A comparison of mecamylamine and bupropion effects on memory-related responses induced by nicotine and scopolamine in the novel object recognition test in mice

BackgroundThe aim of the present study was to evaluate the involvement of the cholinergic receptors ligands in the memory-related responses in mice, using the novel object recognition (NOR) test.MethodsThe NOR test is based on natural, exploratory abilities of animals exposed to a new environment. In the first session, two copies of the same object were presented. In the next sessions (30 min and 24 h after), one of the familiar object and a new object were presented.ResultsThe mice injected with nicotine (0.035 and 0.175 mg/kg, free base, sc) before the first session spent more time exploring the new object than the familiar one at the second and third session, indicating that nicotine improved cognition. In turn, the mice injected with scopolamine (0.3 and 1 mg/kg, ip) before the first session spent less time exploring the new object than the familiar one at the second and third trial, indicating that scopolamine impaired the memory performance. Additionally, the acute injection of drugs used in smoking cessation in humans: mecamylamine (0.5 and 1 mg/kg) and bupropion (5 and 10 mg/kg), prior to injections of nicotine (0.035 mg/kg) or scopolamine (1 mg/kg), significantly prevented nicotine-induced memory improvement or scopolamine-induced memory impairment, at the second and third session.ConclusionsThe results of our studies unveiling neuronal mechanisms for cholinergic system of memory processes, via both nicotinic and muscarinic cholinergic receptors, will be useful for development of more effective pharmacotherapies for memory impairment-like treatment of human disorders in which cholinergic pathways have been implicated.     

Influence of calcium channel antagonists on nonsomatic signs of nicotine and d-amphetamine withdrawal in mice

BackgroundNonsomatic signs of psychostimulant withdrawal, difficult to demonstrate in animal paradigms, may appear to promote drug seeking and drug relapse in humans; thus, it is important to understand the mechanisms that mediate this kind of behaviors. The present study was undertaken to examine the calcium-dependent mechanism of negative nonsomatic and anhedonia-related symptoms of acute and protracted withdrawal of nicotine and d-amphetamine.MethodsMice were chronically treated with nicotine (seven days, three times daily, 3.35 mg/kg, sc) or d-amphetamine (14 days, once daily, 2.5 mg/kg, ip). Then, at the first, seventh or 14th day of withdrawal, anxiety- or depression-related effects, as well as cognition or nociception were studied.ResultsOur results demonstrated that, at the seventh or 14th day of d-amphetamine or nicotine withdrawal, respectively, mice exhibited increased anxiety and depression-like effects, memory impairment and hyperalgesia. Further, major findings showed that calcium channel antagonists, i.e., nimodipine, verapamil and flunarizine (10 and 20 mg/kg, ip), injected before the test, attenuated above-mentioned signs of drug withdrawal.ConclusionsAs an outcome, these findings support the hypothesis that similar calcium-dependent mechanisms are involved in an aversive nonsomatic component, associated with nicotine or d-amphetamine withdrawal. We can suggest that calcium channel blockers have potential to alleviate drug withdrawal and may thus be beneficial as pharmacotherapy of drug cessation and relapse.     

Comparative study of the main characteristics and composition of the mainstream smoke of ten cigarette brands sold in Spain

In this study 10 commercial top selling cigarette brands in Spain have been machine smoked and the mainstream smoke has been analyzed. Multifunctional analysis has been satisfactorily employed to correlate the effect of the main design features of the cigarettes including amount of tobacco, filter size or paper weight with the amount of smoked tobacco and with the ratio CO₂/CO. The composition of the vapor phase and that of the particulate matter have been analyzed. The particulate matter retained in the filter of the cigarettes has also been analyzed showing a distinct behavior of the compounds condensed in the cigarette filters and in the traps, related to their retention time. A general trend for the relative yield of some compounds in the different brands have been identified and confirmed by multifunctional analysis. Nevertheless, there are some noticeable compounds that behave differently in the different brands.     

Nicotine improves AF64A-induced spatial memory deficits in Morris water maze in rats

Ethylcholine mustard aziridinium ion (AF64A) is a neurotoxic derivative of choline that produces not only long-term presynaptic cholinergic deficits, but also various memory deficits in rats similar to some characteristics observed in Alzheimer's disease patients. This study investigated whether nicotine (NCT) administration attenuated spatial learning deficits induced by intracerebroventricular AF64A treatment. AF64A (6 nmol/6 μl)-or saline (SAL)-treated rats were trained in Morris water maze task. NCT (0.025–0.25 mg/kg) was subcutaneously injected 5 min before the training every day. The results showed that moderate dose (0.10 mg/kg) of NCT attenuated AF64A-induced prolongation of escape latency. Furthermore, NCT dose-dependently recovered the AF64A-induced decrease of time spent in the target quadrant in the probe test. These results suggest that NCT improves AF64A-induced spatial memory deficits, and thus it is a potential therapeutic agent for the treatment of memory deficits in dementia.     

Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products

While the health risks associated with adult cigarette smoking have been well described, effects of nicotine exposure during periods of developmental vulnerability are often overlooked. Using MEDLINE and PubMed literature searches, books, reports and expert opinion, a transdisciplinary group of scientists reviewed human and animal research on the health effects of exposure to nicotine during pregnancy and adolescence. A synthesis of this research supports that nicotine contributes critically to adverse effects of gestational tobacco exposure, including reduced pulmonary function, auditory processing defects, impaired infant cardiorespiratory function, and may contribute to cognitive and behavioral deficits in later life. Nicotine exposure during adolescence is associated with deficits in working memory, attention, and auditory processing, as well as increased impulsivity and anxiety. Finally, recent animal studies suggest that nicotine has a priming effect that increases addiction liability for other drugs. The evidence that nicotine adversely affects fetal and adolescent development is sufficient to warrant public health measures to protect pregnant women, children, and adolescents from nicotine exposure.     

