Relations between nicotine-induced convulsive behavior and blood and brain levels of nicotine as a function of sex and age in two inbred strains of mice

doi:10.1016/0091-3057(79)90196-5

Pharmacology Biochemistry and Behavior

Volume 10, Issue 3, March 1979, Pages 349-353

https://doi.org/10.1016/0091-3057(79)90196-5 Get rights and content

Abstract

Nicotine levels in blood and whole brain were measured as a function of sex and age in C57BL/6J and DBA/2J mice and compared to the behavioral responses following an intraperitoneal injection of nicotine. The results indicate that blood levels of nicotine alone do not accurately predict either brain levels of nicotine or the behavioral responses to a single injection of nicotine. It general, brain levels of nicotine proved to be a fairly accurate predictor of the behavioral responses to nicotine. The data indicate that the sexes differ in their sensitivity to nicotine. Forty-two-day-old male mice of both strains given comparable doses of nicotine were found to concentrate the drug in the brain more than females. However, there was no corresponding increase in sensitivity to this increased brain concentration as measured by LD50, ED50, latency to tremor or latency to death.

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Cited by (14)

Effects of Acute Administration of Nicotine on Convulsive Movements and Blood Levels of Corticosterone in Old Rats
1992, The Japanese Journal of Pharmacology
The convulsive movements, blood levels of corticosterone and pharmacokinetics of nicotine after an acute intraperitoneal injection of nicotine (5 mg/kg) were examined in young (6-week-old) and old (2-year-old) rats. In pharmacokinetic study, blood nicotine levels during the elimination phase were significantly higher in old rats than in young rats. However, the duration of convulsions and the elevation of corticosterone levels after the nicotine injection showed significant decreases in old rats compared with those in young rats. These differences of nicotine-induced responses between young and old rats may be involved in the decrease in nicotine sensitivity.
Tolerance to the Convulsions Induced by Daily Nicotine Treatment in Rats
1992, The Japanese Journal of Pharmacology
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 hexamethonium (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 administrations 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 closely related with the increase in brain nicotine level.
Genetic differences in plasma corticosterone levels in response to nicotine injection
1988, Pharmacology, Biochemistry and Behavior
Changes in plasma corticosterone (CCS) levels following intraperitoneal injections of nicotine were measured in four inbred mouse strains: DBA/2Ibg, C57BL/6Ibg, C3H/2Ibg, and A/J. In all four strains, nicotine produced a dose-dependent (0.5–2.0 mg/kg nicotine) increase in plasma CCS levels which peaked 10–30 min after injection. Saline increased plasma CCS levels in C57BL, A, and C3H, but not in DBA mice. After correcting for plasma CCS levels produced by saline injection, the nicotine-induced rise in plasma CCS was significantly lower for the C57BL strain than for the other three strains tested. These mouse strains also varied in their responses to saline injection with the rank order: C57BL > A = C3H > DBA. However, the two most divergent strains (C57BL and DBA) did not differ in the effects of a cold water stress. The response to nicotine was completely inhibited by mecamylamine in two strains tested (C3H and C57BL) whereas the response to saline injection was unaffected, suggesting that only the response to nicotine was mediated by nicotinic receptors. It is clear that elevations in plasma CCS induced either by saline injection or by nicotine are influenced by genetic factors.
Supra-additive toxic interaction of nicotine with antihistamines, and enhancement by the proconvulsant pentylenetetrazole
1985, Pharmacology, Biochemistry and Behavior
