Preadolescent tobacco smoke exposure leads to acute nicotine dependence but does not affect the rewarding effects of nicotine or nicotine withdrawal in adulthood in rats

Epidemiological studies indicate that parental smoking increases the risk for smoking in children. However, the underlying mechanisms by which parental smoking increases the risk for smoking are not known. The aim of these studies was to investigate if preadolescent tobacco smoke exposure, postnatal days 21-35, affects the rewarding effects of nicotine and nicotine withdrawal in adult rats. The rewarding effects of nicotine were investigated with the conditioned place preference procedure. Nicotine withdrawal was investigated with the conditioned place aversion procedure and intracranial self-stimulation (ICSS). Elevations in brain reward thresholds in the ICSS paradigm reflect a dysphoric state. Plasma nicotine and cotinine levels in the preadolescent rats immediately after smoke exposure were 188 ng/ml and 716 ng/ml, respectively. Preadolescent tobacco smoke exposure led to the development of nicotine dependence as indicated by an increased number of mecamylamine-precipitated somatic withdrawal signs in the preadolescent tobacco smoke exposed rats compared to the control rats. Nicotine induced a similar place preference in adult rats that had been exposed to tobacco smoke or air during preadolescence. Furthermore, mecamylamine induced place aversion in nicotine dependent rats but there was no effect of preadolescent tobacco smoke exposure. Finally, preadolescent tobacco smoke exposure did not affect the elevations in brain reward thresholds associated with precipitated or spontaneous nicotine withdrawal. These studies indicate that passive exposure to tobacco smoke during preadolescence leads to the development of nicotine dependence but preadolescent tobacco smoke exposure does not seem to affect the rewarding effects of nicotine or nicotine withdrawal in adulthood.     

Combining clonidine and nicotine replacement for treatment of nicotine withdrawal

The U.S. Surgeon General's 1988 report on nicotine addiction has increased the need for the substance abuse treatment community to become more involved in smoking cessation programs. A unique approach to nicotine detoxification has been developed at the Haight Ashbury Free Clinics' Drug Detoxification, Rehabilitation and Aftercare Project. After an evaluation by a physician, a thorough explanation of the treatment plan, and if the patient is interested, a combination of clonidine via the transdermal patch (Catapres-TTS) and of nicotine replacement via nicotine polacrilex (Nicorette) is used. By combining a Nicorette taper with clonidine, the physician can control the rate of nicotine withdrawal (Nicorette) and the extent to which withdrawal symptoms are treated (clonidine). This appears to be an effective, comfortable method for detoxification from cigarettes and nicotine. Its use should prove helpful as an adjunct to a comprehensive smoking cessation program.     

Baclofen withdrawal following removal of an intrathecal baclofen pump despite oral baclofen replacement

Intrathecal baclofen is used as a muscle relaxant and antispasmodic in cases of spasticity resulting from central nervous system trauma. The baclofen withdrawal syndrome may include hyperthermia, tachycardia, hypertension, seizures, altered mental status, and psychomotor agitation. We report a case in which the removal of a baclofen pump lead tothe development of severe withdrawal symptoms despite oral baclofen replacement therapy. In order to avoid the development of withdrawal, adequate doses of GABA agonist agents should be administered immediately prior to, and following, baclofen pump removal.     

Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt

Aims To examine the effect of varenicline, a selective alpha4-beta2 nicotinic acetylcholine receptor (nAChR) partial agonist, on craving and withdrawal symptoms in smokers making a quit attempt and the rewarding effects of smoking during a lapse after the target quit date (TQD). Materials and methods Pooled data were analysed from two identical double-blind, randomised trials comparing varenicline 1 mg BID, bupropion (sustained release) 150 mg BID and placebo using measures of craving and withdrawal in the first week after the TQD (in abstinent [n = 612] and non-abstinent participants [n = 1,155]) and of the rewarding effects of the first cigarette smoked in non-abstinent participants. Results In abstinent and non-abstinent participants combined, varenicline reduced craving more than bupropion (p < 0.01) and placebo (p < .001); the effect did not differ by whether or not subjects were abstinent; bupropion reduced craving more than placebo (p < 0.001). Among abstinent participants, both varenicline and bupropion reduced negative affect more than those receiving placebo (p < 0.005). Neither active drug reduced restlessness, insomnia or appetite vs placebo. Varenicline reduced ratings of satisfaction and psychological reward after the first cigarette smoked after the TQD vs bupropion (p < 0.005) and placebo (p < 0.001); bupropion also reduced these more than placebo (p < 0.05). Conclusions Varenicline significantly reduces craving and the rewarding effects of smoking after the TQD to a greater extent than bupropion, which may contribute to varenicline’s greater efficacy for smoking cessation. Varenicline’s lack of effect in reducing insomnia, restlessness and increased appetite in this analysis suggests that receptors other than the alpha4-beta2 nAChR subtype may be implicated in these withdrawal symptoms.     

