Nicotine Tartrate Research Articles

Nicotine produces selective degeneration in the medial habenula and fasciculus retroflexus

Nicotine’s neurotoxic properties in rats were investigated by administering (−)-nicotine tartrate for 5 days either continuously in doses of 5.01, 5.72, 6.44, 7.13, 20.41 and 43.1 mg/kg/day via osmotic minipump or intermittently at 11.32 mg/kg/day via one daily subcutaneous injection. As assessed by silver staining, neurotoxicity was seen almost exclusively in the axons of the medial habenula and its output tract, the fasciculus retroflexus, in all treatment groups except the lowest dose. Within the habenula, the damage was noted in the ventral–medial-most portion of the nucleus which is thought to be dense with the α4β2 and/or α3β4 receptor subtypes. Past research has shown the medial habenula to be highly sensitive to the effects of nicotine, and these findings, in conjunction with related research using dopaminergic stimulants, indicate that the habenula may be a weak link in the neurotoxicity seen following stimulant drugs of abuse.

Threshold levels of maternal nicotine impairing protective responses of newborn rats to intermittent hypoxia.

Experiments were carried out to determine the threshold level of maternal nicotine that impairs protective responses of rat pups to hypoxia. From days 6 or 7 of gestation, pregnant rats received either vehicle or nicotine (1.50, 3.00, or 6.00 mg of nicotine tartrate. kg body wt(-1).day(-1)) or vehicle continuously via a subcutaneous osmotic minipump. On postnatal days 5 or 6, pups were exposed to a single period of hypoxia produced by breathing an anoxic gas mixture (97% N(2) or 3% CO(2)) and their time to last gasp was determined, or they were exposed to intermittent hypoxia and their ability to autoresuscitate from hypoxic-induced primary apnea was determined. Perinatal exposure to nicotine did not alter the time to last gasp or the total number of gasps when the pups were exposed to a single period of hypoxia. The number of successful autoresuscitations on repeated exposure to hypoxia was, however, decreased in pups whose dams had received either 3.00 or 6.00 mg of nicotine tartrate/kg body wt; these dosage regimens produced maternal serum nicotine concentrations of 19 +/- 6 and 35 +/- 8 ng/ml, respectively. Thus our experiments define the threshold level of maternal nicotine that significantly impairs protective responses of 5- to 6-day-old rat pups to intermittent hypoxia such as may occur in human infants during episodes of prolonged sleep apnea or positional asphyxia.

Taste Sensitivity of Insect Herbivores to Deterrents is Greater in Specialists Than in Generalists: A Behavioral Test of the Hypothesis with Two Closely Related Caterpillars

Sensitivity of caterpillars of Heliothis virescens, a generalist, and H. subflexa, a specialist, to eight different plant secondary compounds was examined behaviorally. The compounds were nicotine hydrogen tartrate, hordenine, caffeine, sinigrin, linamarin, arbutin, chlorogenic acid, and salicin. All compounds deterred feeding, at least at the higher concentrations, but the generalist was less affected than the specialist. Thus the hypothesis that specialists have greater sensitivity to deterrents than generalists was supported. In most cases deterrence occurred on first encounter, indicating that the response was sensory; in some cases short-term postingestive effects also appeared to play a role. The larger quantities of deterrent-containing food ingested by H. virescens sometimes resulted in measurable postingestive effects during the second control test. This did not occur in H. subflexa, which more commonly rejected the deterrent-containing food on first contact. The contrast between the species is discussed in relation to tradeoffs involved in different diet breadths.

Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats

The aim of the present study was to investigate the relationship between physical abstinence and changes in dopamine release in the nucleus accumbens and in the medial prefrontal cortex induced by mecamylamine and naloxone in rats chronically exposed to nicotine. The rats were implanted with osmotic minipumps (Alzet) delivering nicotine tartrate at a rate of 9 mg/kg/day (3.16 mg of free base) and 8 days later with a dialysis probe in the nucleus accumbens or in the medial prefrontal cortex. Steady-state dopamine output from the nucleus accumbens of the rats implanted with nicotine minipumps was higher than that of sham implanted rats; no differences were observed in the prefrontal cortex. In nicotine but not in sham implanted rats mecamylamine (1 mg/kg s.c.) precipitated a physical abstinence syndrome and brought dopamine output back to control values in the nucleus accumbens. In contrast mecamylamine (1 mg/kg s.c.) increased dopamine output in the medial prefrontal cortex of nicotine but not sham-implanted rats. Naloxone (2 mg/kg) precipitated a physical abstinence syndrome qualitatively similar to that produced by mecamylamine but failed to modify extracellular dopamine in the nucleus accumbens or in the prefrontal cortex of nicotine-implanted and sham-implanted rats. The results indicate that the mesolimbic and mesocortical dopamine system undergo opposite changes during mecamylamine-precipitated abstinence in rats chronically exposed to nicotine and that physical abstinence signs can be dissociated from changes in dopamine transmission.

