Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease.

Expanding the repertoire of L-DOPA’s actions: A comprehensive review of its functional neurochemistry

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function

Long-term levodopa (l-dopa) treatment in patients with Parkinson´s disease (PD) is associated with the development of motor complications (ie, motor fluctuations and dyskinesias). The principal etiopathogenic factors are the degree of nigro-striatal dopaminergic loss and the duration and dose of l-dopa treatment. In this review article we concentrate on analysis of the mechanisms underlying l-dopa-induced dyskinesias, a phenomenon that causes disability in a proportion of patients and that has not benefited from major therapeutic advances. Thus, we discuss the main neurotransmitters, receptors, and pathways that have been thought to play a role in l-dopa-induced dyskinesias from the perspective of basic neuroscience studies. Some important advances in deciphering the molecular pathways involved in these abnormal movements have occurred in recent years to reveal potential targets that could be used for therapeutic purposes. However, it has not been an easy road because there have been a plethora of components involved in the generation of these undesired movements, even bypassing the traditional and well-accepted dopamine receptor activation, as recently revealed by optogenetics. Here, we attempt to unify the available data with the hope of guiding and fostering future research in the field of striatal activation and abnormal movement generation. © 2017 International Parkinson and Movement Disorder Society.

Motor complications in Parkinson's disease: Striatal molecular and electrophysiological mechanisms of dyskinesias.

Understanding the biological mechanisms of l-dopa-induced motor complications is dependent on our ability to investigate these phenomena in animal models of Parkinson's disease. The most common motor complications consist in wearing-off fluctuations and abnormal involuntary movements appearing when plasma levels of l-dopa are high, commonly referred to as peak-dose l-dopa-induced dyskinesia. Parkinsonian models exhibiting these features have been well-characterized in both rodent and nonhuman primate species. The first animal models of peak-dose l-dopa-induced dyskinesia were produced in monkeys lesioned with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated chronically with l-dopa to elicit choreic movements and dystonic postures. Seminal studies were performed in these models using both metabolic mapping and electrophysiological techniques, providing fundamental pathophysiological insights that have stood the test of time. A decade later, it was shown possible to reproduce peak-dose l-dopa-induced dyskinesia in rats and mice rendered parkinsonian with nigrostriatal 6-hydroxydopamine lesions. When treated with l-dopa, these animals exhibit abnormal involuntary movements having both hyperkinetic and dystonic components. These models have enabled molecular- and cellular-level investigations into the mechanisms of l-dopa-induced dyskinesia. A flourishing literature using genetically engineered mice is now unraveling the role of specific genes and neural circuits in the development of l-dopa-induced motor complications. Both non-human primate and rodent models of peak-dose l-dopa-induced dyskinesia have excellent construct validity and provide valuable tools for discovering therapeutic targets and evaluating potential treatments. © 2018 International Parkinson and Movement Disorder Society.

M.A. Cenci

Papers

Activity of serotonin 5-HT1A receptor 'biased agonists' in rat models of Parkinson's disease and l-DOPA-induced dyskinesia.