Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Apr;125(2):291-302.
doi: 10.1111/jnc.12179. Epub 2013 Mar 3.

The nicotine-mediated decline in l-dopa-induced dyskinesias is associated with a decrease in striatal dopamine release

Tanuja Bordia  1 , J Michael McIntosh  2 , Maryka Quik  1
Affiliations

The nicotine-mediated decline in l-dopa-induced dyskinesias is associated with a decrease in striatal dopamine release

Tanuja Bordia et al. J Neurochem. 2013 Apr.

Abstract

l-dopa-induced dyskinesias (LIDs) are a side effect of Parkinson's disease therapy that is thought to arise, at least in part, because of excessive dopaminergic activity. Thus, drugs that regulate dopaminergic tone may provide an approach to manage LIDs. Our previous studies showed that nicotine treatment reduced LIDs in Parkinsonian animal models. This study investigates whether nicotine may exert its beneficial effects by modulating pre-synaptic dopaminergic function. Rats were unilaterally lesioned by injection of 6-hydroxydopamine (6-OHDA) (2 × 3 ug per site) into the medial forebrain bundle to yield moderate Parkinsonism. They were then implanted with minipumps containing vehicle or nicotine (2.0 mg/kg/d) and rendered dyskinetic with l-dopa (8 mg/kg plus 15 mg/kg benserazide). Lesioning alone decreased the striatal dopamine transporter, nicotinic receptor (nAChR) levels, and nAChR-mediated (3)H-dopamine release, consistent with previous results. Nicotine administration reduced l-dopa-induced abnormal involuntary movements throughout the course of the study (4 months). Nicotine treatment led to declines in the striatal dopamine transporter, α6β2* nAChRs and various components of α6β2* and α4β2* nAChR-mediated release. l-dopa treatment had no effect. These data suggest that nicotine may improve LIDs in Parkinsonian animal models by dampening striatal dopaminergic activity.