Nicotine treatment for ulcerative colitis.

Ulcerative colitis and Crohn’s disease are chronic inflammatory bowel diseases of unknown aetiology which, although similar in various aspects, exhibit some contrasting features. A typical example is their relationship with cigarette smoking. While smoking appears to exert deleterious effects in Crohn’s disease [1, 2], there is overwhelming epidemiological evidence that smoking protects against ulcerative colitis, the risk of developing the disease being significantly lower in smokers than in non-smokers or former smokers [2, 3]. The fact that patients with ulcerative colitis who resume or start smoking often experience clinical improvement [4] prompted attempts to verify the hypothesis that nicotine might be the active component of smoking responsible for the beneficial effects on the course of the disease. Preliminary, uncontrolled observations employing nicotine gum, a pharmaceutical form generally poorly tolerated, yielded encouraging but inconclusive results [5]. The introduction of transdermal nicotine in the market made it possible to assess the potential therapeutic role of nicotine in a more extensive way.

Efficacy of providing nicotine in a liquid diet to rats.

To determine if rats would consume nicotine at psychoactive levels, a nutritionally balanced diet with 0, 20, 60, or 200 mg of nicotine tartrate per kg of diet was provided. Diet consumption and body weight differences were recorded for 14 days after which, following 16 hr of withdrawal, animals were given access to a two-bottle choice of the previously presented diet and a nicotine-free diet. Spontaneous horizontal motor activity was recorded 8, 16, and 24 hr after withdrawal. By Day 14, all animals showed a significant increase in diet consumption and significant weight gain compared to Day 1. Animals consumed an average of 2.1, 6.8, or 19.5 mg/kg/day of nicotine on the low, medium, and high-nicotine diets, respectively. However, animals receiving the high-nicotine diet consumed less diet and gained less weight than the control, low, and medium nicotine groups. During only the first 4 hr of the two-bottle choice (16-20 hr postwithdrawal), the high-nicotine group consumed significantly higher amounts of nicotine base than the other groups, but also consumed more of the control diet during the first 2 hr. In a replicate experiment, animals receiving the medium-nicotine diet showed an increased consumption of the nicotine diet and increased preference for nicotine following a 14-day exposure compared to the control-fed animals and compared to a baseline preference test. Also, this group showed differences in locomotor activity consistent with other studies using an injection regimen or subcutaneuos pumps to induce dependence. Finally, animals in all three groups exhibited high plasma nicotine and cotinine (a major nicotine metabolite) levels. Because animals in all groups tolerated the diet well, gained weight, selected the nicotine diet in a choice test, and showed withdrawal symptoms, we conclude that the liquid diet proved to be a satisfactory method of inducing nicotine dependence in rats.

