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PubMed2004

Smoking cigarettes of low nicotine yield does not reduce nicotine intake as expected: a study of nicotine dependency in Japanese males.

BACKGROUND: Many Japanese believe that low-yield cigarettes are less hazardous than regular cigarettes, and many smokers consume low-yield cigarettes to reduce their risks from smoking. We evaluate the association between actual nicotine intake and brand nicotine yield, and the influence of nicotine dependence on this association. METHODS: The study subjects included 458 Japanese male smokers, aged 51.2 +/- 9.9 years, who participated in health check-ups in a hospital in 1998 and 2000. Each subject filled out a self-administered smoking questionnaire and the score of each on the Fagerström Test for Nicotine Dependence was calculated. Urinary cotinine concentration was measured at the time of participation. RESULTS: The geometric mean of urinary cotinine concentration was 535 ng/mgCr for those who smoked brands with the lowest nicotine (0.1 mg on the package), compared with 1010 ng/mgCr for those who smoked brands with the highest (0.9-2.4 mg, weighted mean of 1.1 mg). Thus, despite the 11-fold ratio of nicotine yield on the packages, the ratio of urinary cotinine level was less than twofold. Both nicotine yield on the package and nicotine dependence significantly increased urinary cotinine concentration, and the negative interaction between them almost attained statistical significance. Cotinine concentration in heavily dependent smokers was consistently high regardless of the nicotine yield of brands. CONCLUSIONS: The nicotine yield of cigarettes measured by machine-smoking does not reliably predict the exposure of smokers. Smokers consuming low-yield nicotine cigarettes did not reduce actual intake of nicotine to the level that might be expected, especially for those heavily dependent on nicotine. Current labeling practices are misleading for the two-third of smokers who are moderately or highly dependent on nicotine.

Adult↗
PubMed2006

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.

Analysis of Variance↗
PubMed1985

Exposure to nicotine enhances the behavioral stimulant effect of nicotine and increases binding of [3H]acetylcholine to nicotinic receptors.

Rats were given daily injections of nicotine sulfate in doses ranging from 0.1 to 0.4 mg/kg. The behavioral effect of these injections was measured as locomotor activity in photocell cages. Repeated administration of the same dose to each rat resulted in an enhancement of the stimulant effect of nicotine. This enhanced behavioral effect was quite pronounced within 5 days of repeated injection. Tissue from the cerebral cortex of these rats, exposed to nicotine for 5 days, was assayed for binding of [3H]acetylcholine to nicotinic receptors. These relatively small doses of nicotine resulted in 18-26% increases in cortical nicotinic receptors, compared to saline-treated rats. Rats exposed to 0.2 mg/kg of nicotine for 5 days and then given saline for 7 days still showed an enhanced behavioral response to nicotine on the eighth day after exposure, and nicotinic binding in the cortex was still elevated. However, 21 days after exposure to nicotine both the behavioral response to nicotine and the binding values had returned to the same values as those of saline-treated rats. These data imply that increased binding of [3H]acetylcholine to nicotinic sites and the enhanced behavioral effect of nicotine are functionally linked.

Acetylcholine↗
PubMed2006

Blockade of nicotinic acetylcholine or dopamine D1-like receptors in the central nucleus of the amygdala or the bed nucleus of the stria terminalis does not precipitate nicotine withdrawal in nicotine-dependent rats.

Approximately 70% of tobacco smokers wish to quit, but attempts are often unsuccessful partly due to the aversive nicotine withdrawal syndrome. We investigated the possible involvement of nicotinic and dopaminergic signalling in the central nucleus of the amygdala (CeA) and dorsolateral bed nucleus of the stria terminalis (dlBNST) in the anhedonic depression-like effect of precipitated nicotine withdrawal in rats. Nicotine-dependent rats exhibit elevations in intracranial self-stimulation (ICSS) thresholds compared to control rats after cessation of chronic nicotine administration (spontaneous withdrawal) or systemic or intra-ventral tegmental area (VTA), but not intra-nucleus accumbens (NAcc), administration of nicotinic acetylcholine receptor (nAchR) antagonists while exposed to nicotine (precipitated withdrawal). We examined whether intracerebral administration of the nAChR antagonist dihydro-beta-erythroidine (DHbetaE; 0.6-20 microg total bilateral dose) or the dopamine D1-like receptor antagonist SCH 23390 (2-16 microg total bilateral dose) into the CeA and dlBNST results in withdrawal-like threshold elevations in nicotine-treated rats. Nicotinic acetylcholine and D1-like receptor blockade in the CeA or the dlBNST did not induce differential threshold elevations in nicotine- and saline-treated rats. Further, the highest SCH 23390 dose (16 microg bilateral dose) injected into the dlBNST, but not the CeA, elevated thresholds similarly in both saline- and nicotine-treated rats, suggesting that dopaminergic signalling in the dlBNST may regulate brain reward function under baseline conditions. These results suggest that nACh and D1-like signalling in the CeA and the dlBNST does not develop neuroadaptations with the development of nicotine dependence that may be involved in the depression-like aspects of nicotine withdrawal.

