The striatal cholinergic system in l-dopa-induced dyskinesias

Cholinergic signaling plays a key role in regulating striatal function. The principal source of acetylcholine in the striatum is the cholinergic interneurons which, although low in number, densely arborize to modulate striatal neurotransmission. This modulation occurs via strategically positioned nicotinic and muscarinic acetylcholine receptors that influence striatal dopamine, GABA and other neurotransmitter release. Cholinergic interneurons integrate multiple striatal synaptic inputs and outputs to regulate motor activity under normal physiological conditions. Consequently, an imbalance between these systems is associated with basal ganglia disorders. Here, we provide an overview of how striatal cholinergic interneurons modulate striatal activity under normal and pathological conditions. Numerous studies show that nigrostriatal damage such as that occurs with Parkinson’s disease affects cholinergic receptor-mediated striatal activity. This altered cholinergic signaling is an important contributor to Parkinson’s disease as well as to the dyskinesias that develop with l-dopa therapy, the gold standard for treatment. Indeed, multiple preclinical studies show that cholinergic receptor drugs may be beneficial for the treatment of l-dopa-induced dyskinesias. In this review, we discuss the evidence indicating that therapeutic modulation of the cholinergic system, particularly targeting of nicotinic cholinergic receptors, may offer a novel approach to manage this debilitating side effect of dopamine replacement therapy for Parkinson’s disease.