Antihistamines are being increasingly administered in combination with various other agents, with adverse drug reactions the frequent result. The present study consisted of two experiments. Experiment 1 examined the toxicological response of rats to nicotine tartrate (0.0, 2.0, 4.0, and 8.0 mg/kg) in combination with either of two H₁-histamine receptor antagonists, the ethylene diamine tripelennamine HCl (0.0, 16.0, 32.0, and 64.0 mg/kg) or the aminoethyl ether diphenhydramine HCl (0.0, 32.0, 64.0, and 96.0 mg/kg). Adult female rats received intraperitoneal injections when housed 12 per cage and toxicological response (number dead per group) was assessed 24 hours post-treatment. The results showed that over the dose ranges employed, and when given alone, nicotine was completely non-lethal, tripelennamine was virtually non-lethal and diphenhydramine wastoxic only at the highest dose (5 of 12, at 96.0 mg/kg). However, when nicotine and the antihistamines were delivered in combinations, the toxicological response was markedly altered. Tripelennamine in combination with nicotine yielded supra-additive interaction, with the degree of potentiation being a simple linear function of nicotine within each dose of tripelennamine. The interaction between nicotine and diphenydramine was more complicated, with certain dose combinations yielding supra-additivity, yet with others yielding antagonism. It was suggested that seizure-precipitated cardiopulmonary collapse was the immediate cause of death, plausibly mediated by central mechanisms. As such, Experiment 2 examined the influence of adding the proconvulsant pentylenetetrazole (PTZ) (0.0, 10.0, and 20.0 mg/kg) to nicotine (0.0, 2.0, 4.0, and 8.0 mg/kg)-tripelennamine (0.0 and 32.0 mg/kg) combination treatments. Effects were assessed both at 1.0 and 24.0 hours post-injection. Results showed that PTZ dramatically enhanced the degree of nicotine-tripelennamine toxic interaction, at doses where each of the three drugs was totally non-lethal when given alone. In addition, clonic-tonic convulsions were commonly noted. The results collectively supported the notion that centrally mediated seizure might indeed be related to the immediate cause of death. Results are discussed in terms of other assays with which such interactions might be observed, particularly those procedures employing behavioral endpoints and lower, non-toxicological doses.
A diallel analysis of nicotine-induced hypothermia
1984, Pharmacology Biochemistry and Behavior
The hypothermic responses of mice that occur after acute injection of nicotine show genetic influences. The body temperatures of mice of all five strains tested decreased after injection of either 0.75 or 1.5 mg/kg nicotine, but mice of the C3H strain were less affected than were those of the DBA, BALB, or C57BL strains. Mice of the A strain were the most sensitive to nicotine's effects. Genetic effects on nicotine-induced hypothermia were further examined using a five-by-five diallel cross. Additive genetic variance occurred at both nicotine closes. Substantial dominance variance, including directional dominance toward a large hypothermic response induced by injection of a low dose of nicotine (0.75 mg/kg), suggested that an intense response to a low drug dose is adaptive. The directional dominance was absent after treatment with a high dose (1.5 mg/kg) of the drug. Epistatic interactions occurring in crosses involving C57BL mice were pronounced.
Sex-dependent biological changes following prenatal nicotine exposure in the rat
1982, Pharmacology, Biochemistry and Behavior
Nicotine was administered to adult female rats in drinking water starting 6 weeks before mating and continuing throughout pregnancy. The litters were cross-fostered to control dams at birth. Prenatal nicotine treatment reduced both the number of male rats born and the male birth weight. Female offspring were not significantly affected. Rearing activity was reduced in male but not female offspring either when tested over a 24 hour period in a home cage environment or during a 10 minute exposure in an open field. Horizontal locomotor activity was reduced only during the first 5 minutes in the open field and again the effect was found only in the males. Baseline plasma corticosterone levels were reduced in both male and female offspring but there was no effect on stress-elevated corticosterone levels.

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Relations between nicotine-induced convulsive behavior and blood and brain levels of nicotine as a function of sex and age in two inbred strains of mice

Abstract

Influences of genotype and sex on behavioral tolerance to nicotine in mice

Pharmac. Biochem. Behav.

Enzymatic pathway for the formation of cotinine, a major metabolite of nicotine in rabbit liver

J. Pharmac. exp. Ther.

A simplified method of evaluating dose-effect experiments

J. exp. Ther.