Elsevier

Neuroscience

Volume 112, Issue 3, 5 July 2002, Pages 619-630
Neuroscience

Differential nicotinic receptor expression in monkey basal ganglia: Effects of nigrostriatal damage

https://doi.org/10.1016/S0306-4522(02)00106-9Get rights and content

Abstract

Our previous work showed that there were marked declines in 125I-α-conotoxin MII labeled nicotinic receptors in monkey basal ganglia after nigrostriatal damage, findings that suggest α3/α6 containing nicotinic receptors sites may be of relevance to Parkinson’s disease. We now investigate whether there are differential changes in the distribution pattern of nicotinic receptor subtypes in the basal ganglia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned animals compared to controls to better understand the changes occurring with nigrostriatal damage. To approach this we used 125I-α-conotoxin MII, a marker for α3/α6 nicotinic receptors, and 125I-epibatidine, a ligand that labels multiple nicotinic subtypes.

The results demonstrate that there were medial to lateral gradients in nicotinic receptor distribution in control striatum, as well as ventromedial to dorsolateral gradients in the substantia nigra, which resembled those of the dopamine transporter in these same brain regions. Treatment with MPTP, a neurotoxin that selectively destroys dopaminergic nigrostriatal neurons, led to a relatively uniform decrease in nicotinic receptor sites in the striatum, but a differential effect in the substantia nigra with significantly greater declines in the ventrolateral portion. Competition analysis in the striatum showed that α-conotoxin MII sensitive sites were primarily affected after lesioning, whereas multiple nicotinic receptor populations were decreased in the substantia nigra.

From these data we suggest that in the striatum α3/α6 nicotinic receptors are primarily localized on dopaminergic nerve terminals, while multiple nicotinic receptor subtypes are present on dopaminergic cell bodies in the substantia nigra. Thus, if activation of striatal nicotinic receptors is key in the regulation of basal ganglia function, α3/α6-directed nicotinic receptor ligands may be more relevant for Parkinson’s disease therapy. However, nicotinic receptor ligands with a broader specificity may be more important if receptors in the substantia nigra play a dominant role in controlling nigrostriatal activity.

Section snippets

Animal treatment

Twenty squirrel monkeys (Saimiri sciureus) of either sex weighing between 0.595 and 0.752 kg were obtained from Osage Research Primates (Osage Beach, MO, USA). Animals had free access to food and water and were exposed to a 13/11-h light/dark cycle. All procedures used in this study conform to the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee.

Prior to treatment, locomotor activity was assessed using a computerized

MPTP treatment

Monkeys were treated with MPTP as described in Experimental procedures to selectively damage the dopaminergic nigrostriatal system. The animals were divided into two groups, one with moderate and the other with a more severe nigrostriatal damage, using declines in the striatal dopamine transporter as an index of dopaminergic loss (Alexander et al., 1992, Rioux et al., 1997, Schneider et al., 1999). Overall, 125I-RTI-121 binding was reduced to 28% and 23% in the caudate and putamen,

Discussion

Extensive evidence indicates that the basal ganglia are anatomically heterogeneous and composed of distinct nigral neuronal populations that project to divergent striatal areas (Parent et al., 1983, Schneider et al., 1987, Gibb et al., 1990, Fearnley and Lees, 1991, Haber et al., 2000). In addition, it has been shown that various neurotransmitter receptors, transporters and enzymes are organized in distinct ventromedial to dorsolateral gradients in the striatum (Kemel et al., 1989, Desban et

Conclusions

Our data show that in the striatum alterations in α-CtxMII sensitive nicotinic receptors parallel those in the dopamine transporter, while in the substantia nigra changes in both α-CtxMII sensitive and insensitive sites are linked to the transporter, a dopaminergic neuronal marker. Furthermore, our competition studies show that the majority of striatal 125I-α-CtxMII sensitive sites are lost after MPTP treatment, whereas both 125I-α-CtxMII and 125I-epibatidine sites are similarly reduced in the

Acknowledgements

This work was supported by the California Tobacco Related Disease Research Program, #7RT-0015 and #8RT-0105.

