Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The results of a dose-response study of the effects of nicotine on exploratory behavior in male rats is reported. Nicotine at 0.5 mg/kg elevated locomotor activity without significantly changing other parameters of exploration. Low-dose nicotine (0.2 mg/kg) did not produce any effect on exploration measures, while high-dose nicotine (0.8 mg/kg) produced a state of ataxia in animals and decreased most exploration measures in general. Additional, nicotine at high doses seems to reduce the animal's state of fear/anxiety, while at low dose the drug seems to increase the animal's level of curiosity in a novel environment. Biochemically, nicotine has been found to accelerate dopamine synthesis and norepinephrine turnover, and to decrease serotonin turnover. More importantly, the amino acid precursors tyrosine and tryptophan were found to be the neurochemical measures most related to the behavioral changes produced by nicotine.
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PMID:Effects of nicotine on exploratory behavior in rats: correlation with regional brain monoamine levels. 286 44

Nicotine (0.5 and 1.0 mg/kg) administered subcutaneously to mice decreased the ambulatory activity recorded by an ambulo-meter in a dose-dependent manner from 5 to 60 min after the administration, and the higher dose (1.0 mg/kg) caused a long-lasting ataxia. To be noted was the initial increment of ambulation which usually preceded the ataxia-inducing effect with every dose of nicotine, and the lowest dose (0.10 mg/kg) employed herein induced only the increasing effect on ambulation recorded for the first 20 min after its administration. The ataxia-inducing effect of nicotine (1.0 mg/kg) was attenuated by the pretreatment with mecamylamine (0.4-2.0 mg/kg) in a dose-dependent manner, though the attenuating effect waned at a higher dose (4.0 mg/kg). In contrast, pretreatment with either hexamethonium (2.5 and 5.0 mg/kg) or atropine (1.0, 2.5 and 5.0 mg/kg) did not affect the ataxia-inducing effect of nicotine. Atropine when administered alone was found to markedly increase the ambulatory activity at the doses used for the pretreatment. Measurement of the time-dependent change of [3H]-nicotine level in brain tissue after its subcutaneous injection revealed that there is a good correlation between the brain levels of the alkaloid and the intensity of its ataxic effect rather than the initial increasing effect on ambulation. The results obtained herein suggest that nicotine exerts its ataxic effect centrally, but the site and type of the receptor stimulated by nicotine remains to be identified.
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PMID:Effects of nicotine on ambulatory activity in mice. 337 24

Drug-naive rats were tested for horizontal and vertical activity in photocell cages, for up to 80 min starting immediately after a subcutaneous injection of (-)-nicotine bitartrate or 0.9% w/v NaCl solution (saline). Nicotine (0.1 to 0.4 mg kg-1 base) depressed vertical activity and induced ataxia in the first 20 min, but increased both horizontal and vertical activity later in the session; these actions were dose-dependent. A single intraventricular (i.v.t.) injection of chlorisondamine Cl (2 microgram base), a quaternary ganglion-blocking drug, given one to two weeks before testing, blocked the ataxic and stimulant actions of nicotine. The antagonistic actions of chlorisondamine (0.2, 1.0, 5.0 micrograms i.v.t., single administration) were shown to be dose-dependent. The stimulant actions of nicotine were blocked in a dose-dependent way for the duration of the experiment (5 weeks); nicotine's depressant actions were completely blocked at two weeks but not at five weeks. A ganglion-blocking dose of chlorisondamine (0.1 mg kg-1), given subcutaneously (s.c.), failed to reduce the behavioural actions of nicotine, whereas a much higher systemic dose (10 mg kg-1 s.c.) was effective for at least five weeks. Chlorisondamine failed to alter the behavioural effects of (+)-amphetamine or apomorphine, while blocking those of nicotine. It is concluded that chlorisondamine antagonizes some of nicotine's central actions in a potent, long-lasting and pharmacologically selective way.
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PMID:Chronic central nicotinic blockade after a single administration of the bisquaternary ganglion-blocking drug chlorisondamine. 614 86

In spite of widespread association of nicotine and cannabinoids in humans, very few studies in which nicotine and cannabinoids are co-administered have been reported. Previously, we have reported that intracerebellar (ICB) Delta(9)-tetrahydrocannabinol (Delta(9)-THC) produces dose-dependent cerebellar ataxia. The present study investigated the functional consequences of ICB microinfusion of nicotine on ICB Delta(9)-THC ataxia in CD-1 male mice. Nicotine (0.625, 1.25, 2.5, 5 ng; ICB) markedly attenuated Delta(9)-THC ataxia dose dependently, which was abolished by ICB hexamethonium (5 microg), thus suggesting that the attenuation by nicotine occurred via the nicotinic acetylcholine receptor (nAChR). To further investigate which specific nAChR subtype was involved, ICB microinfusion of RJR-2403 (250, 375, 500, 750 ng), a alpha(4)beta(2) selective nAChR agonist, markedly attenuated Delta(9)-THC ataxia. DHbetaE (500 ng), a alpha(4)beta(2) selective nAChR antagonist, virtually abolished RJR-2403-induced attenuation of Delta(9)-THC ataxia. ICB microinfusion of MLA, a alpha(7) selective nAChR antagonist (1, 5 microg) failed to antagonize nicotine or RJR-2403-induced attenuation of Delta(9)-THC ataxia. This suggested a lack of a role of the alpha(7) subtype and further reinforced the significance of alpha(4)beta(2). Additionally, ICB treatment with DHbetaE virtually abolished nicotine-induced attenuation of Delta(9)-THC ataxia that suggested alpha(4)beta(2) as the primary cerebellar nAChR subtype. Lack of effect of ICB DHbetaE or MLA alone on Delta(9)-THC ataxia ruled out a tonic effect of the alpha(4)beta(2) subtype. The results of the present investigation, therefore, strongly support involvement of the cerebellar alpha(4)beta(2), but not alpha(7), nicotinic receptor subtype in the mediation via nicotine and RJR-2403 on attenuation of Delta(9)-THC ataxia.
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PMID:Mouse cerebellar nicotinic-cholinergic receptor modulation of Delta9-THC ataxia: role of the alpha4beta2 subtype. 1693 31