Efficacy of Providing Nicotine in a Liquid Diet to Rats

To determine if rats would consume nicotine at psychoactive levels, a nutritionally balanced diet with 0, 20, 60, or 200 mg of nicotine tartrate per kg of diet was provided. Diet consumption and body weight differences were recorded for 14 days after which, following 16 hr of withdrawal, animals were given access to a two-bottle choice of the previously presented diet and a nicotine-free diet. Spontaneous horizontal motor activity was recorded 8, 16, and 24 hr after withdrawal. By Day 14, all animals showed a significant increase in diet consumption and significant weight gain compared to Day 1. Animals consumed an average of 2.1, 6.8, or 19.5 mg/kg/day of nicotine on the low, medium, and high-nicotine diets, respectively. However, animals receiving the high-nicotine diet consumed less diet and gained less weight than the control, low, and medium nicotine groups. During only the first 4 hr of the two-bottle choice (16–20 hr postwithdrawal), the high-nicotine group consumed significantly higher amounts of nicotine base than the other groups, but also consumed more of the control diet during the first 2 hr. In a replicate experiment, animals receiving the medium-nicotine diet showed an increased consumption of the nicotine diet and increased preference for nicotine following a 14-day exposure compared to the controlfed animals and compared to a baseline preference test. Also, this group showed differences in locomotor activity consistent with other studies using an injection regimen or subcutaneuos pumps to induce dependence. Finally, animals in all three groups exhibited high plasma nicotine and cotinine (a major nicotine metabolite) levels. Because animals in all groups tolerated the diet well, gained weight, selected the nicotine diet in a choice test, and showed withdrawal symptoms, we conclude that the liquid diet proved to be a satisfactory method of inducing nicotine dependence in rats.

Promising new agents for the treatment of inflammatory bowel disorders.

A groundswell of therapeutic modalities is presently sweeping through the field of inflammatory bowel disease (IBD), revolutionising the treatment and management of these disorders. At the forefront of newer agents are biological therapies, also referred to as 'biologics'. These include infliximab (cA2), CDP 571, rhIL-10, ICAM-1 antisense oligonucleotide (ISIS 2302) and opreleukin (rhIL-11). Among these, infliximab and CDP 571 are perhaps the most promising, particularly in Crohn's disease. Both are anti-TNF alpha monoclonal antibody formulations with proven efficacy at doses of 5 mg/kg for inducing remission in patients with moderate to severe refractory Crohn's disease. Infliximab is beneficial in the treatment of fistulous Crohn's disease as well. Anti-inflammatory cytokines such as rhIL-10 and opreleukin (rhIL-11) in early reports appear efficacious in Crohn's disease but not in ulcerative colitis. Budesonide, a second generation glucocorticoid, in an oral controlled ileal release capsule, is an attractive alternative to prednisone for treating active Crohn's disease of the distal ileum and proximal colon. Also available as an enema, budesonide's efficacy approximates that of prednisolone for inducing remission in active distal ulcerative colitis. Postoperative recurrences of Crohn's disease are a common clinical scenario. Recently, mesalazine, metronidazole and mercaptopurine have been re-evaluated in the postoperative setting. In the largest postoperative prophylaxis trial, mercaptopurine was superior to both placebo and mesalazine in preventing clinical, endoscopic and radiographic relapses. Finally, miscellaneous therapies such as transdermal nicotine, nicotine tartrate enemas and topical lidocaine used in pilot studies for ulcerative colitis have shown promise. Case reports of thalidomide and tacrolimus (FK 506) have reported beneficial effects in treating complicated, refractory Crohn's disease.

The nitric oxide synthesis inhibitor nitro-L-arginine (L-NNA) attenuates nicotine abstinence syndrome in the rat.

Nitric oxide synthesis contributes to opiate tolerance and dependence. Nicotine dependence and abstinence syndrome in the rat appear to involve opiate mechanisms. Therefore, it was postulated that nitric oxide synthase (NOS) activity might be essential for the expression of nicotine abstinence syndrome. Twenty-one rats were rendered dependent by SC infusion of 9 mg/kg per day nicotine tartrate via Alzet osmotic minipump. Rats were pretreated SC with vehicle alone, or with 18 or 30 mg/kg of the NOS inhibitor L-NNA (nitro-L-arginine). Thirty minutes later, rats were challenged by 1 mg/kg of the nicotinic antagonist mecamylamine SC and observed for 30 additional minutes. Rats pretreated with vehicle displayed a total of 68.7+/-8.0 mecamylamine-precipitated abstinence signs (mean+/-SEM), while those receiving 18 or 30 mg/kg L-NNA had 12.7+/-2.0 and 5.1+/-1.7 signs, respectively. All three groups differed significantly from one another according to Dunn's post-hoc procedure. Rats pretreated with L-NNA combined with an excess of the NOS substrate L-arginine had significantly more mecamylamine-precipitated abstinence signs than rats receiving L-NNA combined with D-arginine. Also, D-NNA, which does not selectively bind to NOS, was significantly less effective than L-NNA in preventing mecamylamine-precipitated abstinence syndrome. Additional studies determined the effect of L-NNA on spontaneous nicotine abstinence syndrome. Rats were assessed for abstinence signs at 17 and 20 h after termination of nicotine infusion. They received injections of 9, 18, or 30 mg/kg L-NNA SC or vehicle alone immediately before the 20-h observation; all rats were observed for 30 min. Signs at 20 h (post-injection) as a percentage of signs at 17 h (pre-injection) declined significantly as a function of L-NNA dose. Once again, this effect was attenuated significantly more by co-administration of L-arginine than by D-arginine. The overall pattern of results suggests that nitric oxide synthesis is critical to the expression of nicotine abstinence syndrome.