Amygdala↗
PubMed2005

Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716).

Conditioned stimuli are important for nicotine dependence and may trigger craving and relapse after prolonged nicotine abstinence. However, little is known about the pharmacology of this process. Among the systems that have been shown to play a role in drug-seeking behavior is the endocannabinoid transmission. Therefore, the present study examined the resistance to extinction of drug-seeking behavior elicited by nicotine-associated environmental stimuli and the effects of the selective CB1 cannabinoid antagonist rimonabant (SR141716) on the reinforcing effects of nicotine-related stimuli. Rats were trained to self-administer nicotine (0.03 mg/kg/injection, i.v.) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and stimuli (light and tone). After self-administration acquisition, nicotine was withdrawn and lever pressing was only reinforced by contingent presentation of the audiovisual stimuli. Under such a condition, responding persisted for 3 months, following which nonpresentation of the cues produced a progressive extinction of responding. As expected, rats trained to lever-press for saline injections paired with the audiovisual stimuli did not acquire the self-administration. These findings indicate that the cues required learned association with nicotine to acquire reinforcing properties and to function as conditioned reinforcers. When administered 1 month following nicotine withdrawal, rimonabant (1 mg/kg, i.p.) decreased conditioned behavior. These results showing the persistence of a nicotine-conditioned behavior are congruent with the role of nicotine-related environmental stimuli in nicotine craving in abstinent smokers. Rimonabant, which has been shown previously to reduce nicotine self-administration, may be effective not only as an aid for smoking cessation but also in the maintenance of abstinence.

Acoustic Stimulation↗
PubMed1992

Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment.

DBA mice were chronically treated with nicotine by continuous intravenous infusion of 4.0 mg/kg/hr for 10 d. Drug-treated mice were tolerant to the acute effects of nicotine on locomotor activity and body temperature. The effect of chronic treatment on the amount of L-3H-nicotine binding and RNA encoding for alpha 4, the most widely expressed nicotinic alpha-subunit, was measured in three brain regions. Chronic treatment increased L-3H-nicotine binding in cortex and midbrain but had no effect in cerebellum. In contrast, chronic treatment had no effect on the levels of mRNA encoding for alpha 4 in any of the three brain regions. Subsequently brains were sectioned and L-3H-nicotine binding was measured using quantitative autoradiographic methods. In addition, the relative amounts of mRNA for the major nicotinic receptor subunits (alpha 4 and beta 2), as well as for three additional minor subunits (alpha 2, alpha 3, and alpha 5), were determined by in situ hybridization histochemistry followed by quantitation of image intensity. Chronic nicotine treatment resulted in increases in the amount of L-3H-nicotine binding in many but not all brain areas measured. In contrast, chronic treatment had little effect on the intensity of the hybridization signal for the nicotinic subunit mRNA. The results suggest that chronic treatment with nicotine under conditions resulting in maximal steady-state increases in L-3H-nicotine binding has little effect on RNA levels encoding any of four nicotinic alpha-subunits and the beta 2-subunit.

Animals↗
PubMed1995

Sensitivity of rat frontal cortical neurones to nicotine is increased by chronic administration of nicotine and by lesions of the nucleus basalis magnocellularis: comparison with numbers of [3H]nicotine binding sites.

