Dopaminergic Control of Striatal Cholinergic Interneurons May Cause Antipsychotic-Associated Parkinsonism

Despite the severe symptoms caused by psychotic disorders, patients may feel compelled to opt for those over the disabling adverse effects associated with some antipsychotic medications. These agents block the signaling of dopamine D2 receptors (D2R), which can cause extrapyramidal symptoms such as dystonia, parkinsonism, and tardive dyskinesia, though the underlying mechanisms are not yet clear. Researchers at the Irvine and San Francisco campuses of the University of California, the Gladstone Institutes in San Francisco, and Columbia University in New York aimed to elucidate these processes in a new rodent study reported in Neuron.

Medium spiny neurons (MSN) are the most abundant ones in the striatum, and they are its sole output, making them essential to the functions that are regulated by this structure, including movement. “Neuronal networks formed by extrastriatal and intrastriatal inputs finely regulate MSN activity,” of which dopamine (DA) is a major modulator, explained the authors of the study. The regulation of striatal neurons by DA extends to cholinergic interneurons (Chls), also known as tonically active neurons. Chls “integrate excitatory inputs from the thalamus and cortex with inputs from DA and GABA neurons, leading to regulation of MSN outputs,” they wrote.

As shown in previous findings, there is a reciprocal relationship between DA neurons and Chls: Acetylcholine (ACh) stimulates the activity of dopaminergic neurons and the release of DA and GABA, and in turn, DA either blocks or stimulates the activity of Chls and the release of Ach, which is contingent on whether it acts through D2R or D5R. Muscarinic receptors modulate MSN activity. “The synergism between DA and ACh has important consequences for the activity of MSNs, which compose the direct and indirect pathways…. These findings suggest the presence of a tight DA-regulated interplay between MSN and ChI activity,” the authors explained.

Researchers have found it challenging to investigate the contribution of D2R in specific striatal neurons–particularly in the Chls, which are low in number–because of the complex relationship between neuronal types and DA signaling, as well as the heterogeneous distribution of D2R. To address this issue, the authors of the current study used mice with cell type-specific deletion of D2R in striatal Chls (referred to as ChI-D2RKO mice), which is the first mouse model of this type.

While the antipsychotic haloperidol has been shown to induce catalepsy in rodents, the results of the current investigation reveal that this effect is suppressed in the Chl-D2RKO mice. The Chls of these mice were found to have “significantly shorter pauses in firing after intrastriatal stimulation, corroborating a critical role of D2R signaling in generating the pause in vitro,” according to the paper. “These results underline the importance of D2R signaling in ChIs in the control of motor function and will be valuable toward the development of alternative pharmacological strategies,” the authors concluded.

Reference

Kharkwal G, Brami-Cherrier K, Lizardi-Ortiz JE, et al. Parkinsonism driven by antipsychotics originates from dopaminergic control of striatal cholinergic interneurons. Neuron. 2016;91(1):67-78.