The effect of chronic nicotine treatment on nicotine-induced seizures

Tolerance to nicotine occurs in mice after its chronic administration. This tolerance is accompanied by an up-regulation of nicotinic receptors as assessed by the binding of (³H)-nicotine and -(¹²⁵I)-bungarotoxin (BTX). Past studies (Marks et al. 1983, 1986) have shown that the increase in BTX binding sites is most evident in the hippocampus. Mice that have a greater concentration of BTX binding sites in the hippocampus are more sensitive to the convulsant effects of nicotine (Miner et al. 1984, 1985, 1986). In the study reported here, mice from the DBA/2Ibg strain, which are relatively resistant to nicotine-induced seizures and have a relatively low concentration of hippocampal BTX binding sites (Miner et al. 1984), were infused with nicotine for 10 days. At various time points after cessation of nicotine administration, sensitivity to the convulsant effects of nicotine was assessed. Mice were then sacrificed and BTX binding was determined in three regions: cortex, midbrain, and hippocampus. As expected, chronic treatment with nicotine resulted in a significant up-regulation of BTX binding sites in the hippocampus. Chronic nicotine treatment also produced significant tolerance to nicotine-induced seizures. Hippocampal BTX binding sites returned to control levels within 2 days after stopping nicotine infusion, whereas tolerance was not lost until 5 days. These results suggest that factors other than the number of hippocampal BTX binding sites affect nicotine-induced seizure sensitivity, at least following chronic nicotine treatment.     

Chronic nicotine pretreatment protects the blood-brain barrier against nicotine-induced seizures in the rat.

This study was designed to investigate the possible protective actions of nicotine on cerebrovascular permeability in convulsions during nicotine-induced seizures. We have measured the permeability changes in the blood-brain barrier (BBB) macroscopically and spectrophotometrically by using Evans blue dye. Specific gravity measurements were also performed to assess brain edema which develops after blood-brain barrier opening. The experiments were carried out on Wistar rats. Rats were divided into two groups. They received acutely a convulsive dose of nicotine 3, 5, 8 and 9 mg kg(-1)i.p. or pretreated with a low dose of nicotine (0.8 mg kg(-1)i. p.) for 21 days followed by the procedure mentioned in the first group. Acute nicotine injection induced a significant increase in blood pressure and Evans-blue passage, despite a decline in specific gravity values. Low doses of chronic nicotine administration markedly reduced both the leakage of dye, and brain water content. Chronic treatment with low doses of nicotine (0.8 mg kg(-1)day(-1)s. c.) lessened the intensity of tonic-clonic seizures observed with a single dose of 3, 5, 8 or 9 mg kg(-1)nicotine. The data presented here demonstrate that nicotine pretreatment results in decreased sensitivity to nicotine-induced seizures in rats.     

Desensitization of the nicotine-induced mesolimbic dopamine responses during constant infusion with nicotine.

1. The effects of constant nicotine infusions (0.25, 1.0 and 4.0 mg kg-1 day-1) on extracellular dopamine levels in the nucleus accumbens (NAc) and on locomotor activity have been compared with the changes evoked by repeated daily injections (0.4 mg kg-1 day-1 for 5 days) of the drug. 2. The extracellular dopamine concentration in the NAc was significantly increased (P < 0.05) following a challenge dose of nicotine (0.4 mg kg-1, s.c.) in animals which had been pretreated with daily injections of the drug. This effect was accompanied by an enhanced locomotor response to nicotine. 3. The stimulant effects of nicotine on mesolimbic dopamine secretion and on locomotor activity were significantly inhibited (P < 0.01) by the prior administration of mecamylamine (2.0 mg kg-1, s.c.) but not by hexamethonium (2.0 mg kg-1, s.c.). 4. The constant infusion of nicotine at a rate of 1 and 4 but not 0.25 mg kg-1 day-1 abolished the sensitized dopamine response in the NAc to an injection of nicotine in animals pretreated with the drug. The locomotor responses to nicotine in the nicotine-pretreated rats were significantly attenuated by the infusion of nicotine at all 3 doses, although the nicotine induced locomotor activity, in the rats infused with 0.25 mg kg-1 day-1 was also significantly (P < 0.05) higher than that observed in the rats treated acutely with nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Kynurenic acid does not protect against nicotine-induced seizures in mice

Kynurenic acid, an antagonist of glutamatergic ionotropic receptors and alpha7 nicotinic cholinergic receptors failed to affect nicotine-induced convulsions in mice which may indicate that alpha7 nicotinic receptor-mediated events play no role in seizure activity produced by nicotine.     