The effects of chronic nicotine treatment and of unilateral AMPA lesion of the nucleus basalis magnocellularis (nbm) on the sensitivity of frontal cortical neurones to iontophoretically applied nicotine were studied. Chronic nicotine treatment increased the number of [3H]nicotine binding sites from 2.9 to 3.9 pmol g-1 wet weight, and increased the proportion of cortical neurones responding to nicotine from 32.3% to 60.0%. After unilateral nbm lesions, the densities of AChE-positive fibers and [3H]nicotine binding sites were reduced by approximately 97% and 55%, respectively, and the proportion of neurones responding to nicotine increased from 32.3% to 53.8%. The two treatments, chronic nicotine administration and nbm lesion, also increased the size of individual neuronal responses, prolonged their duration, and shortened the response latency. Responses to glutamate were unaffected by either procedures. The results show that the increase in [3H]nicotine binding produced by chronic nicotine administration is associated with an increased response to iontophoretically applied nicotine, suggesting that the receptor upregulation induced by the chronic treatment were functional. Less easily explained is the association between increased sensitivity of frontal cortical neurons to nicotine after nbm lesion with a decreased receptor density. It is suggested that a substantial proportion of nicotinic receptors are located presynaptically, and that their loss after lesion concealed an upregulation at postsynaptic sites.

Animals↗
PubMed1990

Acute effects of nicotine injection into the nucleus accumbens on locomotor activity in nicotine-naive and nicotine-tolerant rats.

To assess the role of nicotine receptors in the nucleus accumbens on locomotor activity we bilaterally implanted guide cannulae for later injection of (-)-nicotine into the nucleus accumbens of Wistar rats. Motor activity was tested in a complex tunnel maze equipped with photocells for automatic recording. This system of dark tunnels elicits spontaneous exploration even after repeated exposure. Half of the rats were made nicotine-tolerant by daily systemic injections of (-)-nicotine for 15 days (nicotine pretreatment); the other half remained nicotine-naive (saline pretreatment). Whereas (-)-nicotine (40 nmol/0.3 microliter) bilaterally injected into the nucleus accumbens of nicotine-naive animals suppressed locomotor activity, the same amount injected into the nucleus accumbens of nicotine-tolerant rats had no effect on locomotor activity. Systemic injections of nicotine (0.4 mg/kg) induced a depression and stimulation of locomotor activity in saline-pretreated and nicotine-pretreated rats, respectively. Our results support a dual role for nicotine in locomotor activity with the initial depressant effect in nicotine-naive animals due to stimulation of the nucleus accumbens and perhaps other structures.

Animals↗
PubMed1999

Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57Bl/6 mice.

The route of drug delivery is an important consideration in studies that evaluate the long-term bio-behavioral adaptations that occur in response to chronic drug administration. Continuous infusions (intravenous or subcutaneous) or intermittent intraperitoneal (or subcutaneous) injections are the most commonly utilized routes of chronic drug delivery in these studies. The purpose of the present study was to determine the effects of chronic oral nicotine exposure on sensitivity to nicotine and brain nicotinic cholinergic receptors in female C57Bl/6 mice. Mice were randomized to different treatment groups that received 2% saccharin, containing 0-200 microg/ml nicotine (free base). In preliminary experiments, radiotelemetry devices were implanted in the mice; consumption of the nicotine-containing drinking solution caused a significant increase in home-cage nocturnal (but not diurnal) activity and also altered circadian alterations in body temperature. Oral nicotine exposure resulted in dose-related elevations in plasma levels of cotinine, a primary nicotine metabolite. Continuous exposure (30 days) to oral nicotine (200 microg/ml) resulted in the expression of significant tolerance to the locomotor depressant and hypothermic actions of acute nicotine challenge. This tolerance was accompanied by a significant increase in brain nicotinic receptor number assessed by quantitative auto-radiography using [3H]-cytisine (alpha4 nAChr) and [125I]-alpha-bungarotoxin (alpha7 nAChr) as radioligands. These results suggest that chronic oral nicotine delivery to female C57Bl/6 mice results in behavioral and biochemical changes that resemble changes that occur following other routes of chronic nicotine delivery.

Administration, Oral↗
PubMed2000

Nicotine administration in rabbits using Habitrol nicotine patches and nicotine nasal spray.

