041255:detomidine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D003000:Clonidine; D015655:1-Methyl-4-phenylpyridinium