Tolerance to the Convulsions Induced by Daily Nicotine Treatment in Rats

Abstract

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 ...

Effects of Acute Administration of Nicotine on Convulsive Movements and Blood Levels of Corticosterone in Old Rats

“…The nicotine-induced con vulsive movements observed in young and old rats dis appeared within 5 min after the nicotine injection. The onset times of tremor and clonic convulsion and the duration of clonic convulsion in young rats agreed with our previous results (9).…”

“…)-induced convulsive movements were dose-dependent in young rats (9). In the present re sults, nicotine (5 mg/kg, i.p.)…”

“…We have already reported the methods for measuring nicotine-induced convulsive movements and blood nico tine levels (9). After placing the rats in a test-cage (37 X 21 X 15 cm) for 30 min, each rat was injected with nicotine or saline.…”

“…The column was a 2 m X 3 mm glass tubing packed with 10% Apiezon L-10% KOH on WAW 80-100 mesh. The operating conditions were as described by our previous report (9). The blood concentration/time course data for nicotine were evaluated by quantitation of semi logarithmic plots.…”

“…Also, although the blood nicotine levels from 15 to 45 min were higher in old rats than in young rats, the nicotine induced elevations of blood CS levels were less in old rats. The systemic pretreatment with mecamylamine, but not hexamethonium, has been shown to antagonize the nicotine-induced convulsive movements and the elevations of blood CS levels, suggesting that these nicotine-induced responses are mediated through nAChRs in the brain (8,9). Furthermore, several stud ies suggest the age-related decrease in the number of nAChRs in rat brain (3,4).…”