AUTHOR=Kato Masaki , Kunisawa Naofumi , Shimizu Saki , Iha Higor A. , Ohno Yukihiro 

TITLE=Mechanisms Underlying Dopaminergic Regulation of Nicotine-Induced Kinetic Tremor

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.938175

DOI=10.3389/fphar.2022.938175

ISSN=1663-9812

ABSTRACT=<p>Nicotine induces kinetic tremor, which resembles pharmacological features of essential tremors, via activating the inferior olive (IO) neurons. Since nicotine is known to enhance dopamine release by stimulating α4β2 and/or α6 nACh receptors, we examined the effects of various dopamine receptor ligands on nicotine-induced tremor to clarify the role of the dopaminergic system in modulating nicotine tremor. A tremorgenic dose of nicotine increased the dopamine level in the pons and medulla oblongata (P/MO), and the levels of dopamine metabolites in the hippocampus, P/MO, and striatum. Treatment of animals with the D<sub>1/5</sub> agonist SKF-38393 inhibited the induction of nicotine tremor, whereas the D<sub>3</sub> agonist PD-128,907 facilitated nicotine-induced tremor. The D<sub>2</sub> agonist sumanirole showed no effect. In addition, nicotine tremor was significantly enhanced by the D<sub>1/5</sub> antagonist SCH-23390 and inhibited by the D<sub>3</sub> antagonist U-99194. Neither the D<sub>2</sub> (L-741,626) nor D<sub>4</sub> (L-745,870) antagonist affected the generation of nicotine tremor. Furthermore, microinjection of U-99194 into the cerebellum significantly inhibited nicotine-induced tremor, whereas its injection into IO or the striatum did not affect tremor generation. Although intrastriatal injection of SCH-23390 showed no effects, its injection into IO tended to enhance nicotine-induced tremor. The present study suggests that dopamine D<sub>3</sub> and D<sub>1/5</sub> receptors regulate the induction of nicotine tremor in an opposite way, D<sub>3</sub> receptors facilitately and D<sub>1/5</sub> receptors inhibitorily. In addition, the cerebellar D<sub>3</sub> receptors may play an important role in modulating the induction of nicotine tremor mediated by the olivo-cerebellar system.</p>