Analgesia induced by chronic nicotine infusion in rats: differences by gender and pain test

RATIONALE: Acute administration of nicotine induces analgesia with subsequent development of tolerance. In human studies, females are less sensitive to the analgesic effects of nicotine than males. Few previous animal studies have investigated analgesic effects of chronic nicotine administration or addressed gender differences. OBJECTIVES: To investigate whether chronic administration of nicotine induces analgesia in male and female rats as assessed by a battery of standard pain assays, if tolerance develops, and if hyperalgesia occurs following cessation of nicotine. METHODS: Nicotine (free base; 6 mg/kg/day i.v.) or saline was administered for 2 weeks via implanted osmotic pumps. Pain behavior was assessed before, during, and for 3 weeks after nicotine infusion by measuring tail flick latency, hot-plate latency, and thermal paw withdrawal latency. The paw-withdrawal threshold to non-noxious mechanical stimuli was also measured. Effects of nicotine infusion, gender, and time were assessed by three-way analyses of variance. RESULTS: Both male and female rats exhibited a comparable degree of analgesia in the hot-plate test with development of tolerance during the 2-week infusion period. Males, but not females, showed analgesia in the tail flick test. Analgesia was not observed for thermally evoked paw withdrawal in either males or females, nor did nicotine affect non-noxious mechanically evoked paw withdrawals. Males and females showed cessation of weight gain during the first week of nicotine infusion. CONCLUSIONS: Chronic nicotine-induced analgesia was confirmed in both male and female rats as assessed using the hot-plate test which reflects integrated pain behavior. Males, but not females, exhibited analgesia in a nociceptive withdrawal reflex test (tail flick), indicating that nicotine-induced analgesia may depend on both the type of pain test and gender. The lack of nicotine-induced analgesia assessed by the tail flick reflex test in female rats is consistent with recent human studies showing that nicotine reduces pain elicited by brief noxious cutaneous stimulation in male but not female subjects.     

Prenatal nicotine exposure increased duration of nicotine-induced analgesia in adult rats

The effect of prenatal exposure to nicotine on nicotine-induced analgesia was studied in rats. The analgesic effect of a single dose of nicotine (1 mg/kg SC) was measured by the tail-flick technique, and two subsequent studies were carried out. In the first study, 7-month-old male rats, born to dams chronically treated with nicotine during pregnancy (NIC), exhibited prolonged nicotine-induced analgesia compared to matched controls. The second study was designed to explore whether rats prenatally exposed to nicotine (NIC rats) are born with an increased sensitivity to nicotine and whether there is any sex difference. The analgesic effect of nicotine was tested on control and NIC rats of both sexes once a month from 2 to 7 months of age. At an early age, male but not female NIC rats, exhibited shorter analgesic responses to nicotine than did the matched controls. With increasing age, however, the duration of nicotine analgesia began to be prolonged in NIC rats of both sexes. Significant differences between control and NIC rats were found at the age of 6 and 7 months, in both sexes. Thus, rats prenatally exposed to nicotine are not born with an increased sensitivity to the analgesic effect of a single dose of nicotine. This phenomenon develops later, during the course of life, independently of gender.     