Neuroleptic malignant-like syndrome after abrupt withdrawal of baclofen

We present the case of a 36-year-old man who presented with a clinically neuroleptic malignant-like syndrome involving disorientation, signs of autonomic dysfunction, rigidity and raised total creatine kinase level, but in the absence of any neuroleptic medication. He had, however, abruptly stopped taking his long-term baclofen in the days prior to presentation. He improved markedly after the reintroduction of baclofen, and we postulate that his clinical syndrome resulted from the sudden withdrawal of this drug. We concur with the concept that neuroleptic malignant syndrome represents a spectrum of disorders, and add it to the list of possible sequelae after abrupt withdrawal of baclofen.     

Attenuation of morphine tolerance and withdrawal syndrome by coadministration of nalbuphine

Morphine has been used widely on the treatment of many types of chronic pain. However the development of tolerance to and dependence on morphine by repeat application is a major problem in pain therapy. The purpose of the present study was to investigate whether combined administration of nalbuphine with morphine affects the development of tolerance to and dependence on morphine. We hypothesize that the use of nalbuphine, κ-agonist may prove to be useful adjunct therapy to prevent morphine-induced undesirable effects in the management of some forms of chronic pain. Morphine (10 mg/kg) was injected to rats intraperitoneally for 5 day. The variable dose of nalbuphine (0.1, 1.0 and 5.0 mg/kg) was administered (i.p.) in combination with morphine injection. The development of morphine tolerance was assessed by measuring the antinociceptive effect with the Randall-Selitto apparatus. The development of dependence on morphine was determined by the scoring the precipitated withdrawal signs for 30 min after injection of naloxone (10 mg/kg, i.p.). Nalbuphine did not attenuate antinociceptive effect of morphine in rats. Interestingly, combined administration of morphine with nalbuphine (10∶1) significantly attenuated the development of dependence on morphine. The elevation of [³H]MK-801 binding in frontal cortex, dentate gyrus, and cerebellum after chronic morphine infusion was suppressed by the coadministration of nalbuphine. In addition, the elevation of NR1 expression by morphine was decreased by the coadministration of nalbuphine in rat cortex. These results suggest that the coadministration of nalbuphine with morphine in chronic pain treatment can be one of therapies to reduce the development of tolerance to and dependence on morphine.     

The nicotine withdrawal assessment for youth: initial instrument validation and psychometric properties

Within the field of adolescent tobacco use, there does not exist a consistently used and validated measure of adolescent nicotine withdrawal symptoms. The purpose of this study was to evaluate the psychometric properties of the Nicotine Withdrawal Assessment for Youth (N-WAY), a new measure of adolescent nicotine withdrawal symptoms. Smokers and nonsmokers, ranging from 13 to 19 years old, were administered the N-WAY and other smoking information questionnaires in order to examine its reliability and validity. The N-WAY demonstrated satisfactory test-retest reliability (r=0.74-88) and internal consistency (Cronbach's α=0.90-0.92). Its total symptom score accurately discriminated current smokers from nonsmokers. The N-WAY was demonstrated to measure a construct different than nicotine dependence symptoms while correlates of nicotine withdrawal symptoms, such as number of daily cigarettes smoked and prior quit attempts, accurately predicted total N-WAY symptom and impact scores. Preliminary results indicate the N-WAY is a reliable and valid assessment of adolescent nicotine withdrawal symptoms among current smokers.     