Critical role of Nitric Oxide on Nicotine‐Induced Hyperactivation of Dopaminergic Nigrostriatal System: Electrophysiological and Neurochemical evidence in Rats

Nicotine, the main psychoactive ingredient in tobacco, stimulates dopamine (DA) function, increasing DA neuronal activity and DA release. DA is involved in both motor control and in the rewarding and reinforcing effects of nicotine; however, the complete understanding of its molecular mechanisms is yet to be attained. Substantial evidence indicates that the reinforcing properties of drugs of abuse, including nicotine, can be affected by the nitric oxide (NO) system, which may act by modulating central dopaminergic function. In this study, using single cell recordings in vivo coupled with microiontophoresis and microdialysis in freely moving animals, the role of NO signaling on the hyperactivation elicited by nicotine of the nigrostriatal system was investigated in rats. Nicotine induced a dose‐dependent increase of the firing activity of the substantia nigra pars compacta (SNc) DA neurons and DA and 3,4‐dihydroxyphenylacetic acid (DOPAC) release in the striatum. Pharmacological manipulation of the NO system did not produce any change under basal condition in terms of neuronal discharge and DA release. In contrast, pretreatments with two NO synthase (NOS) inhibitors, N‐ω‐nitro‐l ‐arginine methyl ester (l ‐NAME) and 7‐nitroindazole (7‐NI) were both capable of blocking the nicotine‐induced increase of SNc DA neuron activity and DA striatal levels. The effects of nicotine in l ‐NAME and 7‐NI‐pretreated rats were partially restored when rats were pretreated with the NO donor molsidomine. These results further support the evidence of an important role played by NO on modulation of dopaminergic function and drug addiction, thus revealing new pharmacological possibilities in the treatment of nicotine dependence and other DA dysfunctions.     

Smokers deprived of cigarettes for 72 h: effect of nicotine patches on craving and withdrawal

Abstract Rationale. Research on the effects of nicotine abstinence and nicotine replacement has not provided consistent information about the impact of replacement therapies on tobacco withdrawal and craving. Objective. This study investigated craving and withdrawal symptoms over a 72-h period of abstinence from cigarettes. Methods. Twenty-four healthy volunteers, not intending to quit smoking, were housed in an experimental unit during three 72-h conditions, consisting of either free smoking, enforced smoking cessation with nicotine replacement therapy (NRT) patches, or enforced smoking cessation with placebo patches. The conditions were adhered to using a randomized crossover design, each separated by at least 10 days of washout. Patches, administered in a double-blind fashion, were given as nicotine (21 mg/24 h) and placebo every 24 h. Self-reported cigarette craving and withdrawal were assessed using multi-item scales at fixed intervals over each condition period. Urinary and plasma cortisol levels were also assayed at fixed intervals over each period. Results. Craving intensity was significantly lower with free smoke than with placebo and with NRT patches than with placebo. No difference in craving levels was found between those who smoked or those who had NRT patches. Withdrawal symptoms were significantly lower with free smoke than with either placebo or NRT patches, but there was no difference in levels of withdrawal between those on NRT patches and those on placebo. During the placebo and NRT patch periods, craving intensity displayed a circadian rhythm, with craving levels lowest in the morning and peaking in the evening. Nicotine delivered via the patch had no impact on these circadian variations in craving. There was no evidence of systematic temporal variations in craving levels during the free smoking period. Conclusions. The data suggested that craving and withdrawal symptoms may be sustained by different physiological pathways, and that only selected components of cigarette craving are influenced by NRT. Electronic Publication     

Sex differences in the subjective and reinforcing effects of cigarette nicotine dose

RATIONALE: Some research with novel nicotine delivery methods suggests that nicotine itself may be less reinforcing in women than in men. However, sex differences in the reinforcing effects of nicotine dose via cigarette smoking have received little attention. OBJECTIVES: Sex differences in the subjective and reinforcing effects of smoking were examined as a function of two cigarette nicotine "dose" levels (moderate - subjects' preferred brand, > or = 0.7 mg yield; low - Carlton "ultra-light", 0.1 mg yield). METHODS: Male and female smokers ( n = 30) participated in three sessions, the first two involving independent assessment (only one brand available), and the third involving concurrent assessment (both brands available), of subjective ratings (e.g. "liking") and reinforcement for the two cigarette brands. Subjects were blind to the brand of each cigarette, and subjects abstained overnight prior to each session. Reinforcement was determined by responses on a computer task to earn single puffs on the designated cigarette. RESULTS: Subjective ratings differed between the low versus moderate cigarette nicotine dose under both independent and concurrent assessment conditions, as expected. Notably, this dose difference was smaller in women than in men (i.e. significant sex by dose interactions). The dose effect on smoke reinforcement also was smaller in women than men, but only under the independent and not concurrent assessment condition. CONCLUSIONS: These results indicate that cigarette nicotine dose is a less important influence on the subjective and, under some conditions, reinforcing effects of smoking in women than in men.