Differential Alterations in Nicotinic Receptor α6 and β3 Subunit messenger RNAs in Monkey Substantia nigra 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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2018, Neuroscience LettersCitation Excerpt :Epibatidine is an alkaloid secreted on the skin of the Ecuadorian poison arrow frog (Epipedobates tricolor), and potently activates α4β2 and α3β4 nAChRs [68,144]. Epibatidine binds to nAChRs with very high affinity and radiolabelled epibatine has been used to study the binding and conformational changes of nAChRs as well as changes to receptor subunit expression in disease states and brain regions [95,145,159]. The toxin has also been used to elucidate neurotransmitter release mechanisms [184] and has been used in animal models to demonstrate the role of nAChRs in analgesia [144].
Role of α6 nicotinic receptors in CNS dopaminergic function: Relevance to addiction and neurological disorders
2011, Biochemical PharmacologyCitation Excerpt :To approach this, work has been done in parkinsonian animal models in which the nigrostriatal pathway is selectively damaged with dopaminergic neurotoxins such as 6-hydroxydopamine or MPTP. Such lesions result in a decrease in α6β2β3* nAChR expression and function that closely parallels the decline in dopaminergic terminal integrity [19,20,22,112,113]. These findings indicate that α6β2β3* nAChRs are primarily localized to dopaminergic terminals in the striatum.
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2007, Neuroscience and Biobehavioral ReviewsChronic pre-treatment with nicotine enhances nicotine-evoked striatal dopamine release and α<inf>6</inf> and β<inf>3</inf> nicotinic acetylcholine receptor subunit mRNA in the substantia nigra pars compacta of the rat
2006, NeuropharmacologyCitation Excerpt :However, the relatively restricted localisation of the α6 and β3 subunits in the SNc, coupled with additional evidence of their restricted expression to dopaminergic neurons, makes them particularly attractive therapeutic targets in PD. Further support for α6 as a principal target stems from the observation that the levels of expression of this subunit gene are increased in the SNc of the well-established MPTP-treated primate model of PD (Quik et al., 2000). However, the heterogenous nature of nicotinic receptors, the loss of dopaminergic neurons and potential denervation- and treatment-induced compensation (up- or down-regulation) make our understanding of the key nicotinic receptors contributing to functional dopamine release in pathological conditions rather difficult.
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