18-Methoxycoronardine attenuates nicotine-induced dopamine release and nicotine preferences in rats

Two studies were conducted to assess, in vivo, potential anti-nicotinic effects of the iboga alkaloid ibogaine and its synthetic congener 18-methoxycoronaridine (18-MC). As previously demonstrated for ibogaine, using microdialysis, pretreatment (19 h beforehand) with 18-MC (40 mg/kg, IP) significantly attenuated nicotine-induced dopamine release in the nucleus accumbens of awake and freely moving rats. In an oral model of nicotine self-administration, both ibogaine and 18-MC decreased rats’ preferences for nicotine for at least 24 h. Acutely, during the first hour after administration, ibogaine depressed responding for water as well as for nicotine; however, during this same time, 18-MC reduced nicotine intake without affecting responding for water. The results suggest that 18-MC might be the prototype of a new treatment for smoking. Received: 26 November 1997/Final version: 17 February 1998     

Continuous nicotine infusion reduces nicotine self-administration in rats with 23-h/day access to nicotine

The effects of continuous nicotine infusion on nicotine self-administration (NSA) were studied in rats as a model of nicotine replacement therapy (NRT) in humans. A NSA model in which rats had 23-h/day access to nicotine was used to approximate nicotine access conditions in cigarette smokers. In order to estimate serum nicotine concentrations associated with NSA, arterial and venous serum nicotine concentrations were measured during a simulation of NSA. Nicotine was noncontingently administered as 30 doses/12 h of 0.03 mg/kg/i.n.f. or 60 doses/12 h of 0.01 mg/kg/i.n.f. daily. Venous serum nicotine concentrations were measured after the first nicotine dose of the day, and arterial and venous concentrations were measured after doses in the middle of the day. The range of mean concentrations measured was similar to those reported in cigarette smokers (venous concentrations 6-59 ng/ml, arterial concentrations 42-96 ng/ml). The effects of continuous nicotine infusion on NSA were studied by noncontingently administering nicotine at various rates via osmotic pump to animals self-administering nicotine (0.01 or 0.03 mg/kg/i.n.f.) during 23-h/day sessions. Continuous nicotine infusion at all infusion rates substantially suppressed NSA, but suppression was rate-related only for the 0.01-mg/kg/inf NSA unit dose. Nicotine infusion rates producing venous serum nicotine concentrations equaling or exceeding the peak venous levels associated with simulated NSA were more effective than lower infusion rates only at the lower NSA unit dose. The highest nicotine infusion rate had no sustained effect on food-maintained responding, demonstrating its specificity for suppression of NSA. These data provide a model for studying NRT in the rat.     

Vaccination against nicotine does not prevent nicotine-induced changes in fetal nicotinic receptor binding and c-fos mRNA expression in rats

Gestational exposure of rats to nicotine produces long-lasting alterations in brain development. Vaccination of adult female rats against nicotine reduces the distribution of maternally administered nicotine to fetal brain, suggesting that vaccination might protect against these effects. In the current study, the effects of vaccination on nicotine-induced changes in fetal (3)H-epibatidine binding and c-fos mRNA expression were evaluated using tissue from a previous pharmacokinetic study of vaccination. An intermittent nicotine dosing regimen designed to resemble nicotine intake in a smoker was administered from GD1-20. Peak nicotine levels in fetal brain were reduced by vaccination, whereas the chronic accumulation of nicotine in fetal brain was not. Gestational nicotine exposure produced significant increases in (125)I-epibatidine binding to brain and spinal cord on GD20, and decreased c-fos mRNA expression in fetal striatum, adrenal and lung. Vaccination did not significantly alter these effects. These data suggest that nicotine dosing, using a clinically relevant intermittent bolus dose regimen, produces substantial changes in fetal nicotinic receptor and c-fos mRNA expression. The decrease in c-fos mRNA expression contrasts with previously reported increases, and suggests that the nicotine dosing regimen used may influence its effects. The lack of effect of vaccination suggests that the cumulative exposure of fetal tissues to nicotine may influence the measured parameters to a greater extent than peak exposure levels.     

