Typical Antipsychotics Induce Parkinsonism via D2R Antagonism on Various Cell Types of the Striatum
Introduction. There are several illicit and therapeutic drugs that can induce movement disorders. Among all these drugs, typical antipsychotics specifically are thought to possess similar mechanistic causations of motor deficiencies observed in drug induced Parkinsonism, which is the classic motor presentation of Parkinson’s disease.1, 2 It is believed that these symptoms are elicited from issues of communication between dopaminergic neurons and dopamine transmission within the striatum of the substantia nigra pars compacta.3 Methods/Results. It is known that haloperidol has an antagonistic effect of D2Rs within the striatum.6 The relationship of these D2Rs with various other cell types were observed and measured using multiple approaches. Ablation of D2R in cholinergic interneurons (ChI-D2RKO) in mice allowed for observation of the effect of D2R on movement. Synergy between the D2R and cholinergic interneurons had profound effects on the fine tuning of motor movement.4 In ChI-D2RKO, haloperidol did not induce catalepsy, proving that parkinsonism induced effect of typical antipsychotics such as haloperidol that are known D2R antagonists, are dependent on the presence of D2R in cholinergic interneurons in the striatal pathway to induce their debilitating motor deficiency’s.4 Parkinsonism was induced in mouse models by giving three different dosages of haloperidol (5mg/kg, 10mg/kg, and 15mg/kg) over a 14-day period. Groups treated with 15mg/kg we’re observed to have markedly enlarged medium and small spiny neurons of the dorsal striatum. Nissl body degeneration was shown on H&E stain to be significant for the 15mg/kg group with loss shown in the lesser dosage groups as well. Prolonged blockage of the D2R in the striatum lead to death of the dopamine neurons or loss of synaptic connection with the post synaptic neuron, causing the eventual manifestation of Parkinsonism.5 Conclusion. The inhibition of D2R by haloperidol has a vast inhibitory effect on multiple pathways in the striatum that are dependent on a form of coordination between the D2R and various other cell types.4, 5, 6, 7, 8 To say one specific pathway being altered is the causation is neglectful and dismissive to the various other pathways/systems being affected. Because of this lack of control, it has become of interest to develop therapeutic agents that either target specific D2Rs of a precise cell type or pathway in the striatum, or to attempt and develop an antipsychotic that avoids the inhibition of D2Rs altogether.4, 5, 6, 7, 8
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- Kharkwal G, Brami-Cherrier K, Lizardi-Ortiz JE, et al. Parkinsonism driven by antipsychotics originates from dopaminergic control of striatal cholinergic interneurons. Neuron. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939839/#__ffn_sectitle. Published July 6, 2016. Accessed February 7, 2022.
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- Functionally biased D2R antagonists: Targeting the arrestin pathway to improve antipsychotic treatment. doi:10.1021/acschembio.8b00168.s001