Mediation of nicotine-induced convulsions by central nicotinic receptors of the ‘C6’ type

Caulfield, Malcolm P.; Higgins, Guy A.

doi:10.1016/0028-3908(83)90251-4

Cited by 38 publications

(8 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This ganglionic blocking agent acts only on peripheral nAChRs (23) and, injected in a dose (19 mol/kg s.c.) known to block several cardiovascular, gastrointestinal, and respiratory responses induced by nicotine (23), fails to block the decrease of DNMT1 expression elicited by nicotine (Table 1).…”

Section: Selection Of Nicotine Dose and Time Schedulementioning

confidence: 99%

Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons

Satta

Maloku

Zhubi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

183

120

View full text Add to dashboard Cite

Tobacco smoking is frequently abused by schizophrenia patients (SZP). The major synaptically active component inhaled from cigarettes is nicotine, hence the smoking habit of SZP may represent an attempt to use nicotine self-medication to correct (i) a central nervous system nicotinic acetylcholine receptor (nAChR) dysfunction, (ii) DNA-methyltransferase 1 (DMT1) overexpression in GABAergic neurons, and (iii) the down-regulation of reelin and GAD 67 expression caused by the increase of DNMT1-mediated hypermethylation of promoters in GABAergic interneurons of the telencephalon. Nicotine (4.5-22 mol/kg s.c., 4 injections during the 12-h light cycle for 4 days) decreases DNMT1 mRNA and protein and increases GAD 67 expression in the mouse frontal cortex (FC). This nicotine-induced decrease of DNMT1 mRNA expression is greater (80%) in laser microdissected FC layer I GABAergic neurons than in the whole FC (40%), suggesting selectivity differences for the specific nicotinic receptor populations expressed in GABAergic neurons of different cortical layers. The down-regulation of DNMT1 expression induced by nicotine in the FC is also observed in the hippocampus but not in striatal GABAergic neurons. Furthermore, these data show that in the FC, the same doses of nicotine that decrease DNMT1 expression also (i) diminished the level of cytosine-5-methylation in the GAD67 promoter and (ii) prevented the methionine-induced hypermethylation of the same promoter. Pretreatment with mecamylamine (6 mol/kg s.c.), an nAChR blocker that penetrates the blood-brain barrier, prevents the nicotine-induced decrease of FC DNMT1 expression. Taken together, these results suggest that nicotine, by activating nAChRs located on cortical or hippocampal GABAergic interneurons, can up-regulate GAD67 expression via an epigenetic mechanism. Nicotine is not effective in striatal medium spiny GABAergic neurons that primarily express muscarinic receptors.antagonists ͉ epigenetic mechanisms ͉ nicotinic acetylcholine receptor agonists ͉ schizophrenia T obacco smoking is frequently abused by schizophrenia patients (SZP) (for reviews see refs. 1 and 2). Because nicotine is a potent cholinergic receptor agonist that is inhaled with tobacco smoking and both the expression and function of nicotinic acetylcholine receptors (nAChRs) are down-regulated in the brain of SZP, one may conclude that the high level of tobacco smoking in these patients represents an attempt to self-medicate; i.e., correction of some disease-associated abnormalities of cholinergic (nicotinic) neurotransmission (3, 4), possibly related to the decrease of GABAergic function occurring in the brain of SZP (5-9).Typically, plasma nicotine levels in heavy smokers (Ϸ20-30 cigarettes a day) oscillate between 0.3 and 0.6 M. Because in humans nicotine half-life is Ϸ2 h, the nicotine plasma levels in heavy smokers progressively increase during the day but fluctuate in a ''peak and trough'' fashion after each cigarette (10, 11). These submicromolar concentrations of nicotine, which act at heteroolig...

show abstract

Section: Selection Of Nicotine Dose and Time Schedulementioning

confidence: 99%

Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons

Satta

Maloku

Zhubi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

183

120

View full text Add to dashboard Cite

show abstract

“…These results contrasted with observations that i.c.v. administration of quaternary ganglion-blockers potently blocked convulsions produced by nicotine in mice (Aceto et al, 1969;Caulfield & Higgins, 1983).…”

Section: Introductionmentioning

confidence: 97%

Nicotine cue in rats: effects of central administration of ganglion‐blocking drugs