Protection against the neurotoxicity of 1-methyl-4-phenyl-tetrahydropyridine in rats by chronic nicotine treatment

Ｐｒｏｔｅｃｔｉｏｎａｇａｉｎｓｔｔｈｅｎｅｕｒｏｔｏｘｉｃｉｔｙｏｆ１┐ｍｅｔｈｙｌ┐４┐ｐｈｅｎｙｌ┐ｔｅｔｒａｈｙｄｒｏｐｙｒｉｄｉｎｅｉｎｒａｔｓｂｙｃｈｒｏｎｉｃｎｉｃｏｔｉｎｅｔｒｅａｔｍｅｎｔ１ＧＡＯＺｈａｎ－Ｇｕｏ，ＹＵＡＮＢｅｎ－Ｌ...     

Inhibition of platelet aggregation following chronic in vivo treatment of rats with nicotine: prevention by simultaneous application of propranolol

Platelet aggregability is known to be enhanced and platelet-survival time shortened in smokers when compared with nonsmokers. Up to now it is unknown which of the substances in tobacco smoke are responsible for these effects. To evaluate a possible role of nicotine, rats were chronically treated with the alkaloid (10 mg/kg/day), continuously released from subcutaneously implanted osmotic minipumps. Surprisingly, after 8 weeks, platelet sensitivity toward the aggregating stimulus adenosine 5'-diphosphate (ADP) was markedly reduced. The mean ADP concentration required to induce half the maximum rate of aggregation (EC50) was 0.88 mumol/L in nicotine-treated animals, as compared with 0.67 mumol/L in controls (p less than 0.002). Platelet aggregability remained normal when the rats were treated simultaneously with nicotine and the beta blocker propranolol (3.5 mg/kg/day); for these animals, the mean EC50 for ADP was 0.73 mumol/L. These results are suggestive of a catecholamine-mediated action of nicotine. However, neither the basal levels of cAMP in platelet-rich plasma, nor the cAMP levels attained after stimulation of platelet adenylate cyclase with prostaglandin E1 (PGE1), were affected by 8 weeks of treatment with nicotine or nicotine plus propranolol. No effect on platelet aggregation was observed when the rats were treated with nicotine for only 2 weeks, or when nicotine or nicotine plus cotinine were added to platelet-rich plasma in vitro in concentrations equal to those attained in vivo after 8 weeks. Thus, prolonged application of nicotine in vivo caused an inhibition of ADP-induced rat platelet aggregation presumably mediated by beta-catecholaminergic stimulation of platelets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Receptor mechanisms of nicotine-induced locomotor hyperactivity in chronic nicotine-treated rats

Rats were pretreated with saline or nicotine (1.5 mg/kg per day) by subcutaneously implanting each animal with an Alzet osmotic mini-pump which continuously released saline or nicotine for 1, 5 and 14 days. At the end of each pretreatment period, animals were used for (i) determining their locomotor response to acutely injected nicotine (0.2 mg/kg, s.c.) and (ii) measuring the density of L-[3H]nicotine and [3H]spiperone binding sites in the striatum. We observed no changes in nicotine-induced locomotor response, striatal L-[3H]nicotine and [3H]spiperone binding in the animals pretreated with nicotine for 1 day. In rats which were pretreated with nicotine for 5 days, there was a significant increase in the nicotine-stimulated locomotor response which was associated with an increase in the number of L-[3H]nicotine binding sites and also with an elevated dopamine (DA) level in the striatum. The number of striatal [3H]spiperone binding sites was not affected. In animals pretreated with nicotine for 14 days, the nicotine-induced locomotor response remained to be potentiated. However, this response was correlated with an elevated number of striatal [3H]spiperone binding sites, whereas the number of striatal L-[3H]nicotine binding sites and the striatal DA level were normal. These results suggest that chronic nicotine-treated rats develop locomotor hyperactivity in response to nicotine initially due to increases of both the density of nicotinic receptors and DA concentration, followed by inducing DA receptor supersensitivity in the striatum.     

Stress triggered rise in plasma aldosterone is lessened by chronic nicotine infusion

The ability of nicotine infusion to modulate plasma aldosterone levels in response to different stressors was investigated. Sprague-Dawley rats given nicotine (5 mg/kg/day) or saline for 14 days were subjected to stress. Baseline plasma aldosterone (86+/-17 pmol/l) was unaffected by nicotine. Aldosterone was significantly elevated by restraint (450+/-72 pmol/l) and especially with cold (1249+/-172 pmol/l) or immobilization (1779+/-247 pmol/l) stress. Nicotine infusion attenuated the rise in aldosterone with restraint and cold stress, but not immobilization. These results reveal that nicotine infusion can attenuate the aldosterone response, depending on the type of stress.     