Neurobiology of the nicotine withdrawal syndrome

The aversive aspects of withdrawal from chronic nicotine exposure are thought to be an important motivational factor contributing to the maintenance of the tobacco habit in human smokers. Much emphasis has been placed on delineating the underlying neurobiological mechanisms mediating different components of the nicotine withdrawal syndrome. Recent studies have shown that both central and peripheral populations of nicotinic acetylcholine receptors (nAChRs) are involved in mediating somatic signs of nicotine withdrawal as measured by the rodent nicotine abstinence scale. However, only central populations of nAChRs are involved in mediating affective aspects of nicotine withdrawal, as measured by elevations in brain-stimulation reward thresholds and conditioned place aversion. Nicotine interacts with several neurotransmitter systems, including acetylcholine, dopamine, opioid peptides, serotonin, and glutamate systems. Evidence so far suggests that these neurotransmitters play a role in nicotine dependence and withdrawal processes. The available evidence also suggests that different underlying neurochemical deficits mediate somatic and affective components of nicotine withdrawal. The aim of the present review is to discuss preclinical findings concerning the neuroanatomical and neurochemical substrates involved in these different aspects of nicotine withdrawal.     

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-β-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.     

Temporal effects of nicotine nasal spray and gum on nicotine withdrawal symptoms

Nicotine nasal spray and nicotine gum have been found to be effective in relieving nicotine withdrawal symptoms. In this randomized single-blind study, 91 cigarette smokers were randomly assigned to a single 1 mg dose of active nicotine nasal spray (n = 29), active 4 mg nicotine gum (n = 31), saline placebo nasal spray (n = 16) or placebo gum (n = 15). Following overnight abstinence, subjects repeatedly completed visual analog scales for assessing nicotine withdrawal symptoms over 30 min preceding (time -30 min to time 0) and 120 min following a single dose of study medication. This sequence was performed 3 times during the day. Nicotine withdrawal symptoms were assessed on a 41-point visual analog scale (1 = no withdrawal, 41 = extreme withdrawal). At the initial session only, blood samples for serum nicotine levels were taken at baseline, then at 5, 10, 30 and 120 min following study drug administration. The mean (± SD) age of the subjects was 38.6 (±10.1) years, 48% were females, smoking rate was 24.5 (±7.8) cigarettes per day, and years of smoking was 19.9 (±10.0). A single 1 mg dose of nicotine nasal spray provided more immediate relief for craving for a cigarette compared to a single 4 mg dose of nicotine gum. Serum venous nicotine levels for the active nicotine nasal spray and nicotine gum were comparable at 5 and 10 min while the levels were higher for nicotine gum at 30 and 120 min. Changes in withdrawal symptoms were not found to be related to serum venous nicotine levels. Our findings provide a rationale for the as needed use of nicotine nasal spray to control withdrawal symptoms, possibly in combination with other medications with longer acting effects. Received: 18 February 1998/Final version: 1 May 1998     

Monoamine oxidase inhibitors allow locomotor and rewarding responses to nicotine.

Although nicotine is generally considered to be the main compound responsible for the addictive properties of tobacco, experimental data indicate that nicotine does not exhibit all the characteristics of other abused substances, such as psychostimulants and opiates. For example, nicotine is only a weak locomotor enhancer in rats and generally fails to induce a locomotor response in mice. This observation contradicts the general consensus that all drugs of abuse release dopamine in the nucleus accumbens, a subcortical structure, and thus increase locomotor activity in rodents. Because tobacco smoke contains monoamine oxidase inhibitors (MAOIs) and decreases MAO activity in smokers, we have combined MAOIs with nicotine to determine whether it is possible to obtain a locomotor response to nicotine in C57Bl6 mice. Among 15 individual or combined MAOIs, including harmane, norharmane, moclobemide, selegiline, pargyline, clorgyline, tranylcypromine and phenelzine, only irreversible inhibitors of both MAO-A and -B (tranylcypromine, phenelzine, and clorgyline+selegiline) allowed a locomotor response to nicotine. The locomotor stimulant interaction of tranylcypromine and nicotine was absent in beta2-nicotinic acetylcholine receptor subunit knockout mice. Finally, it was found that, whereas na?ve rats did not readily self-administer nicotine (10 microg/kg/injection), a robust self-administration of nicotine occurred when animals were pretreated with tranylcypromine (3 mg/kg). Our data suggest that MAOIs contained in tobacco and tobacco smoke act in synergy with nicotine to enhance its rewarding effects.     

Effects of chronic nicotine,nicotine withdrawal and subsequent nicotine challenges on behavioural inhibition in rats

Rationale  

Drug addiction is a chronically relapsing disorder characterised by compulsive drug use and loss of control over drug intake. Although several theories propose impulsivity as a key component of addiction, the precise nature of this relationship remains unclear.     