Nicotine Abstinence Syndrome Precipitated by the Competitive Nicotinic Antagonist Dihydro-β-Erythroidine

Rats infused subcutaneously with 9 mg/kg/day nicotine tartrate for 7 days exhibit behavioral abstinence signs following either termination of nicotine infusion or injection of the noncompetitive nicotinic antagonists mecamylamine (SC) or hexamethonium (ICV). This study examined the abstinence precipitating effects of dihydro-β-erythroidine (DHβE), a competitive nicotinic antagonist. Twenty-four nicotine-dependent rats were injected in the third ventricle with 10, 18, or 25 μg DHβE in 20 μl saline or with saline alone and observed for abstinence signs over a 20-min period. There was a significant positive linear trend of overall abstinence signs as a function of dose, p < 0.01. In 12 nondependent rats, the high dose of DHβE did not induce more abstinence-like signs than saline alone. In a second experiment, 18 nicotine-dependent rats were injected SC with 1 or 6 mg/kg of the muscarinic antagonist scopolamine or with saline alone. Few abstinence signs were observed in any group; there was no significant drug effect. The results suggest that nicotine abstinence signs observed in the rat are specific to reduced stimulation of previously overstimulated nicotinic receptors.

Nicotine Abstinence Syndrome Precipitated by Central But Not Peripheral Hexamethonium

A rodent model of nicotine dependence has been developed based on continuous subcutaneous (SC) infusion of nicotine tartrate. Nicotine abstinence syndrome was precipitated by SC injection of the nicotinic antagonist mecamylamine, which freely crosses the blood–brain barrier. In contrast, the nicotinic antagonist hexamethonium crosses the blood–brain barrier very poorly. This study determined whether central or peripheral administration of hexamethonium could precipitate nicotine abstinence. In the first experiment, 26 nicotine-dependent rats were injected SC with 0.5, 5 or 10 mg/kg hexamethonium dichloride or saline alone and observed for 20 min. Few abstinence signs were observed in any group; there was no significant drug effect. In the second experiment, 18 rats were cannulated in the third ventricle and rendered nicotine dependent. One week later, rats were injected through the cannula with 12 or 18 ng hexamethonium or saline alone and observed for 20 min. Both dose groups differed significantly from the saline-injected group, and there was a significant positive linear trend of signs as a function of dose. The high dose had no significant effect in 14 nondependent rats. We conclude that hexamethonium is much more potent by the central route, and there is a major central nervous system component in nicotine dependence.

The cardiorespiratory response to anoxia: normal development and the effect of nicotine

Maternal smoking increases the risk of the sudden infant death syndrome (SIDS) 2–4-fold. The mechanism is unknown but may be related to hypoxia responses. Recovery from hypoxic apnea by young mammals depends on gasping and bradycardia. We asked whether prenatal nicotine exposure, reported to reduce hypoxic survival in 2 day old rat pups, acted by impairing gasping or bradycardia. Pregnant rats were infused throughout gestation and 1 week postnatally with nicotine tartrate (NIC) 12 mg/kg per day or saline (CON). Maternal plasma nicotine was 134.4±42 ng/ml, significantly reducing pup body weight. Pups at 3–28 days were exposed to anoxia (97% N 2/3% CO 2) until gasping ceased, while breathing and heart rate were recorded. NIC and CON groups were not significantly different at any age, in baseline heart rate, respiratory rate, the time course for bradycardia, time to gasp onset, duration of gasping, or number of gasps, although most of these variables declined significantly with age. We conclude that responses to anoxia are not affected by prenatal high-dose nicotine.

