Nicotine evokes kinetic tremor by activating the inferior olive via α7 nicotinic acetylcholine receptors

Kunisawa, Naofumi; Iha, Higor A.; Shimizu, Saki; Tokudome, Kentaro; Mukai, Takahiro; Kinboshi, Masato; Serikawa, Tadao; Ohno, Yukihiro

doi:10.1016/j.bbr.2016.08.013

Cited by 12 publications

(11 citation statements)

References 48 publications

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“…We have previously reported that kinetic tremors induced by a low dose (1 mg/kg, i.p.) of nicotine are mediated by α7 nACh receptors, whereas α4β2 nACh receptors are negligibly involved in tremor induction ( Kunisawa et al, 2016 ). Therefore, α7 nACh receptors are likely to play a key role in producing motor excitations (e.g., tremor and seizure generation) with nicotine.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated that a low dose (1 mg/kg, i.p.) of nicotine, which reportedly induces cognitive enhancement ( Swan and Lessov-Schlaggar, 2007 ), antidepressant effects ( Vieyra-Reyes et al, 2008 ; Mineur and Picciotto, 2010 ) and positive reinforcement ( Harrington et al, 2016 ), as well as kinetic tremor ( Kunisawa et al, 2016 ), region-specifically elevated Fos expression in four brain regions; the PirC, MHb, Sol, and IO. In the present study, a convulsive dose (4 mg/kg, i.p.)…”

Section: Discussionmentioning

confidence: 99%

“…Animals were intraperitoneally injected with nicotine (1–4 mg/kg) or saline (vehicle) and placed in an individual observation box (25 cm × 42 cm × 20 cm). Nicotine-induced behavioral excitement was evaluated over 15 min after the nicotine injection using a six point-ranked score (0: no effect; 1: mild head tremor and Straub tail; 2: apparent tremors in extended regions, 3: severe tremors with wild running; 4: clonic seizures; 5: tonic or tonic-clonic seizures) modified from previous reports ( Kunisawa et al, 2016 ; Tokudome et al, 2016 ). Incidence of convulsive seizures was judged as positive when scores were 4 or higher.…”

Section: Methodsmentioning

confidence: 99%

“…Electrical lesion studies were performed using SD rats as reported previously ( Ohno et al, 2015 ; Kunisawa et al, 2016 ). Briefly, animals were anesthetized with pentobarbital (60 mg/kg, i.p.)…”

Section: Methodsmentioning

confidence: 99%

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Nicotine Elicits Convulsive Seizures by Activating Amygdalar Neurons

et al. 2017

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Nicotinic acetylcholine (nACh) receptors are implicated in the pathogenesis of epileptic disorders; however, the mechanisms of nACh receptors in seizure generation remain unknown. Here, we performed behavioral and immunohistochemical studies in mice and rats to clarify the mechanisms underlying nicotine-induced seizures. Treatment of animals with nicotine (1–4 mg/kg, i.p.) produced motor excitement in a dose-dependent manner and elicited convulsive seizures at 3 and 4 mg/kg. The nicotine-induced seizures were abolished by a subtype non-selective nACh antagonist, mecamylamine (MEC). An α7 nACh antagonist, methyllycaconitine, also significantly inhibited nicotine-induced seizures whereas an α4β2 nACh antagonist, dihydro-β-erythroidine, affected only weakly. Topographical analysis of Fos protein expression, a biological marker of neural excitation, revealed that a convulsive dose (4 mg/kg) of nicotine region-specifically activated neurons in the piriform cortex, amygdala, medial habenula, paratenial thalamus, anterior hypothalamus and solitary nucleus among 48 brain regions examined, and this was also suppressed by MEC. In addition, electric lesioning of the amygdala, but not the piriform cortex, medial habenula and thalamus, specifically inhibited nicotine-induced seizures. Furthermore, microinjection of nicotine (100 and 300 μg/side) into the amygdala elicited convulsive seizures in a dose-related manner. The present results suggest that nicotine elicits convulsive seizures by activating amygdalar neurons mainly via α7 nACh receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Nicotine Elicits Convulsive Seizures by Activating Amygdalar Neurons

et al. 2017

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“…We previously showed that nicotine at relatively low doses (0.5–1 mg/kg, i.p.) evokes kinetic tremor in rodents ( Kunisawa et al, 2016 ; Kunisawa et al, 2017 ; Kunisawa et al, 2018 ). Immunohistochemical analysis of Fos protein expression, a biological marker of neural excitation ( Iha et al, 2016 ), revealed that tremorgenic doses of nicotine region-specifically increased the activities of the inferior olive (IO) neurons ( Kunisawa et al, 2016 ) similarly to the rat model of essential tremor ( Ohno et al, 2015a ).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying Dopaminergic Regulation of Nicotine-Induced Kinetic Tremor

Kato

Kunisawa²,

Shimizu³

et al. 2022

Front. Pharmacol.

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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 D1/5 agonist SKF-38393 inhibited the induction of nicotine tremor, whereas the D3 agonist PD-128,907 facilitated nicotine-induced tremor. The D2 agonist sumanirole showed no effect. In addition, nicotine tremor was significantly enhanced by the D1/5 antagonist SCH-23390 and inhibited by the D3 antagonist U-99194. Neither the D2 (L-741,626) nor D4 (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 D3 and D1/5 receptors regulate the induction of nicotine tremor in an opposite way, D3 receptors facilitately and D1/5 receptors inhibitorily. In addition, the cerebellar D3 receptors may play an important role in modulating the induction of nicotine tremor mediated by the olivo-cerebellar system.

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