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. 2011 Sep;338(3):932-41.
doi: 10.1124/jpet.111.182949. Epub 2011 Jun 10.

Nicotine reduces L-DOPA-induced dyskinesias by acting at beta2* nicotinic receptors

Luping Z Huang  1 , Sharon R Grady, Maryka Quik
Affiliations

Nicotine reduces L-DOPA-induced dyskinesias by acting at beta2* nicotinic receptors

Luping Z Huang et al. J Pharmacol Exp Ther. 2011 Sep.

Abstract

L-DOPA-induced dyskinesias or abnormal involuntary movements (AIMs) are a debilitating adverse complication associated with prolonged L-DOPA administration for Parkinson's disease. Few treatments are currently available for dyskinesias. Our recent data showed that nicotine reduced L-DOPA-induced AIMs in parkinsonian animal models. An important question is the nicotinic acetylcholine receptor (nAChR) subtypes through which nicotine exerts this beneficial effect, because such knowledge would allow for the development of drugs that target the relevant receptor population(s). To address this, we used β2 nAChR subunit knockout [β2(-/-)] mice because β2-containing nAChRs are key regulators of nigrostriatal dopaminergic function. All of the mice were lesioned by intracranial injection of 6-hydroxydopamine into the right medial forebrain bundle. Lesioning resulted in a similar degree of nigrostriatal damage and parkinsonism in β2(-/-) and wild-type mice. All of the mice then were injected with L-DOPA (3 mg/kg) plus benserazide (15 mg/kg) once daily for 4 weeks until AIMs were fully developed. L-DOPA-induced AIMs were approximately 40% less in the β2(-/-) mice compared with the wild-type mice. It is interesting to note that nicotine (300 μg/ml in drinking water) reduced L-DOPA-induced AIMs by 40% in wild-type mice but had no effect in β2(-/-) mice with partial nigrostriatal damage. The nicotine-mediated decline in AIMs was much less pronounced in wild-type mice with near-complete degeneration, suggesting that presynaptic nAChRs on dopaminergic terminals have a major influence. These data demonstrate an essential role for β2* nAChRs in the antidyskinetic effect of nicotine and suggest that drugs targeting these subtypes may be useful for the management of L-DOPA-induced dyskinesias in Parkinson's disease.