Attenuation of mecamylamine-precipitated nicotine-withdrawal aversion by the 5-HT 3 receptor antagonist ondansetron

The effect of ondansetron (0.01-0.1 mg kg , s.c.), a selective 5-HT 3 receptor antagonist, on mecamylamine-precipitated nicotine-withdrawal aversion was examined in the conditioned place preference paradigm. Male Sprague-Dawley rats were chronically treated subcutaneously with 9 mg kg/day (−)-nicotine tartrate using an osmotic minipump. After nicotine treatment for 7 days, mecamylamine (1 mg kg , s.c.), a nicotinic receptor antagonist, produced place aversion in nicotine-dependent rats. This aversive effect was dose-dependently antagonized by pretreatment with ondansetron 30 min prior to the conditioning. These results suggest that ondansetron may attenuate the place aversion associated with nicotine withdrawal, and may be useful for the treatment of nicotine dependence.

Nicotine alleviation of nicotine abstinence syndrome is naloxone-reversible

In a recently introduced rodent model of nicotine abstinence syndrome, the observed signs closely resembled those typical of rat opiate abstinence syndrome. Signs were precipitated by naloxone and potently reversed by morphine as well as nicotine itself, suggesting that nicotine might relieve nicotine abstinence syndrome through releasing endogenous opioids. To test this hypothesis, rats were continuously infused subcutaneously (SC) for 7 days with 9 mg/kg per day nicotine tartrate. Each rat was observed for abstinence signs at 18 and 21 h after termination of infusion. Three minutes before the 21-h test, all rats received 0.35 mg/kg nicotine tartrate, SC; 5 min before the nicotine injection, subjects received 9 or 4.5 mg/kg naloxone or saline alone, SC. Abstinence reversal scores were calculated as signs at 21 h as a percentage of signs at 18 h. Naloxone prevented nicotine alleviation of nicotine abstinence in a dose-related manner. However, naloxone in the absence of a nicotine injection had no effect on abstinence severity in either highly dependent or moderately dependent rats (infused with 9 or 5 mg/kg per day nicotine tartrate, respectively). These results support the hypothesis that endogenous opioids play a role in nicotine dependence and abstinence.

Peripheral nicotine administration increases rubral firing rates in the urethane-anesthetized rat

The presence of cholinergic input to the red nucleus (RN) in the cat is demonstrated by choline acetyltransferase (ChAT) staining; however, it is unclear what effect this cholinergic input has on neurons of the RN. Further, the presence of cholinergic neurons in the rat RN has been the subject of controversy. The present study examined the effects of intravenous injections of S(−)-nicotine tartrate (62.5–250 μg/kg) on the firing rate of rubral neurons. Dose-dependent increases in firing rates were observed which were blocked by pre-treatment with the nicotinic antagonist, mecamylamine hydrochloride. Smaller consistent increases were found after pretreatment with 62.5 μg/kg) or 125 μg/kg) doses of nicotine than were observed following the initial administration, suggesting a desensitizing response typical of nicotinic receptors.

The nicotinic antagonist mecamylamine precipitates nicotine abstinence syndrome in the rat

Recently, a rodent model of nicotine abstinence syndrome has been developed based on observing the frequency of spontaneous behavioral signs following termination of continuous subcutaneous infusion of nicotine tartrate. In the present study, the nicotinic antagonist mecamylamine precipitated an abstinence syndrome in nicotine-dependent rats. Twelve rats were each infused for 7 days with 9 mg/kg per day nicotine tartrate in saline via Alzet osmotic minipumps; another 12 rats were sham-operated and remained nicotine-naive. Six rats from each group received 1 mg/kg mecamylamine in saline SC immediately before a 30-min observation, while the remaining six rats from each group received saline alone. Nicotine-infused rats receiving mecamylamine exhibited significantly more (P < 0.01), overall abstinence signs than all other groups. In terms of categories of signs, they displayed significantly more gasps/writhes, teeth chatter/chews, shakes/tremors and ptosis. In a second experiment utilizing only nicotine-naive rats, a far higher dose of mecamylamine (5 mg/kg sc) induced a quasi-nicotine abstinence syndrome. The results provide further validation for this rodent model of nicotine abstinence syndrome.

Metabolic effects of nicotine on human adipose tissue in organ culture.