Enhanced attenuation of nicotine discrimination in rats by combining nicotine-specific antibodies with a nicotinic receptor antagonist

Tobacco addiction requires activation by nicotine of a variety of central nicotinic acetylcholine receptors (nAChRs). In animals, both nAChR antagonists and immunization against nicotine can reduce nAChR activation by nicotine and block a variety of addiction-relevant behaviors. However, clinical use of nAChR antagonists for smoking cessation is limited by dose-related side effects, and immunization does not reliably produce sufficient antibody levels in smokers to enhance smoking cessation rates. Combining these approaches may be one way of addressing the limitations of each while enhancing overall efficacy. This study examined the individual and combined effects of passive immunization with the monoclonal nicotine-specific antibody Nic311 and the nicotinic receptor antagonist mecamylamine (MEC) on nicotine's discriminative stimulus effects. Rats were trained to discriminate 0.4 mg/kg of nicotine from saline using a two-lever operant discrimination procedure. Antagonism of nicotine discrimination by Nic311 (160 mg/kg i.v.) and ascending doses of MEC (0.03, 0.1, 0.3, and 1.0 mg/kg s.c.) was assessed across four consecutive daily 2-min extinction test sessions using a 2 × 2 design. Nic311 alone produced a 24-48% reduction in % nicotine-lever responding (%NLR) across all four test sessions. MEC produced a dose-dependent decrease in %NLR, with no effect at the two lowest doses and 80-93% attenuation at the two highest doses. Nic311 combined with MEC significantly suppressed %NLR at every MEC dose (85-92% reduction across all four test sessions). Very low doses of MEC that were ineffective alone completely blocked nicotine discrimination when combined with Nic311. These data demonstrate that nicotine-specific antibodies and MEC can work synergistically to suppress the subjective effects of nicotine and suggest that low doses of MEC may significantly enhance the efficacy of immunotherapy.     

Inhibition by thyrotropin-releasing hormone of epileptic seizures in spontaneously epileptic rats

The effects of thyrotropin-releasing hormone (TRH) were investigated on absence-like seizures, which are characterized by the sudden appearance of 5-7 Hz spike-wave-like complexes in the cortical and hippocampal EEG, and on tonic convulsions of spontaneously epileptic rats (SER; zi/zi, tm/tm), a double mutant obtained by mating zitter homozygote (zi/zi) with tremor heterozygote rats (tm/+). TRH (5 and 10 mg/kg i.v.) inhibited the appearance of both absence-like seizures and tonic convulsions of SER without inducing obvious changes in the background EEG. The inhibitory effects were seen 5-20 min after injection of 10 mg/kg TRH and were antagonized by pretreatment with haloperidol (0.5 and 1.0/kg i.p.), although haloperidol alone did not affect the seizures. These results suggest that TRH has an antiepileptic effect in the genetically defined animal model, SER, and that the effect is mediated by the central dopaminergic system.     

mGlu1 receptor blockade attenuates cue- and nicotine-induced reinstatement of extinguished nicotine self-administration behavior in rats

