Abstract
The development of abnormal involuntary movements (AIMs) or dyskinesias is a serious complication of l-DOPA [l-3,4-dihydroxyphenylalanine] therapy for Parkinson's disease. Our previous work had shown that intermittent nicotine dosing reduced l-DOPA-induced dyskinetic-like movements in nonhuman primates. A readily available nicotine formulation is the nicotine patch, which provides a constant source of nicotine. However, constant nicotine administration more readily desensitizes nicotinic receptors, to possibly yield alternate behavioral outcomes. Therefore, we investigated whether constant nicotine administration reduced l-DOPA-induced AIMs in a rat parkinsonian model, with results compared with those with intermittent nicotine dosing. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion were exposed to either intermittent (drinking water) or constant (minipump) nicotine for ≥2 weeks at doses that yielded plasma levels of the nicotine metabolite cotinine similar to those in smokers. The rats were next treated with l-DOPA/benserazide (8 or 12 mg/kg/15 mg/kg) for ≥3 weeks to allow for the development of AIMs, with nicotine treatment continued. Both modes of nicotine administration resulted in ≥50% decline in l-DOPA-induced AIMs. Nicotine treatment also significantly reduced AIMs in l-DOPA-primed rats using either dosing regimen, whereas nicotine removal led to an increase in AIMs. There was no effect of nicotine on various measures of motor performance in 6-OHDA-lesioned rats. In summary, nicotine provided either via the drinking water or minipump reduced l-DOPA-induced AIMs in a rat model of Parkinson's disease. These results suggest that either intermittent or constant nicotine treatment may be useful in the treatment of l-DOPA-induced dyskinesias in patients with Parkinson's disease.
Footnotes
-
This work was supported by National Institutes Health Grants NS42091 and NS47162.
-
T.B. and C.C. contributed equally to the work.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.140897.
-
ABBREVIATIONS:l-DOPA, l-3,4-dihydroxyphenylalanine; 6-OHDA, 6-hydroxydopamine; AIM, abnormal involuntary movement; RTI-121, 3β-(4-iodophenyl)tropane-2β-carboxylic acid isopropyl ester; ANOVA, analysis of variance.
- Received May 6, 2008.
- Accepted July 22, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|