1. Several methods are used to provide predictable and effective nicotine to experimental animals in scientific studies. Due to the expense and technical challenges of these methods, we sought suitable alternatives. Consequently, the purpose of the present study was to develop a reliable experimental nicotine protocol in rabbits that included either Habitrol nicotine patches (Novartis Consumer Health Inc., Summit, NJ, USA) or nicotine nasal spray. 2. Administration of one of three doses of nicotine (2.5, 5, or 10 mg) was accomplished daily on 13 rabbits divided between either the patch or spray groups. Systemic nicotine and cotinine levels at 0 h, 15 min and 8 and 24 h were assayed. Data were analysed by a Fisher's protected least significant difference test at P = 0.05. 3. Rabbits treated with Habitrol patches exhibited consistent and predictable systemic nicotine levels. The nicotine nasal spray produced an immediate dose-dependent response with no measurable nicotine serum levels at 8 h. 4. For nicotine administration in rabbits, nicotine patches are easy to administer and provide a nicotine serum level between 5 and 25 ng/mL, which is consistent with the average daily level found in a patient who smokes cigarettes.

Administration, Cutaneous↗
PubMed1994

Sensitivity to nicotine and brain nicotinic receptors are altered by chronic nicotine and mecamylamine infusion.

DBA/2 mice were chronically infused with saline (control), 4 mg/kg/hr of nicotine, 4 mg/kg/hr of mecamylamine or nicotine+mecamylamine for 7 days. The binding of L-[3H]nicotine was significantly increased in seven of eight brain regions dissected from mice 5 hr after cessation of drug treatment. Similarly, [3H]nicotine binding was increased in six of eight regions by chronic mecamylamine treatment. Treatment with both drugs led to increases in [3H]nicotine binding that were at least the sum of the those observed with either drug alone. These increases were partially reversed 48 hr after cessation of treatment. No significant effects of nicotine or mecamylamine treatment on alpha-[125I]bungarotoxin binding were observed 5 hr after treatment was stopped when assayed using a single ligand concentration. However, saturation analyses of the cerebral cortex detected small increases from control after treatment with nicotine or both drugs. No effects of chronic treatment on alpha-[125I]bungarotoxin binding were evident 48 hr after treatment was stopped. Mice treated with nicotine, mecamylamine or both drugs tested 5 hr after withdrawal were less sensitive to acute injection with nicotine than were saline-infused mice. However, the effects of mecamylamine may have been influenced by continued presence of this drug at the time of testing. Mice tested 48 hr after cessation of treatment were more sensitive to nicotine than those tested after 5 hr, but some tolerance to the effects of nicotine persisted in the nicotine-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Activation of platelets exposed to shear stress in the presence of smoke extracts of low-nicotine and zero-nicotine cigarettes: the protective effect of nicotine.

Mainstream and sidestream smoke extracts of both high-tar and low-tar cigarettes have been shown to increase platelet activation directly and to sensitize them to further activation by exposure to mechanical stimuli such as shear stress. However, nicotine has an inhibitory effect on platelet activation, opposite to that of whole cigarette smoke extracts. To distinguish between the nicotine-dependent and non-nicotine-dependent effects of smoke, platelets were exposed to mainstream and sidestream smoke extracts of low-nicotine and zero-nicotine cigarettes in vitro under flow conditions comparable with the normal circulation, and their activation state was measured using a modified prothrombinase-based assay. Both low-nicotine and zero-nicotine extracts caused increased platelet activation upon exposure to shear stress, and they caused significantly greater activation than extracts from ordinary high-tar, high-nicotine cigarettes. That nicotine was crucial was confirmed by adding 50 nM nicotine (comparable with the nicotine level in smokers' plasma) to zero-nicotine smoke extracts and demonstrating a reduction in the shear-dependent rate of platelet activation of more than 75%.

Adult↗
PubMed2005

Chronic pre-treatment with nicotine enhances nicotine-evoked striatal dopamine release and alpha6 and beta3 nicotinic acetylcholine receptor subunit mRNA in the substantia nigra pars compacta of the rat.

