Mechanisms Underlying Dopaminergic Regulation of Nicotine-Induced Kinetic Tremor.

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 α4ß2 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.

Pharmacological characterization of nicotine-induced tremor: Responses to anti-tremor and anti-epileptic agents.

We previously showed that nicotine evoked kinetic tremor by activating the inferior olive, which is implicated in the pathogenesis of essential tremor, via α7 nicotinic acetylcholine receptors. Here, we evaluated the effects of various anti-tremor and anti-epileptic agents on nicotine-induced tremor in mice to clarify the pharmacological characteristics of nicotine tremor. Drugs effective for essential tremor, propranolol, diazepam and phenobarbital, all significantly inhibited kinetic tremor induced by an intraperitoneal (i.p.) injection of nicotine (1 mg/kg). In contrast, none of the medications for Parkinson's disease, l-DOPA, bromocriptine or trihexyphenidyl, affected the nicotine tremor. Among the anti-epileptic agents examined, valproate, carbamazepine and ethosuximide, significantly inhibited nicotine-induced tremor. In addition, a selective T-type Ca2+ channel blocker, TTA-A2, also suppressed the nicotine tremor. However, neither gabapentin, topiramate, zonisamide nor levetiracetam significantly affected nicotine-induced tremor. The present results show that nicotine-induced tremor resembles essential tremor not only on the neural basis, but also in terms of the pharmacological responses to anti-tremor agents, implying that nicotine-induced tremor can serve as a model for essential tremor. In addition, it is suggested that anti-epileptic agents, which have stimulant actions on the GABAergic system or blocking actions on voltage-gated Na+ channels and T-type Ca2+ channels, can alleviate essential tremor.

Glycine-Binding Site Stimulants of NMDA Receptors Alleviate Extrapyramidal Motor Disorders by Activating the Nigrostriatal Dopaminergic Pathway.

Dysfunction of the N-methyl-d-aspartate (NMDA) receptor has been implicated in the pathogenesis of schizophrenia. Although agonists for the glycine-binding sites of NMDA receptors have potential as new medication for schizophrenia, their modulation of antipsychotic-induced extrapyramidal side effects (EPS) has not yet been clarified. We herein evaluated the effects of glycine-binding site stimulants of NMDA receptors on antipsychotic-induced EPS in mice and rats. d-cycloserine (DCS) and d-serine significantly improved haloperidol (HAL)-induced bradykinesia in mice, whereas glycine showed no effects. Sodium benzoate, a d-amino acid oxidase inhibitor, also attenuated HAL-induced bradykinesia. Improvements in HAL-induced bradykinesia by DCS were antagonized by the NMDA antagonist dizocilpine or nitric oxide synthase inhibitor L-NG-Nitro-l-arginine methyl ester. In addition, DCS significantly reduced HAL-induced Fos expression in the dorsolateral striatum without affecting that in the nucleus accumbens. Furthermore, a microinjection of DCS into the substantia nigra pars compacta significantly inhibited HAL-induced EPS concomitant with elevations in dopamine release in the striatum. The present results demonstrated for the first time that stimulating the glycine-binding sites of NMDA receptors alleviates antipsychotic-induced EPS by activating the nigrostriatal dopaminergic pathway, suggesting that glycine-binding site stimulants are beneficial not only for efficacy, but also for side-effect management.

Serotonergic modulation of nicotine-induced kinetic tremor in mice.

We previously demonstrated that nicotine elicited kinetic tremor by elevating the neural activity of the inferior olive via α7 nicotinic acetylcholine (nACh) receptors. Since α7 nACh receptors reportedly facilitate synaptic monoamine release, we explored the role of 5-HT receptors in induction and/or modulation of nicotine tremor. Treatment of mice with nicotine induced kinetic tremor that normally appeared during movement. The 5-HT1A agonist, 8-hydroxydipropylaminotetraline (8-OH-DPAT), significantly enhanced nicotine-induced tremor and the action of 8-OH-DPAT was antagonized by WAY-100135 (5-HT1A antagonist). In addition, the cerebral 5-HT depletion by repeated treatment with p-chlorophenylalanine did not reduce, but rather potentiated the facilitatory effects of 8-OH-DPAT. In contrast, the 5-HT2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), significantly attenuated nicotine tremor, which was antagonized by ritanserin (5-HT2 antagonist). The 5-HT3 agonist SR-57227 did not affect nicotine-induced tremor. Furthermore, when testing the direct actions of 5-HT antagonists, nicotine tremor was inhibited by WAY-100135, but was unaffected by ritanserin, ondansetron (5-HT3 antagonist) or SB-258585 (5-HT6 antagonist). These results suggest that postsynaptic 5-HT1A receptors are involved in induction of nicotine tremor mediated by α7 nACh receptors. In addition, 5-HT2 receptors have an inhibitory modulatory role in induction of nicotine tremor.

Nicotine Elicits Convulsive Seizures by Activating Amygdalar Neurons.

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 α4ß2 nACh antagonist, dihydro-ß-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.

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

Nicotinic acetylcholine (nACh) receptors are implicated in the pathogenesis of movement disorders (e.g., tremor) and epilepsy. Here, we performed behavioral and immunohistochemical studies using mice and rats to elucidate the mechanisms underlying nicotine-induced tremor. Treatments of animals with nicotine (0.5-2mg/kg, i.p.) elicited kinetic tremor, which was completely suppressed by the nACh receptor antagonist mecamylamine (MEC). The specific α7 nACh receptor antagonist methyllycaconitine (MLA) also inhibited nicotine-induced tremor, whereas the α4ß2 nACh antagonist dihydro-ß-erythroidine (DHßE) or the peripheral α3ß4 nACh antagonist hexamethonium showed no effects. Mapping analysis of Fos protein expression, a biological marker of neural excitation, revealed that a tremorgenic dose (1mg/kg) of nicotine region-specifically elevated Fos expression in the piriform cortex (PirC), medial habenula, solitary nucleus and inferior olive (IO) among 44 brain regions examined. In addition, similarly to the tremor responses, nicotine-induced Fos expression in the PirC and IO was selectively antagonized by MLA, but not by DHßE. Furthermore, an electrical lesioning of the IO, but not the PirC, significantly suppressed the induction of nicotine tremor. The present results suggest that nicotine elicits kinetic tremor in rodents by activating the IO neurons via α7 nACh receptors.