Elsevier

Neuroscience

Volume 100, Issue 1, 7 September 2000, Pages 63-72
Neuroscience

Differential Alterations in Nicotinic Receptor α6 and β3 Subunit messenger RNAs in Monkey Substantia nigra After Nigrostriatal Degeneration

https://doi.org/10.1016/S0306-4522(00)00244-XGet rights and content

Abstract

Our previous studies showed that α4, α6, α7, β2, β3 and β4 nicotinic acetylcholine receptor messenger RNAs are present in monkey substantia nigra, with a particularly intense and localized labelling of the α6 and β3 subunit messenger RNAs to this brain region. Because loss of nigrostriatal neurons is a central feature of Parkinson’s disease and evidence suggests that nicotinic agonists potentiate antiparkinsonian effects of l-dopa, experiments were done to determine whether nicotinic receptor subunit messenger RNAs and binding sites were altered in the basal ganglia after nigrostriatal degeneration. Squirrel monkeys (Saimiri sciureus) were rendered parkinsonian by systemic injection of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Behavioral studies showed that this treatment decreased baseline motor activity to 36±11% of control. One month after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, caudate and putamen dopamine levels were reduced to 51±15% and 43±6% of control, respectively, while the number of tyrosine hydroxylase-positive neurons in the substantia nigra was 75±6% of control. Despite the reduction in nigral cell number after nigrostriatal degeneration, there were no changes in α4, α7, β2 and β4 messenger RNA levels in the substantia nigra. In contrast, α6 mRNA levels were significantly increased (143±10%) and the β3 transcript decreased (62±6%) in the substantia nigra after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Declines were also observed in [125I]epibatidine binding in both the caudate–putamen and substantia nigra, with no change in α7 receptor binding.

These results may suggest a dissociation in the regulation of receptor messenger RNA and binding sites, and/or that there are differential alterations in the different receptor subtypes measured using [125I]epibatidine. The changes in the two nicotinic receptor subunit messenger RNAs, α6 and β3, which exhibit a selective localization to the substantia nigra, may indicate that nicotinic receptors containing these subunits are altered after nigrostriatal degeneration.

Section snippets

Animals

Six adult male squirrel monkeys (Saimiri sciureus) weighing from 0.7 to 1.0 kg were obtained from Osage Research Primates (Osage Beach, MO, USA). The precise age of the monkeys was not known because the animals were feral reared; however, they appeared to be in mid-adulthood. All animals were housed separately with free access to food and water, using a 13-h light–11-h dark cycle. After quarantine and testing according to standard veterinary practice, three animals were randomly assigned to the

Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment on behavior

In the present study, monkeys were given a single dose of MPTP with the objective of obtaining an intermediate level of nigrostriatal degeneration, rather than the very severe damage which occurs after multiple MPTP injections. To determine the effect of such a lesion on animal behavior, baseline locomotor activity was tested before and after MPTP administration as described in the Experimental Procedures. As shown in Table 2, there was a significant reduction (64%) in baseline motor activity

Discussion

In the present study we investigated the effect of nigrostriatal degeneration on α4, α6, α7, β2, β3 and β4 neuronal nicotinic acetylcholine receptor subunit transcripts in monkey substantia nigra. These subunit mRNAs were selected because: (i) receptors containing the α4 and β2 subunits comprise the greater majority of neuronal nicotinic receptors in the brain; (ii) α7 is the primary subunit of the α-bungarotoxin nicotinic receptor population; and (iii) α6 and β3 subunit mRNAs exhibit a

Conclusions

The present studies are the first to investigate the effect of MPTP treatment on nicotinic receptor subunit mRNAs in the substantia nigra and to show that there is a differential regulation of the α6 and β3 nicotinic receptor mRNAs after nigrostriatal damage. If these changes are reflected in alterations in nicotinic receptor composition and/or number after lesioning, these results may have implications for potential therapeutic strategies in Parkinson’s disease.

Acknowledgements

This research was supported by The Parkinson’s Institute, Sibia Neurosciences and the California Tobacco Related Disease Research Program, #7RT-0015. The authors thank Drs M. Marks and G. Jeyarasasingam for helpful comments on the manuscript.

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