Keywords: LIDs; dopamine; nicotine; nicotinic receptors; nigrostriatal lesion.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Treatment timeline depicting 6-OHDA lesioning, drug treatment and behavioral testing.
Fig. 2
Fig. 2
Nicotine treatment reduced L-dopa-induced AIMs in rats. 6-OHDA lesioned rats were implanted with minipumps containing nicotine (2 mg/kg) or vehicle. They were then injected with 8 mg/kg L-dopa methyl ester plus benserazide and AIMs rated as depicted in Fig. 1. AIMs were rated 3 wk after the start of L-dopa treatment with significant declines at 3, 8 and 12 wk after L-dopa treatment (top panels). The daily time course of total AIMs at wk 12 (bottom panel left) shows a reduction in AIMs at all time points after L-dopa administration using two-way ANOVA followed by a Bonferroni post hoc test. The nicotine-mediated decline in total AIMs was due to a reduction in oral and forelimb AIMs (bottom panels right) using Student’s t-test. Values are the mean ± S.E.M. of 9–13 rats. Significance of difference from control group, *p < 0.05, **p < 0.01, ***p < 0.001.
Fig. 3
Fig. 3
Nicotine treatment decreases total nicotine-evoked dopamine release from rat striatal synaptosomes. 6-OHDA-lesioned rats, implanted with minipumps containing nicotine (Nic, 2 mg/kg/d) or vehicle, were injected with 8 mg/kg L-dopa methyl ester (LD) plus benserazide until the end of the study. They were then killed 60 min after L-dopa administration, when its effects are maximal. NAChR-mediated 3H-dopamine release was determined in response to 1 and 10 μM nicotine. 6-OHDA lesioning resulted in ~50% decline in dopamine release. Nicotine treatment significantly reduced 3H-dopamine release in all cases, except with 1 μM nicotine stimulation in intact striatum. Data are expressed as % intact control, that is, the intact side of animals not treated with nicotine and L-dopa. Values represent the mean ± S.E.M. of 9–13 rats. Significant main effect of nicotine (p < 0.05) using two-way ANOVA.
Fig. 4
Fig. 4
Nicotine treatment decreases α6β2* nAChR-mediated dopamine release from rat striatal synaptosomes. Striatal synaptosomes were prepared from 6-OHDA-lesioned rats, treated with and without nicotine (Nic) and/or L-dopa (LD). At the end of the treatment phase, the rats were killed and synaptosomal 3H-dopamine release determined in response to 1 and 10 μM nicotine. 6-OHDA lesioning resulted in ~50% decline in α6β2* nAChR-mediated release. Nicotine treatment significantly reduced 3H-dopamine release with submaximal (1 μM) nicotine stimulation. Values represent the mean ± S.E.M. of 9–13 rats. Significant main effect of nicotine (*p < 0.05) using two-way ANOVA.
Fig. 5
Fig. 5
Nicotine treatment decreases α4β2* nAChR-mediated dopamine release from rat striatal synaptosomes. Striatal synaptosomes were prepared from 6-OHDA-lesioned rats, treated with and without nicotine (Nic) and/or L-dopa (LD). At the end of the treatment phase, the rats were killed and synaptosomal 3H-dopamine release determined in response to 1 and 10 μM nicotine. 6-OHDA lesioning resulted in ~50% decline in α4β2* nAChR-mediated release. Nicotine treatment significantly reduced release on both the intact and lesioned side at maximal nicotine stimulation (10 μM). Values represent the mean ± S.E.M. of 9–13 rats. Significant main effect of nicotine (*p < 0.05, **p < 0.01) using two-way ANOVA.
Fig. 6
Fig. 6
Effect of lesioning and drug treatment on dopamine transport. The dopamine transporter was measured using 125I-RTI-121 autoradiography, with representative autoradiographic images from the intact and lesioned striatum of nicotine (Nic)-treated rats in the top panels. Quantitative analyses of the data from all treatment groups are provided in the middle panel. Lesioning significantly reduced the transporter by about 60%. Nicotine treatment also led to a small reduction in the transporter on the lesioned side. As an indirect measure of dopamine transport, we also measured synaptosomal 3H-dopamine content when release was complete (bottom panel). Results were similar to those observed with dopamine transporter autoradiography. Values are the mean ± S.E.M. of 9–13 rats. Significance of difference from own intact side: **p < 0.01, ***p < 0.001; significance of difference from own no nicotine-treated group, #p < 0.05, ##p < 0.01 using two-way ANOVA followed by a Bonferroni post hoc test.
Fig. 7
Fig. 7
Effect of lesioning and drug treatment on striatal α6β2* nAChRs. α6β2* nAChR were then measured using 125I-α-CtxMII autoradiography. Representative autoradiograms from the intact and lesioned striatum of nicotine (Nic)-treated rats are depicted in the upper panels. Quantitative analyses of the data from all treatment groups are provided in the lower panel. Lesioning significantly reduced binding. Nicotine treatment also decreased binding on the lesioned and intact side. Values are the mean ± S.E.M. of 9–13 rats. Significance of difference from own intact side: ***p < 0.001; significance of difference from own no nicotine-treated group, #p < 0.05, ##p < 0.01, ###p < 0.001 using two-way ANOVA followed by a Bonferroni post hoc test.
Fig. 8
Fig. 8
Effect of lesioning and drug treatment on striatal α4β2* nAChRs. α4β2* nAChRs were measured using 125I-epibatidine autoradiography in the presence of α-CtxMII. Representative autoradiograms from the intact and lesioned striatum of nicotine (Nic)-treated rats are depicted in the upper panels. Quantitative analyses of the data from all treatment groups are provided in the lower panel. Lesioning led to a small decline in binding. Nicotine treatment increased binding on both the lesioned and intact side. Values are the mean ± S.E.M. of 9–13 rats. Significance of difference from own intact side: *p < 0.05; significance of difference from own no nicotine-treated group, ###p < 0.001 using two-way ANOVA followed by a Bonferroni post hoc test.
Fig. 9
Fig. 9
Schematic representation of the effect of long-term nicotine treatment on dopamine (DA) release from nigrostriatal terminals. The nicotine-induced decline in striatal dopamine release may counterbalance the effect of excess dopamine production (due to L-dopa) that is not cleared because of the dopamine nerve terminal loss.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Anderson SM, Brunzell DH. Low Dose Nicotine and Antagonism of beta2 Subunit Containing Nicotinic Acetylcholine Receptors Have Similar Effects on Affective Behavior in Mice. PLoS One. 2012;7:e48665. - 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. Berthet A, Bezard E. Dopamine receptors and L-dopa-induced dyskinesia. Parkinsonism Relat Disord. 2009;15(Suppl 4):S8–12. - PubMed
    1. Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci. 2001;2:577–588. - PubMed
    1. Bordia T, Campos C, Huang L, Quik M. Continuous and intermittent nicotine treatment reduces L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a rat model of Parkinson’s disease. J Pharmacol Exp Ther. 2008;327:239–247. - PubMed

Publication types

LinkOut - more resources