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. 2011 May;60(6):861-8.
doi: 10.1016/j.neuropharm.2010.12.032. Epub 2011 Jan 11.

Nicotinic receptor agonists decrease L-dopa-induced dyskinesias most effectively in partially lesioned parkinsonian rats

Luping Z Huang  1 , Carla Campos, Jason Ly, F Ivy Carroll, Maryka Quik
Affiliations

Nicotinic receptor agonists decrease L-dopa-induced dyskinesias most effectively in partially lesioned parkinsonian rats

Luping Z Huang et al. Neuropharmacology. 2011 May.

Abstract

L-dopa therapy for Parkinson's disease leads to dyskinesias or abnormal involuntary movement (AIMs) for which there are few treatment options. Our previous data showed that nicotine administration reduced L-dopa-induced AIMs in parkinsonian monkeys and rats. To further understand how nicotine mediates its antidyskinetic action, we investigated the effect of nicotinic receptor (nAChR) agonists in unilateral 6-OHDA-lesioned rats with varying striatal damage. We first tested the drugs in L-dopa-treated rats with a near-complete striatal dopamine lesion (>99%), the standard rodent dyskinesia model. Varenicline, an agonist that interacts with multiple nAChRs, did not significantly reduce L-dopa-induced AIMs, while 5-iodo-A-85380 (A-85380), which acts selectively at α4β2* and α6β2* subtypes, reduced AIMs by 20%. By contrast, both varenicline and A-85380 reduced L-dopa-induced AIMs by 40-50% in rats with a partial striatal dopamine lesion. Neither drug worsened the antiparkinsonian action of L-dopa. The results show that selective nicotinic agonists reduce dyskinesias, and that they are optimally effective in animals with partial striatal dopamine damage. These findings suggest that presynaptic dopamine terminal α4β2* and α6β2* nAChRs are critical for nicotine's antidyskinetic action. The current data have important implications for the use of nicotinic receptor-directed drugs for L-dopa-induced dyskinesias, a debilitating motor complication of dopamine replacement therapy for Parkinson's disease.

