Role of nicotine and nAChRs in L-dopa-induced dyskinesias.
Initial Award Abstract
Parkinson’s disease is characterized by a progressive neurodegeneration of nigrostriatal dopamine neurons, which affects ~1% of the populations over the age of 60 years. Current therapy using dopamine replacement with L-dopa greatly improves parkinsonian symptoms, including akinesia, rigity, tremor and postural imbalance. However, most patients develop side effects, such as dyskinesias or abnormal involuntary movements (AIMs) that can be as debilitating as the disease itself. Currently, the lack of treatment for dyskinesias limits the utility of L-dopa therapy for Parkinson’s disease. There are three strategies have been used to delay the onset of this motor complication. These include the use of dopamine receptor agonists, glutamate antagonists, and deep brain stimulation. However, these treatments either yield inconsistent improvement or lead to severe side effects. Since L-dopa is still the best treatment for Parkinson’s disease, therapies to prevent/reduce L-dopa-induced dyskinesias are being tested.
Our recent studies show that nicotine, a component present in tobacco, reduces L-dopa-induced dyskinesias. Nicotine acts on multiple nicotinic receptors located at both central and peripheral sites, which results in the desired responses but also other effects. Interestingly, only select nAChR subtypes are expressed in the nigrostriatal pathway, the brain system relevant to Parkinson’s disease and L-dopa-induced dyskinesias. Thus, the goal of the present proposal is to identify the specific nicotinic receptor subtypes through which nicotine treatment reduces L-dopa-induced dyskinesias and the molecular mechanisms that are involved. To approach this, we will use nicotinic receptor subunit null mutant mice. These include â2, á4, á6 and á7 subunit null mutant mice, because nicotinic receptors containing these subunits are expressed in the nigrostriatal pathway linked to L-dopa-induced dyskinesias. These studies would provide information to identify the involvement of specific nicotinic receptor subtypes in nicotine-mediated antidyskinetic effect. In addition, we will also investigate the pre- and postsynaptic mechanisms whereby nicotine reduces L-dopa-induced dyskinesias. These include measures of dopamine levels and dopamine metabolism at presynaptic sites, as well as the changes in postsynaptic dopamine receptor-mediated signaling cascades such as protein kinase A (PKA) and dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP32).
Taken together, this study will advance our knowledge of the roles of nicotinic receptor subtypes and their downstream signaling in development of L-dopa-induced dyskinesias forParkinson’s disease. The outcomes of these experiments have important implications for the development of therapeutic strategies for L-dopa-induced dyskinesias. |
|Nicotinic receptor agonists dectease L-dopa-induce dyskinesias most effectively in partially lesioned parkinsonian rats.
|Authors: Huang LZ, Campos C, Ly K, Ivy Carroll F, Quik M