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Figures

Fig. 1.
Fig. 1.
Treatment timeline to determine l-DOPA and nicotine dose-response effects. Mice were lesioned unilaterally with 6-OHDA injected into the right medial forebrain bundle at week 0. Two weeks later, they were given a 2% saccharin solution for 2 days. Nicotine treatment then was initiated in the drinking water, starting at 25 μg/ml for 2 days. The dose of nicotine in the drinking water was increased gradually (nicotine titration) to 300 μg/ml over 10 days and subsequently maintained at that dose. After 2 weeks of nicotine treatment at the final dose (300 μg/ml), a dose-response curve was done for l-DOPA (1–6 mg/kg) plus benserazide (15 mg/kg) administration, with l-DOPA plus benserazide administered on a once daily basis throughout the study. The effect of varying nicotine treatment (50–500 μg/ml) next was determined on AIMs using a fixed dose of l-DOPA (3 mg/kg). AIMs were rated throughout the study, and the cylinder test was performed as indicated.
Fig. 2.
Fig. 2.
Effect of nicotine on AIMs at varying l-DOPA doses in lesioned control mice. Two weeks after 6-OHDA lesioning, nicotine treatment was initiated as outlined in Fig. 1 and detailed under Results. Mice were maintained at the final dose of nicotine (300 μg/ml) for at least 2 weeks, after which various doses of l-DOPA (1, 2, 3, and 6 mg/kg) plus benserazide (15 mg/kg) were administered subcutaneously once daily each for several weeks. Animals were rated for axial, oral, and forelimb AIMs for 1 min every 15 min over a 2-h period, with the total AIMs representing the sum of these three components. Values are the mean ± S.E.M. of 9 to 14 mice. Significance of difference from control: *, p < 0.05. Data were analyzed by Mann-Whitney U test (total AIMs) or one-way repeated measures ANOVA followed by a Bonferroni post hoc test (time course).
Fig. 3.
Fig. 3.
Nicotine at a dose of 300 μg/ml optimally decreased l-DOPA-induced AIMs in lesioned control mice. Mice were administered the indicated doses of nicotine or vehicle in the drinking water. After 2 weeks of the indicated dose of nicotine, l-DOPA (3 mg/kg) plus benserazide (15 mg/kg) was injected subcutaneously once daily for several weeks with the nicotine dosing continued. Animals then were rated for axial, oral, and forelimb AIMs for 1 min every 15 min over a 2-h period, with the total AIMs representing the sum of these three components. Values are the mean ± S.E.M. of 9 to 19 mice. Significance of difference from control: *, p < 0.05; **, p < 0.01. Data were analyzed by one-way ANOVA followed by a Dunnett's multiple comparison test (total, axial, oral, and forelimb AIMs) or one-way repeated measures ANOVA followed by a Bonferroni post hoc test (time course). Because nicotine at doses of 400 and 500 μg/ml had no significant effect on the time course of l-DOPA-induced AIMs, the data were omitted from the graph for clarity.
Fig. 4.
Fig. 4.
Nicotine did not affect parkinsonism in lesioned control mice either OFF or ON l-DOPA. Mice were rated for forelimb use asymmetry (cylinder test) as an index of motor dysfunction. Impaired forelimb use was measured for 3 min 45 min after subcutaneous administration of l-DOPA (3 mg/kg) plus benserazide (15 mg/kg). Each value represents the mean ± S.E.M. of 6 to 10 mice. There was a significant main effect of l-DOPA treatment (***, p < 0.001). Data were analyzed by two-way ANOVA followed by a Bonferroni post hoc test.
Fig. 5.
Fig. 5.
Treatment timeline for the study using β2(−/−) nAChR and wild-type mice. All of the mice were lesioned unilaterally with 6-OHDA injected into the right medial forebrain bundle at week 0. l-DOPA (3 mg/kg) plus benserazide (15 mg/kg) was administered subcutaneously for 2 weeks. They next were given a 2% saccharin solution for 2 days. Nicotine treatment then was initiated in the drinking water, starting at 25 μg/ml for 2 days. The dose of nicotine in the drinking water was increased gradually (nicotine titration) to 300 μg/ml over 10 days and subsequently maintained at that dose. l-DOPA plus benserazide was administered once daily throughout the study. AIMs were rated, and the cylinder test was performed as indicated. Mice were killed at week 26.
Fig. 6.
Fig. 6.
Nicotine treatment reduces l-DOPA-induced AIMs by interacting at β2* nAChRs. Lesioned mice were injected subcutaneously with l-DOPA (3 mg/kg) plus benserazide (15 mg/kg) for 2 weeks. They then were divided into two groups (moderate and high) based on the severity of the l-DOPA-induced AIM scores. Nicotine treatment was initiated as described, with the mice maintained on the final dose (300 μg/ml) for 4 weeks. Mice then were rated for axial, oral, and forelimb AIMs for 1 min every 15 min over a 2-h period, with the total AIMs representing the sum of these three components. Values are the mean ± S.E.M. of 3 to 8 mice. Significance of difference from control: *, p < 0.05; **, p < 0.01; ***, p < 0.001. Significance of difference from wild-type: #, p < 0.05. Significance of difference from the control wild-type group: ++, p < 0.01; +++, p < 0.001. Data were analyzed by two-way ANOVA (total, axial, oral, and forelimb AIMs) or one-way repeated measures ANOVA followed by a Bonferroni post hoc test (time course).
Fig. 7.
Fig. 7.
Reduction in l-DOPA-induced AIMs is maintained with continued nicotine treatment in mice with moderate AIM scores. Lesioned mice were injected subcutaneously with l-DOPA (3 mg/kg) plus benserazide (15 mg/kg) as outlined in Fig. 5. Nicotine treatment was initiated as described, with the mice maintained on the final dose (300 μg/ml) for 15 weeks. Mice then were rated for axial, oral, and forelimb AIMs for 1 min every 15 min over a 2-h period, with the total AIMs representing the sum of these three components. Values are the mean ± S.E.M. of 3 to 8 mice. Significance of difference from control: *, p < 0.05; **, p < 0.01; ***, p < 0.001. Significance of difference from wild-type: #, p < 0.05; ##, p < 0.01. Significance of difference from the control wild-type group: +, p < 0.05; ++, p < 0.01; +++, p < 0.001. Data were analyzed by two-way ANOVA (total, axial, oral, and forelimb AIMs) or one-way repeated measures ANOVA followed by a Bonferroni post hoc test (time course).
Fig. 8.
Fig. 8.
Striatal dopamine transporter levels in wild-type and β2(−/−) mice with moderate and high AIM scores. [125I]RTI-121 autoradiography was done to measure the dopamine transporter as described under Materials and Methods. The autoradiographic images (top) and quantitative analyses (bottom) indicate that mice with moderate AIM scores had a partial striatal lesion, whereas mice with severe AIM scores had a near-complete striatal dopamine lesion. Each value represents the mean ± S.E.M. of 6 to 8 mice in the groups with a partial lesion and 2 to 4 mice in the groups with a near-complete lesion. Significance of difference from the intact side: ***, p < 0.001. Data were analyzed by two-way ANOVA followed by a Bonferroni post hoc test.
Fig. 9.
Fig. 9.
Effect of nicotine treatment (300 μg/ml) on striatal β2* nAChR expression in 6-OHDA-lesioned mice. [125I]Epibatidine was used to evaluate β2* nAChRs in mouse striatum. Binding was decreased with nigrostriatal damage and increased with nicotine treatment in wild-type mice. No binding was detected in the brains of β2(−/−) mice (data not shown). Each value represents the mean ± S.E.M. of 6 to 8 mice in the groups with a partial lesion and 2 to 4 mice in the groups with a near-complete lesion. Significance of difference from the control group: **, p < 0.01; ***, p < 0.001. Significance of difference from the intact side: #, p < 0.05; ##, p < 0.01; ###, p < 0.001. Data were analyzed by two-way ANOVA followed by a Bonferroni post hoc test.
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