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The Journal of Neuroscience, April 26, 2006, 26(17):4681-4689; doi:10.1523/JNEUROSCI.0215-06.2006

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Neurobiology of Disease
Chronic Oral Nicotine Normalizes Dopaminergic Function and Synaptic Plasticity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Primates

Maryka Quik, Li Chen, Neeraja Parameswaran, Xinmin Xie, J. William Langston, and Sarah E. McCallum

The Parkinson’s Institute, Sunnyvale, California 94089

Correspondence should be addressed to Maryka Quik, The Parkinson’s Institute, 1170 Morse Avenue, Sunnyvale, CA 94089. Email: mquik{at}thepi.org

Our recent studies show that chronic oral nicotine partially protects against striatal damage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. To identify the cellular changes associated with this protective action, we investigated the effects of nicotine treatment on stimulus-evoked dopamine release, dopamine turnover, and synaptic plasticity in striatum from lesioned and unlesioned animals. Monkeys were chronically (6 months) treated with nicotine in the drinking water and subsequently lesioned with the dopaminergic neurotoxin MPTP (6 months) while nicotine was continued. Nigrostriatal damage increased nicotinic acetylcholine receptor (nAChR)-mediated fractional dopamine release from residual terminals, primarily through changes in 3*/6* nAChRs. In contrast, fractional receptor-evoked dopamine release was similar to control in unlesioned and lesioned animals with chronic oral nicotine. Long-term nicotine administration also attenuated the enhanced K⁺-evoked fractional dopamine release from synaptosomes of MPTP-lesioned animals, suggesting that nicotine treatment had a generalized effect on dopaminergic function. This premise was further supported by experiments showing that nicotine dosing decreased the elevated dopamine turnover that occurs after nigrostriatal damage. We next investigated changes in synaptic plasticity with lesioning and nicotine treatment. Nicotine treatment alone enhanced synaptic plasticity by lowering the threshold for long-term depression (LTD) in the corticostriatal pathway. MPTP lesioning led to a loss of LTD, a measure of short-term synaptic plasticity. In contrast, LTD was preserved in nicotine-treated lesioned animals. Thus, the present data show that the disruptions in striatal dopaminergic function after nigrostriatal damage were attenuated with chronic nicotine administration. These cellular alterations may underlie the ability of nicotine to maintain/restore normal function with nigrostriatal damage.

Key words: nicotine; Parkinson’s disease; nonhuman primates; nicotinic; dopamine; MPTP

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Received Jan. 17, 2006; revised March 26, 2006; accepted March 27, 2006.

Correspondence should be addressed to Maryka Quik, The Parkinson’s Institute, 1170 Morse Avenue, Sunnyvale, CA 94089. Email: mquik{at}thepi.org

This article has been cited by other articles:

				T. Bordia, N. Parameswaran, H. Fan, J. W. Langston, J. M. McIntosh, and M. Quik Partial Recovery of Striatal Nicotinic Receptors in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Lesioned Monkeys with Chronic Oral Nicotine J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 285 - 292. [Abstract] [Full Text] [PDF]

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