Whilst local intrastriatal infusion of nicotine consistently elicits striatal dopamine release, systemic administration often fails to do so. Since chronic nicotine administration is known to result in desensitisation-induced upregulation of nicotinic acetylcholine receptors (nAChRs), the present study investigated whether chronic pre-treatment could enhance the response to systemic nicotine and, if so, whether increases in specific nAChR subunit mRNA levels in the substantia nigra pars compacta (SNc) may underlie this effect. In vivo microdialysis studies in male Sprague-Dawley rats revealed that following 4 days pre-treatment with nicotine (0.8 mg kg(-1)s.c.), local intrastriatal nicotine infusion (3 mM) elicited significantly higher dopamine efflux compared to vehicle pre-treated controls (peak release: 1273 +/- 199% basal versus 731 +/- 113% basal), whereas systemic nicotine challenge (0.8 mg kg(-1)s.c.) elicited no response. In contrast, following 8 days pre-treatment with nicotine (0.8 mg kg(-1)s.c.), systemic nicotine challenge (0.8 mg kg(-1)s.c.) now produced significantly higher dopamine efflux than that of vehicle pre-treated controls (147 +/- 30% basal versus 91 +/- 5% basal). Eight days pre-treatment with nicotine also significantly elevated the levels of alpha6 (approximately 55%) and beta3 (approximately 43%) nAChR subunit mRNA in the SNc, suggesting that up-regulation of these nAChR subunit genes in the nigrostriatal tract may contribute to the enhanced nicotine-evoked striatal dopamine release.

Animals↗
PubMed2003

Effects of repeated withdrawal episodes, nicotine dose, and duration of nicotine exposure on the severity and duration of nicotine withdrawal in rats.

RATIONALE: The aversive aspects of nicotine withdrawal contribute to high relapse rates to tobacco smoking after cessation attempts. OBJECTIVES: To investigate the influence of nicotine dose, duration of nicotine exposure, and withdrawal history on the severity of nicotine withdrawal in rats, as assessed by brain stimulation reward thresholds and somatic signs of withdrawal. METHODS: Repeated spontaneous and precipitated withdrawals were investigated through four successive removals of osmotic minipumps delivering nicotine/saline, or with daily injections of the nicotinic receptor antagonist dihydro-beta-erythroidine during chronic nicotine/saline exposure, respectively. The effects of dose and duration of exposure were investigated using minipumps of varying duration delivering different nicotine doses. RESULTS: Increased duration of nicotine exposure: a). prolonged the duration but did not alter the magnitude of withdrawal-associated threshold elevations; b). increased somatic signs early during withdrawal. Increased total nicotine exposure (i.e. increased dose and exposure duration) increased the duration of threshold elevations (no effect on magnitude) but had no effect on somatic signs. Neither repeated spontaneous nor repeated precipitated withdrawals altered the magnitude of withdrawal significantly. CONCLUSIONS: Increases in total nicotine dose resulted in increased severity of the affective aspects of withdrawal. Further, continuous drug exposure resulted in longer lasting withdrawal than intermittent administration even when the total nicotine dose was the same. There was no correlation between threshold elevations and somatic signs of withdrawal. In conclusion, the severity of nicotine withdrawal is mitigated by characteristics of the drug exposure regimen such as drug dose, duration of exposure and whether exposure is continuous or intermittent.

Animals↗
PubMed2001

Inhibition of nicotine-induced seizures in rats by combining vaccination against nicotine with chronic nicotine infusion.

The ability of a nicotine vaccine to protect against nicotine-induced seizures was studied in rats. Groups of 10 rats were vaccinated with 3 doses of either a nicotine conjugate vaccine over 6 weeks to elicit high titers of nicotine-specific antibodies or with a control vaccine. Rats were then pretreated with a 1-week subcutaneous infusion of either nicotine 1 mg/kg/day or saline and then received a single 2 mg/kg ip dose of nicotine to provoke seizures. Vaccination reduced the incidence of seizures. The combination of vaccination and pretreatment with nicotine infusion was more effective than either treatment alone. These data suggest that vaccination is protective against this toxic effect of nicotine and that combining vaccination and chronic nicotine administration may provide a novel strategy for blocking some effects of nicotine.

Animals↗
PubMed1998

Effects of chronic nicotine treatment on expression of diverse nicotinic acetylcholine receptor subtypes. I. Dose- and time-dependent effects of nicotine treatment.