Ventral striatal blood flow is altered by acute nicotine but not withdrawal from nicotine.

Neural mechanisms underlying the reinforcing effects of nicotine and other drugs have been widely studied and are known to involve the ventral striatum, which is part of the mesocorticolimbic dopamine system. In contrast, mechanisms of nicotine withdrawal have received less attention although subjective withdrawal likely contributes to the difficulty of quitting. The goal of this study was to determine if nicotine withdrawal was associated with alterations of cerebral blood flow (CBF) in ventral striatum. Twelve smokers, moderately dependent on nicotine, underwent MR dynamic susceptibility contrast (DSC) imaging at baseline, after overnight withdrawal from nicotine, and after nicotine replacement. DSC images were used to calculate CBF in three regions of interest: ventral striatum, thalamus, and medial frontal cortex. Subjective withdrawal symptoms were measured at each time point. In spite of significant subjective withdrawal symptoms, there was no main effect of withdrawal on CBF in the three regions. However, there was a significant correlation between the increase in withdrawal symptoms and a reduction in thalamic CBF. In contrast to withdrawal, nicotine replacement significantly increased CBF in ventral striatum. Our findings are consistent with the known role of ventral striatum in drug reward. The lack of a main effect on withdrawal, but correlation of thalamic blood flow with withdrawal symptoms suggests that more complex mechanisms mediate the subjective features of the withdrawal state.     

Attenuation of morphine withdrawal signs by intracerebral administration of 18-methoxycoronaridine

18-Methoxyroconaridine (18-MC), a synthetic derivative of ibogaine, reduces morphine self-administration and alleviates several signs of acute opioid withdrawal in rats. Although there is already well documented evidence of the mechanism mediating 18-MC's action to reduce the rewarding effects of morphine, nothing is known about the mechanism responsible for 18-MC's attenuation of opioid withdrawal. In vitro studies have demonstrated that 18-MC is a potent antagonist of alpha3beta4 nicotinic receptors (IC50=0.75 microM), which are predominantly located in the medial habenula and interpeduncular nuclei. Previous work indicating that alpha3beta4 nicotinic receptors mediate 18-MC's effects on drug self-administration prompted us to assess whether brain areas having high or moderate densities of alpha3beta4 receptors might be involved in 18-MC's modulation of opioid withdrawal. To test this possibility, 18-MC was locally administered into the medial habenula, interpeduncular nucleus and locus coeruleus of morphine-dependent rats; this treatment was followed by naltrexone to precipitate a withdrawal syndrome. Pretreatment with various doses of 18-MC into the locus coeruleus significantly reduced wet-dog shakes, teeth chattering, burying and diarrhea, while pretreatment into the medial habenula attenuated teeth chattering, burying, and weight loss. Some doses of 18-MC administered into the interpeduncular nucleus significantly ameliorated rearing, teeth chattering, and burying, while other doses exacerbated diarrhea and teeth chattering. The present findings suggest that 18-MC may act in all three nuclei to suppress various signs of opioid withdrawal.     

Attenuation of nicotine-induced rewarding effects in A2A knockout mice

The non-selective A2A antagonist caffeine has been reported to modify nicotine-induced locomotor and reinforcing effects. In the present study, we have investigated the specific role of A2A adenosine receptors in the behavioural responses induced by nicotine by using genetically modified mice lacking A2A adenosine receptors. Acute nicotine administration induced a similar decrease of locomotor activity in A2A knockout mice and wild-type littermates. Acute antinociceptive responses elicited by nicotine in the tail-immersion and hot-plate tests were unaffected in these mutant mice. The rewarding properties of nicotine were then investigated using the place-conditioning paradigm. Nicotine-induced conditioned place preference was suppressed in A2A knockout mice. Accordingly, in vivo microdialysis studies revealed that the extracellular levels of dopamine in the nucleus accumbens were not increased after nicotine administration in mutant mice. Wild-type and A2A knockout mice were trained in conditioned taste aversion procedure in which drinking a saccharin or saline solution was paired with nicotine or saline injections. A similar reduction in the intake of nicotine-paired solution in this paradigm was obtained in both genotypes. Finally, the administration of the nicotinic antagonist mecamylamine in nicotine-dependent mice precipitated a similar withdrawal syndrome in both genotypes. Together, the present results identify A2A adenosine receptors as an important factor that contributes to the rewarding properties of nicotine.     

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.