Glutamatergic neurotransmission is believed to be critically involved in the acquisition and maintenance of drug addiction. The present study evaluated the role of metabotropic glutamate (mGlu) 1 receptors in the reinstatement of nicotine-seeking behavior. Rats were trained to nose-poke to receive response-contingent intravenous infusions of nicotine (0.01 mg/kg/infusion, free base). Following the subsequent extinction phase, reinstatement tests were conducted in animals that were exposed either to response-contingent presentations of the nicotine-associated discrete light cues or to non-contingent nicotine priming injection (0.3mg/kg, s.c., salt) just prior to the test session. In a separate experiment, rats were subjected to the nearly identical response-reinstatement procedure but operant responding was established using food pellets instead of nicotine infusions. Pretreatment with the mGlu1 receptor antagonist EMQMCM (JNJ16567083, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) significantly inhibited cue-induced reinstatement of nicotine-seeking behavior (5 and 10, but not 2.5 mg/kg). EMQMCM (5 mg/kg) also prevented nicotine priming-induced reinstatement of nicotine-seeking behavior. At the highest tested dose only (10 mg/kg), EMQMCM attenuated cue-induced reinstatement of food-seeking behavior. Taken together with the previous reports, the present findings further suggest that blockade of mGlu1 receptors may be beneficial for preventing relapse to tobacco smoking in nicotine-dependent individuals.     

Acute and chronic tolerance to nicotine measured by activity in rats

Spontaneous locomotor activity has been used to assess the development and the dissipation of tolerance to nicotine in rats. Nicotine administered i.p. to experimentally naive rats depressed activity in a Y-shaped runway in a dose-related manner. After a single i.p. dose of nicotine, acute tolerance to the depressant action of a second dose developed with a definite time-course, becoming maximal after 2 h and wearing off after about 8 h. Repeated i.p. doses of nicotine (3 times daily for 8 days) elicited chronic tolerance, which was found to persist for at least 90 days after the end of regular treatment with the drug. Tolerance was also produced when nicotine was administered in rats' drinking water and through reservoirs implanted subcutaneously. We conclude that tolerance to nicotine in rats can develop quickly, may be measured easily, and persists for prolonged periods after withdrawal. A nicotine abstinence syndrome was not detected. The doses (mg/kg i.p.) of nicotine necessary to induce chronic tolerance in rats were similar to those probably obtained by cigarette smokers, but the different routes and rates of administration make precise comparisons difficult. However, it is suggested that relapse to tobacco use in man may be associated with the persistence of tolerance.     

Trait differences in response to chronic nicotine and nicotine withdrawal in rats

Introduction

Understanding an individual’s vulnerability to drug addiction has important implications for the development of effective personal treatment plans. Although theories acknowledge impulsive behaviour as a key component of drug addiction, little is known about the influence of trait impulsivity on an individual’s susceptibility to the effects of psychostimulants on impulsivity at critical phases of the addiction cycle.

Methods

This study investigated the short and longer-term effects of chronic nicotine administration on impulsive choice in rats selected for high (HI) and low impulsivity (LI) on a delay discounting task. Rats prepared with subcutaneously osmotic mini-pumps received either nicotine (3.16 mg/kg/day [freebase]) or saline for 7 days. Performance was assessed during chronic treatment, early and late withdrawal, and in response to acute nicotine challenges following prolonged abstinence.

Results

Chronic nicotine increased impulsive choice in LI but not HI animals. Spontaneous withdrawal was associated with a nicotine abstinence syndrome, the early stages of which were characterised by opposing effects on impulsive choice in HI and LI animals. A transient decrease in impulsivity was observed in HI animals whilst the LI group remained more impulsive for up to 1 week following drug termination. Following normalisation of behaviour, acute nicotine challenges (0.125, 0.25, 0.5 mg/kg, SC) markedly increased impulsive choice regardless of trait impulsivity and drug history.

Conclusion

The results indicate that only LI individuals are vulnerable to chronic drug- and withdrawal-induced impairments in self-control which may increase the likelihood of the transition to, and maintenance of, nicotine dependence.     

Histidine enhances carbamazepine action against seizures and improves spatial memory deficits induced by chronic transauricular kindling in rats

AIM：To investigate whether histidine can enhance the anticonvulsant efficacy of carbamazepine （CBZ） and simultaneously improve the spatial memory impairment induced by transauricular kindled seizures in Sprague-Dawley rats. METHODS： Chronic transauricular kindling was induced by repeated application of initially subconvulsive electrical stimulation through ear-clip electrodes once every 24 h until the occurrence of three consecutive clonic-tonic seizures. An 8 - arm radial maze （ 4 arms baited） was used to measure spatial memory,