Nicotinic acetylcholine receptors (nAChRs) exist as a diverse family of physiologically important ligand-gated ion channels active in classic, excitatory neurotransmission and perhaps in more novel forms of neurochemical signaling. Because of their critical functional roles centrally and peripherally, nAChRs are ideal targets for the regulation of nervous system function. nAChRs also are targets of nicotine, which acts acutely like acetylcholine to stimulate nAChR function. Here, we report studies using model cell culture systems testing the general hypothesis that more chronic nicotine exposure has unique effects on nAChRs. Chronic nicotine treatment induces increases in numbers of human muscle-type nAChRs containing alpha-1, beta-1, gamma and delta subunits, a human ganglionic nAChR subtype containing alpha-3 and beta-4 subunits and a human ganglionic nAChR containing alpha-7 subunits in intracellular and (except for alpha-7 nAChRs) in cell surface pools. However, the half-maximal potency with which nicotine has these effects differs across these nAChR subtypes, as do rates and magnitudes of the "nicotine-induced nAChR up-regulation." These changes in nAChR numbers are not attributable to either transient or sustained changes in nAChR subunit mRNA levels. Nicotine exposure more potently, more rapidly, and with nAChR-subtype specificity, induces two phases of losses in functional responsiveness of muscle-type nAChRs and alpha-3 beta-4 nAChRs, including a "persistent inactivation" that is distinct from classicly defined "desensitization." Based on these results, we hypothesize that chronic nicotine treatment induces persistent functional inactivation and numerical up-regulation of all nAChR subtypes via distinct post-transcriptional mechanisms and with potencies, at rates and with magnitudes that are nAChR-subtype specific. We also hypothesize that chronic nicotine exposure produces long-lasting changes in nervous system function, at least in part, by disabling rather than activating nicotinic cholinergic signaling.

Blotting, Northern↗
PubMed2006

Genetic dissociation of two behaviors associated with nicotine addiction: beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome.

RATIONALE: Nicotine addiction is characterized by two distinct behaviors, chronic compulsive self-administration and the induction of a withdrawal syndrome upon cessation of nicotine consumption. OBJECTIVE: To examine if these two processes rely on beta2-containing nicotinic receptors--beta2*nAChRs--we analyzed the behavior of mice lacking these receptors in the two situations. RESULTS: First, we showed that, in contrast to wild-type (WT) mice, beta2-knockout (beta2-/-) mice exhibit no intra-ventral tegmental area (VTA) nicotine self-administration, whereas their ability to self-administer morphine is intact. However, beta2-/- mice showed some sensitivity to locomotor effects of nicotine, implying an effect of the drug on other nicotinic subtypes. Then, we observed that beta2-/- mice exhibited a normal nicotine withdrawal syndrome, i.e., increased levels of rearing and jumping upon precipitated withdrawal. Thus, the beta2*nAChRs are not involved in the behaviors induced by cessation of nicotine consumption. CONCLUSION: Taken together, the present data demonstrated a genetic dissociation of two distinct behavioral patterns associated with nicotine addiction. They further suggested that independent molecular mechanisms underlie these two aspects, offering the possibility of controlling them separately.

Animals↗
PubMed1999

Effects of chronic treatment with (+)-nicotine on the stress-induced hypertension and downregulation of central nicotinic receptors in rats: comparative study with (-)-nicotine.

The effects of chronic treatment with (+)-nicotine on the immobilization stress-induced changes in blood pressure, body weight, and [3H]cytisine binding to brain nicotinic receptors were examined in rats and were compared with those of (-)-nicotine. Immobilization stress (2 hr/day(-1), for 2 weeks) induced a moderate elevation of blood pressure, loss of body weight gain, and downregulation of [3H]cytisine binding sites in cerebral cortex and midbrain. Chronic treatment with (+)- or (-)-nicotine inhibited the stress-induced hypertension but did not suppress the inhibition of body weight gain by stress. Body weight before stress load was also reduced by (-)-nicotine but not (+)-nicotine treatment. Treatment with each isomer increased the maximum number of [3H]cytisine binding sites (Bmax) of brain stem, cerebral cortex, and hippocampus. The Bmax in midbrain was also increased by (+)-nicotine but not by (-)-nicotine. Stress-induced downregulation in cerebral cortex was inhibited by both isomers. These results suggest that (+)- and (-)-nicotine cause various effects, including anti-stress effect, on the central nervous system in rats, which are slightly different between the isomers.

Alkaloids↗