Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation
Delle Donne, K.T.; Sonsalla, P.K.
Journal of Pharmacology and Experimental Therapeutics 271(3): 1320-1326
1994
ISSN/ISBN: 0022-3565 PMID: 7996441 Document Number: 424927
Methamphetamine (METH)-induced neurotoxicity to nigrostriatal dopaminergic neurons in experimental animals appears to have a glutamatergic component because blockade of N-methyl-D-aspartate receptors prevents the neuropathologic consequences. Because adenosine affords neuroprotection against various forms of glutamate-mediated neuronal damage, the present studies were performed to investigate whether adenosine plays a protective role in METH-induced toxicity. METH-induced decrements in neostriatal dopamine content and tyrosine hydroxylase activity in mice were potentiated by concurrent treatment with caffeine, a nonselective adenosine antagonist that blocks both A-1 and A-2 adenosine receptors. In contrast, chronic treatment of mice with caffeine through their drinking water for 4 weeks, which increased the number of adenosine A-1 receptors in the neostriatum and frontal cortex, followed by drug washout, prevented the neurochemical changes produced by the treatment of mice with METH treatment. In contrast, this treatment did not prevent 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. Furthermore. concurrent administration of cyclopentyladenosine, an adenosine A-1 receptor agonist, attenuated the METH-induced neurochemical changes. This protection by cyclopentyladenosine was blocked by cyclopentyltheophylline, an A-1 receptor antagonist. These results indicate that activation of A-1 receptors can protect against METH-induced neurotoxicity in mice.