Kumar

Reavill

Stolerman

1987

British J Pharmacology

View full text Add to dashboard Cite

In rats trained to discriminate nicotine from saline, a single intraventricular injection of a small dose of the quaternary ganglion‐blocking drug chlorisondamine blocked the response to nicotine for four weeks. Pentolinium was only weakly active and hexamethonium was inactive as a nicotine antagonist under the conditions used, even in doses that were just below those producing myoclonic jerks. Chlorisondamine had no blocking effect in rats trained to discriminate the non‐nicotinic drugs midazolam or morphine from saline. Intraventricular injections of chlorisondamine have a specific and unusually persistent nicotine‐blocking action, the mechanism of which requires further investigation.

show abstract

“…With in tracerebroventricular (i.c.v.) injections of nicotine, Caulfield and Higgins (8) reported that the nicotine-in duced convulsions in mice possessed a similar pharma cological profile to those by an activation of ganglionic (C6) receptors, rather than neuromuscular (C10) recep tors. Beleslin and Krestic (9) also demonstrated that the i.c.v.-injection of mecamylamine and C6 antago nized the convulsions evoked by nicotine in cats.…”

mentioning

confidence: 99%

Tolerance to the Convulsions Induced by Daily Nicotine Treatment in Rats

Okamoto

Kita

Okuda

et al. 1992

Japanese Journal of Pharmacology

View full text Add to dashboard Cite

Development of tolerance to the nicotine-induced convulsions in rats was examined. Acute intraperitoneal (i.p.) administration of nicotine (2.5, 3.75 and 5 mg/kg) produced convulsions in a dose-dependent manner. Mecamylamine (1 mg/kg, i.p.) antagonized the convulsions, but hexametho nium (5 mg/kg, i.p.) did not modify them. Daily nicotine administration (2.5, 3.75 and 5 mg/kg, i.p.) once a day for 6 days developed tolerance to the convulsions induced by nicotine. After the daily admin istrations of nicotine for 6 days, the effects of a challenge administration of nicotine (2 mg/kg) on the nicotine-induced convulsions were tested on the 7th-day. Further tolerances were also developed by the 7th-day challenge administration. After the 7th-day test, nicotine levels of the brain and blood 15 min after the challenge injection were measured. With nicotine (5 mg/kg once a day)-treatment, nicotine levels of all the brain regions were increased. In contrast, a similar challenge injection had no effect on blood nicotine level. These results indicate that the development of tolerance to the nicotine-induced convulsions is produced relatively earlier and day by day by daily administrations to rats, which is close ly related with the increase in brain nicotine level.Keywords: Nicotine, Tremor, Convulsion, Tolerance, Brain nicotine level A variety of studies have already demonstrated the nicotine-induced behaviors in rodents (1 3). Acute sys temic injection of nicotine at high concentrations de presses locomotor activity (3, 4) and produces tremors (1), prostration (5) and convulsions (1, 2) in rats and mice. In pharmacological studies, it has been shown that the nicotine-induced convulsions are blocked by small doses of ganglion blocking agents such as mecamylamine and chlorisonidamine (6, 7). With in tracerebroventricular (i.c.v.) injections of nicotine, Caulfield and Higgins (8) reported that the nicotine-in duced convulsions in mice possessed a similar pharma cological profile to those by an activation of ganglionic (C6) receptors, rather than neuromuscular (C10) recep tors. Beleslin and Krestic (9) also demonstrated that the i.c.v.-injection of mecamylamine and C6 antago nized the convulsions evoked by nicotine in cats. These results suggest that the nicotine-induced convulsions may be mediated by nicotinic acetylcholine receptors (nAChRs) in the brain.There is a relationship between the nicotine-induced convulsive movements and nicotine levels of the blood and brain. Mice exhibiting a higher nicotine concentra tion in the brain suffered severe convulsions with a shorter latency than mice exhibiting a lower nicotine level after an acute i.p.-injection of nicotine, although the nicotine levels of the blood were unaffected (10). On the other hand, the tolerance to the nicotine-in duced behavior, especially the depressant effect on the locomotor activity, in rats and mice has also been stud ied (3,11,12). In a study of tolerance to nicotine-in duced convulsions, Miner and Collins (13) reported that mice pretreated ...

show abstract

Mediation of nicotine-induced convulsions by central nicotinic receptors of the ‘C6’ type

Cited by 38 publications

References 17 publications

Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons

Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons

Nicotine cue in rats: effects of central administration of ganglion‐blocking drugs

Tolerance to the Convulsions Induced by Daily Nicotine Treatment in Rats

Contact Info

Product

Resources

About