1. In unanaesthetized cats intraventricular injections of 2.5-10 mug nicotine produced blinking, narrowing of the palpebral fissures, retching, vomiting and asynchronous twitching of the ears. With larger doses (30-100 mug) the ear twitching was interrupted for a short time by laying back of the ears. Respiration first became laboured and deep, then rapid and shallow following which panting occurred. There was salivation, loud calling, micturition and defaecation. With still larger doses (300-1000 mug) there was torticollis, ataxia and blind charging sometimes followed by a clonic-tonic convulsion.2. In cats anaesthetized with chloralose only some of these effects followed the intraventricular injection of nicotine, i.e. the ear response, respiratory changes and salivation. In addition, the pinna reflex was facilitated.3. The ear response and the facilitation of the pinna reflex did not occur on perfusion of nicotine from a lateral ventricle to aqueduct. They result from an action on superficial structures in the cervical cord between C1 and C2. Applied to this region of the cord, nicotine produced the ear response within 10-60 sec, sometimes in concentrations as low as 1/100,000. Applied below C2, nicotine was ineffective.4. Transecting the cord below C2 or cutting the dorsal and ventral roots of C1, C2 and C3 bilaterally did not affect the ear response produced by topical application or by intraventricular injection of nicotine. Transection of the cord above C1 abolished it.5. Hexamethonium applied to the cervical cord between C1 and C2 inhibited the ear response and the facilitation of the pinna reflex whether produced by nicotine applied topically or injected intraventricularly.6. The salivation and the respiratory changes produced by intraventricular injections of nicotine did not occur when nicotine was perfused from a lateral ventricle to the aqueduct. They result from an action of the nicotine on structures situated superficially in the brain stem. Nicotine had no sialogogue or respiratory effect when applied to the region of the cord at which it produced an ear response, but perfused through the subarachnoid space from interpeduncular fossa to cisterna magna or injected into the subarachnoid space alongside the brain stem, it produced these effects.7. Hexamethonium perfused from interpeduncular fossa to cisterna magna inhibited the salivary secretion as well as the respiratory changes produced by nicotine similarly applied.8. The efferent pathway for the salivation is parasympathetic since it no longer occurred after cutting the chorda-lingual nerve or after intravenous atropine.9. Intravenous injections of nicotine also produced the ear response with facilitation of the pinna reflex, salivation and hyperventilation in the anaesthetized cat, but only the ear response and facilitation of the pinna reflex are central effects. The salivation and hyperventilation following intravenous injection are due to peripheral actions of nicotine.
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PMID:Analysis of some central actions of nicotine injected into the cerebral ventricles of cats. 1699 28

Neuronal nicotinic acetylcholinic receptors (nAChR) are promising targets for the development of novel analgesics. Nicotine and other nAChR-agonists produce profound analgesia in rodent models of acute and persistent pain. However, significant side-effects are of concern. Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine. Little is known about its analgesic properties. In the present study, the S(-)- and R(+)-enantiomers of nornicotine were characterized with regard to analgesia and side-effects profile. Efficacy was demonstrated in rat models of pain where central sensitization is involved: i.e. the chronic constriction nerve injury model of peripheral neuropathy and the formalin model of tonic inflammatory pain. The desirable (analgesic) properties resided predominantly in the S(-)- rather than the R(+)-enantiomer. In contrast, undesirable effects (motor in-coordination, reduced locomotor activity, ataxia) were more pronounced with the R(+)-enantiomer. This is an interesting finding, which may suggest separation of toxicity from analgesia by utilization of S(-)-enantiomer of nornicotine. Maximum analgesic effectiveness without significant side-effects was achieved when S(-)-nornicotine (sub-analgesic dose) was combined with a low-dose of the micro-opioid, morphine. These preclinical data suggest that S(-)-nornicotine may be of value, either alone or in combination with an opioid, for treatment of a broad-spectrum of pain (i.e. nociceptive, neuropathic, and mixed pain).
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PMID:The analgesic and toxic effects of nornicotine enantiomers alone and in interaction with morphine in rodent models of acute and persistent pain. 1980 Sep 11

Emerging studies indicate that striatal cholinergic interneurons play an important role in synaptic plasticity and motor control under normal physiological conditions, while their disruption may lead to movement disorders. Here we discuss the involvement of the cholinergic system in motor dysfunction, with a focus on the role of the nicotinic cholinergic system in Parkinson's disease and drug-induced dyskinesias. Evidence for a role for the striatal nicotinic cholinergic system stems from studies showing that administration of nicotine or nicotinic receptor drugs protects against nigrostriatal degeneration and decreases L-dopa-induced dyskinesias. In addition, nicotinic receptor drugs may ameliorate tardive dyskinesia, Tourette's syndrome and ataxia, although further study is required to understand their full potential in the treatment of these disorders. A role for the striatal muscarinic cholinergic system in movement disorders stems from studies showing that muscarinic receptor drugs acutely improve Parkinson's disease motor symptoms, and may reduce dyskinesias and dystonia. Selective stimulation or lesioning of striatal cholinergic interneurons suggests they are primary players in this regulation, although multiple central nervous systems appear to be involved.
Nicotine Tob Res 2019 02 18
PMID:Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders. 3013 17