Year: 2025
Type: article
Abstract: Haloperidol is used to manage psychotic symptoms in several neurological disorders through mechanisms that involve antagonism of dopamine D2 receptors that are highly expressed in the striatum. Significant side effects of haloperidol, known as extrapyramidal symptoms, lead to motor deficits similar to those seen in Parkinson's disease and present a major challenge in clinical settings. The underlying molecular mechanisms responsible for these side effects remain poorly understood. Parkinson's disease-associated leucine-rich repeat kinase 2 (LRRK2) has an essential role in striatal physiology and a known link to dopamine D2 receptor signaling. Here, we systematically explore convergent signaling of haloperidol and LRRK2 through pharmacological or genetic inhibition of LRRK2 kinase, as well as knock-in mouse models expressing pathogenic mutant LRRK2 with increased kinase activity. Behavioral assays show that LRRK2 kinase inhibition ameliorates haloperidol-induced motor changes in mice. A combination of electrophysiological and anatomical approaches reveals that LRRK2 kinase inhibition interferes with haloperidol-induced changes, specifically in striatal neurons of the indirect pathway. Proteomic studies and targeted intracellular pathway analyses demonstrate that haloperidol induces a similar pattern of intracellular signaling as increased LRRK2 kinase activity. Our study suggests that LRRK2 kinase plays a key role in striatal dopamine D2 receptor signaling underlying the undesirable motor side effects of haloperidol. This work opens up new therapeutic avenues for dopamine-related disorders, such as psychosis, also furthering our understanding of Parkinson's disease pathophysiology.
Source: Molecular Psychiatry
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,490
Funders: U.S. Department of Health and Human Services, Michael J. Fox Foundation for Parkinson's Research, Northwestern University, National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Center for Information Technology
Awards: G1136421102, G1280792157, G1284175734, Diversity Supplement: Mechanisms of striatal structural and functional plasticity, G2761295875, G3053718721, LRRK2-mediated molecular and synaptic events in the striatum, G5414792815, G6280846582, The Role of Striatal Astrocytic Dopamine D2 Receptor Signaling in the Pathogenesis of LRRK2-Mediated Parkinson's Disease, Chemistry of Life Processes Predoctoral Training Program, G7517546096, G8093032105, G896068630, G9000046704, G9000231858, G9000294165, The Robert H. Lurie Comprehensive Cancer Center
OpenAlex ID: W4409722820