References (68)

  • A.M. Graybiel et al.

    Levodopa-induced dyskinesias and dopamine-dependent stereotypies: a new hypothesis

    Trends Neurosci.

    (2000)
  • S. Hernandez-Lopez et al.

    Cholinergic stimulation of rostral and caudal substantia nigra pars compacta produces opposite effects on circling behavior and striatal dopamine release measured by brain microdialysis

    Neuroscience

    (1994)
  • A. Ishikawa et al.

    Effects of smoking in patients with early-onset Parkinson’s disease

    J. Neurol. Sci.

    (1993)
  • S. Jones et al.

    Nicotinic receptors in the brain: correlating physiology with function

    Trends Neurosci.

    (1999)
  • A. Kuryatov et al.

    Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses

    Neuropharmacology

    (2000)
  • E.P. Lapin et al.

    Dopamine-like action of nicotine: lack of tolerance and reverse tolerance

    Brain Res.

    (1987)
  • W. Lichtensteiger et al.

    Stimulation of nigrostriatal dopamine neurones by nicotine

    Neuropharmacology

    (1982)
  • J.G. Nutt et al.

    Continuous dopamine-receptor stimulation in advanced Parkinson’s disease

    Trends Neurosci.

    (2000)
  • J.A. Obeso et al.

    Levodopa motor complications in Parkinson’s disease

    Trends Neurosci.

    (2000)
  • J.A. Obeso et al.

    Pathophysiology of the basal ganglia in Parkinson’s disease

    Trends Neurosci.

    (2000)
  • A. Parent et al.

    The output organization of the substantia nigra in primate as revealed by a retrograde double labeling method

    Brain Res. Bull.

    (1983)
  • A. Parent et al.

    Organization of the basal ganglia: the importance of axonal collateralization

    Trends Neurosci.

    (2000)
  • E.K. Perry et al.

    Alteration in nicotine binding sites in Parkinson’s disease, Lewy body dementia and Alzheimer’s disease: possible index of early neuropathology

    Neuroscience

    (1995)
  • M. Quik et al.

    Differential alterations in nicotinic receptor alpha6 and beta3 subunit messenger RNAs in monkey substantia nigra after nigrostriatal degeneration

    Neuroscience

    (2000)
  • J.S. Schneider et al.

    Selective loss of subpopulations of ventral mesencephalic dopaminergic neurons in the monkey following exposure to MPTP

    Brain Res.

    (1987)
  • Y. Smith et al.

    Anatomy of the dopamine system in the basal ganglia

    Trends Neurosci.

    (2000)
  • S. Wonnacott

    Presynaptic nicotinic ACh receptors

    Trends Neurosci.

    (1997)
  • E.X. Albuquerque et al.

    Properties of neuronal nicotinic acetylcholine receptors: pharmacological characterization and modulation of synaptic function

    J. Pharmacol. Exp. Ther.

    (1997)
  • I. Aubert et al.

    Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer’s and Parkinson’s diseases

    J. Neurochem.

    (1992)
  • F. Calon et al.

    Molecular basis of levodopa-induced dyskinesias

    Ann. Neurol.

    (2000)
  • D.R. Canfield et al.

    Autoradiographic localization of cocaine binding sites by [3H]CFT ([3H]WIN 35, 428) in the monkey brain

    Synapse

    (1990)
  • P.B. Clarke et al.

    Electrophysiological actions of nicotine on substantia nigra single units

    Br. J. Pharmacol.

    (1985)
  • P. Clemens et al.

    The short-term effect of nicotine chewing gum in patients with Parkinson’s disease

    Psychopharmacology (Berl.)

    (1995)
  • R. De La Garza et al.

    Non-amine dopamine transporter probe [(3)H]tropoxene distributes to dopamine-rich regions of monkey brain

    Synapse

    (1999)
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