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Figures

Fig. 1
Fig. 1
The nonselective nAChR agonist varenicline did not reduce L-dopa-induced AIMs in rats with a near-complete striatal dopamine lesion. Lesioned rats were given varenicline (s.c.) twice daily at an 8-hr interval for 4 consecutive days. L-dopa methyl ester (8 mg/kg) plus benserazide (15 mg/kg) was given s.c. once daily 10 min after the first dose of varenicline. After 4 days of treatment, the rats were evaluated for axial, oral, and forelimb AIMs, with the total AIMs representing the sum of these three components. Values are the mean ± S.E.M. Controls, n = 12; varenicline-treated (0.5 mg/kg), n = 4; varenicline-treated (1.0 mg/kg), n = 9.
Fig. 2
Fig. 2
The nonselective nAChR agonist varenicline reduced L-dopa-induced AIMs in rats with a partial striatal dopamine lesion. Lesioned rats were given varenicline (s.c.) twice daily at an 8-hr interval for 4 consecutive days. L-dopa methyl ester (8 mg/kg) plus benserazide (15 mg/kg) was given s.c. once daily 10 min after the first dose of varenicline. After 4 days of treatment, the rats were evaluated for axial, oral, and forelimb AIMs, with the total AIMs representing the sum of these three components. Values are the mean ± S.E.M. Controls, n = 8; varenicline-treated (0.2 mg/kg), n = 8; varenicline treated (0.5 mg/kg), n = 9; varenicline-treated (1.0 mg/kg), n = 8; varenicline treated (2.0 mg/kg), n = 9. Significance of difference from vehicle: *p < 0.05, **p < 0.01, ***p < 0.001. There was a significant main effect of nicotine with time (bottom panels, #p < 0.05). Data were analyzed by one-way ANOVA followed by Dunnett’s multiple comparison test (total, axial, oral, and forelimb AIMs) or one-way repeated ANOVA followed by a Bonferroni post hoc test (time course).
Fig. 3
Fig. 3
Minimal decrease in L-dopa-induced AIMs in rats with a near-complete striatal dopamine lesion with the α4β2*/α6β2* selective nAChR agonist A-85380. Lesioned rats were given A-85380 (A85, i.p.) twice daily at an 8-hr interval for 4 consecutive days. L-dopa methyl ester (8 mg/kg s.c.) plus benserazide (15 mg/kg s.c.) was administered once daily 10 min after the first dose of A-85380. After 4 days of treatment, the rats were evaluated for axial, oral, and forelimb AIMs, with total AIMs representing the sum of these three components. Values are the mean ± S.E.M of 10 rats in each treatment group. Significance of difference from vehicle: *p < 0.05. Data were analyzed by one-way repeated ANOVA followed by a Bonferroni post hoc test (time course).
Fig. 4
Fig. 4
The α4β2*/α6β2* selective nAChR agonist A-85380 decreased L-dopa-induced AIMs more effectively in rats with a partial striatal dopamine lesion. Lesioned rats were given A-85380 (A85, i.p.) twice daily at an 8-hr interval for 4 consecutive days. L-dopa methyl ester (8 mg/kg s.c.) plus benserazide (15 mg/kg s.c.) was administered once daily 10 min after the first dose of A-85380. After 4 days of treatment, the rats were evaluated for axial, oral, and forelimb AIMs, with total AIMs representing the sum of these three components. Values are the mean ± S.E.M of 8 rats in each treatment group. Significance of difference from vehicle: *p < 0.05. Data were analyzed by a Mann-Whitney test (total, axial, oral, and forelimb AIMs) or one-way repeated ANOVA followed by a Bonferroni post hoc test (time course).
Fig. 5
Fig. 5
Speculative schematic illustrating the striatal nAChR subtypes that may be involved in the nAChR-mediated antidyskinetic effect. In the intact striatum (left), α6β2* nAChRs are exclusively expressed on the nigrostriatal dopaminergic terminals (DA) and are composed of α6α4β2β3 and α6β2β3 subtypes (Bordia et al., 2007). α4β2* nAChRs (~20%) are also expressed on dopaminergic terminals and include both the α4β2 and α4α5β2 populations (Grady et al., 2009). The remaining 80% of α4β2* nAChRs are present on GABAergic neurons (GABA) as well as other striatal neuronal or non-neuronal cells (Other) and are most likely composed of only the α4β2 subunits (Gotti et al., 2009; Grady et al., 2009). In addition, α7 nAChRs are located on striatal glutamatergic (Glu) terminals (Kaiser and Wonnacott, 2000). In rats with a partial striatal dopamine lesion (middle), the α6α4β2β3 subtype is lost (Bordia et al., 2007). This suggests that α6β2β3 subtypes, as well as α4β2 and α4α5β2 nAChRs may mediate antidyskinetic effects. Since the majority of presynaptic nAChRs are lost in rats with a near-complete striatal lesion (right), postsynaptic α4β2 and possibly α7 nAChRs may contribute to the nAChR-mediated antidyskinetic effect in such rats. A potential role for nAChRs on dopaminergic neurons in the substantia nigra or in other brain areas remains to be determined.
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References

    1. Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev. 2009;89:73–120. - PMC - PubMed
    1. Artymyshyn R, Smith A, Wolfe BB. The use of 3H standards in 125I autoradiography. J Neurosci Methods. 1990;32:185–192. - PubMed
    1. Bezard E, Gross CE. Compensatory mechanisms in experimental and human parkinsonism: towards a dynamic approach. Prog Neurobiol. 1998;55:93–116. - PubMed
    1. Bordia T, Campos C, Huang LZ, Quik M. Continuous and intermittent nicotine treatment reduces L-DOPA-induced dyskinesias in a rat model of Parkinson's disease. J Pharmacol Exp Ther. 2008;327:239–247. - PubMed
    1. Bordia T, Campos C, McIntosh JM, Quik M. Nicotinic receptor-mediated reduction in L-DOPA-induced dyskinesias may occur via desensitization. J Pharmacol Exp Ther. 2010;333:929–938. - PMC - PubMed

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