Fragments of human adipose tissue were maintained in culture for 1 week in a medium containing 1 mU/ml insulin and 100 ng/ml dexamethasone. Under these conditions lipoprotein lipase activity was present in human adipose tissue fragments which converted [14C]glucose to 14CO2 and [14C]triglyceride. Both metabolic parameters studied were affected by human tumor necrosis factor and brefeldin A. When fragments of human adipose tissue after 1 week in culture were incubated with nicotine tartrate for 20 h, a slight but significant increase in lipoprotein lipase activity was observed, and an increased conversion of [14C]glucose to 14CO2 and [14C]triglyceride occurred. Nicotine was taken up by human adipose tissue, but no conversion to cotinine was observed. Our data demonstrate a direct effect of nicotine on human adipose tissue metabolism. Furthermore, it is suggested that weight loss in smokers is a multifactorial phenomenon, and one of the important factors to be considered is the direct effect of nicotine within the tissue.

Naloxone precipitates nicotine abstinence syndrome in the rat.

Recently, a rodent model of nicotine abstinence syndrome has been developed based on continuous subcutaneous infusion of nicotine tartrate and observing the frequency of spontaneous behavioral signs following termination of infusion. The observed signs closely resemble those commonly seen in rat opiate abstinence syndrome, raising the possibility that there is an endogenous opioid component in nicotine dependence. The present study demonstrates that the opiate antagonist naloxone can precipitate an abstinence syndrome in nicotine-dependent rats. Fourteen rats were infused for 7 days with 9 mg/kg/day nicotine tartrate in saline via an Alzet osmotic minipump. Fourteen rats were sham-operated and remained nicotine-naive. Half of each group received 4.5 mg/kg naloxone SC immediately before a "blind" 15-min observation, while the other half received saline alone. ANOVA revealed significant nicotine infusion, naloxone injection and interaction effects. Post-hoc analysis showed that the nicotine-infused rats injected with naloxone had significantly more signs than all other groups (P < 0.01). In a second experiment, 2 mg/kg morphine sulfate SC produced a significant (P < 0.01) 91.2% reduction of spontaneous abstinence signs observed 21 h after termination of nicotine infusion. These results are consistent with the hypothesized endogenous opioid component in nicotine dependence and abstinence syndrome.

Rodent model of nicotine abstinence syndrome

Few animal models are currently in use for the recognized clinical problem of nicotine dependence and abstinence. This study introduces a rapid and convenient model using the rat. Sixteen male rats were rendered nicotine dependent by 7 days of continuous subcutaneous infusion of either 3 mg/kg/day ( n = 8) or 9 mg/kg/day ( n = 8) nicotine tartrate salt; 8 control rats were infused with saline alone. Rats were observed for 15 min before, during, and after the drug infusion period using a tally sheet modified from a standard checklist of opiate abstinence signs. There were few signs observed in any group at baseline and at the end of the infusion period. However, nicotine-infused rats showed a significant, dose-related increase over the control group at 16 h after the end of infusion, largely subsiding by 40 h. The most frequently observed signs during withdrawal include: teeth chattering/chews, writhes/gasps, ptosis, tremors/ shakes, and yawns. A significant drop in locomotor activity and increase in weight gain following termination of nicotine infusion provided additional evidence of an abstinence syndrome. This syndrome was alleviated by SC administration of 0.4 mg/kg nicotine tartrate.

Tobacco smoke releases performed mediators from canine mast cells and modulates prostaglandin production

The role of an extract of tobacco smoke in activating mast cells was studied. With the use of isolated, canine mast cells as a model, we found that cigarette smoke solution (CSS) induced the release of the performed mediators histamine and tryptase from these cells in an energy- and temperature-dependent, non-cytotoxic manner. There was no requirement for extracellular calcium. Nicotine tartrate did not reproduce the effect of CSS. Interestingly, mast cells produced little prostaglandin D2 (PGD2) in response to the CSS, and there was a concentration-related inhibition of calcium ionophore A23187-induced PGD2 synthesis. This suggests at least two mechanisms acting on the mast cell: tobacco smoke can directly activate mast cells to release performed mediators and can simultaneously inhibit prostaglandin production. These observations suggest a mechanism by which mast cells may participate in the bronchospastic and proinflammatory changes seen in the lungs and airways of smokers.