Nicotine In Animal Models Research Articles

Chronic exposure to cigarette smoke extract increases nicotine withdrawal symptoms in adult and adolescent male rats.

The aim of the current study was to determine whether non-nicotine constituents of cigarette smoke contribute to nicotine dependence in adolescent and adult male Sprague Dawley rats. For 10days animals were given three times daily intravenous injections of nicotine (1.5mg/kg/day) or cigarette smoke extract (CSE) containing an equivalent dose of nicotine. Both spontaneous and mecamylamine-precipitated withdrawal were then measured. Chronic treatment with CSE induced significantly greater somatic and affective withdrawal signs than nicotine in both adolescents and adults. Mecamylamine-precipitated somatic signs were similar at both ages. In contrast, animals spontaneously withdrawn from chronic drug treatment exhibited significant age differences: whereas adolescents chronically treated with nicotine did not show somatic signs, those treated with CSE showed similar physical withdrawal to those of adults. Mecamylamine did not precipitate anxiety-like behavior at either age. However, both adolescents and adults showed significant anxiety in a light-dark box test 18h after spontaneous withdrawal. Anxiety-like behavior was still evident in an open field test 1month after termination of drug treatment, with adolescents showing significantly greater affective symptoms than adults. Our findings indicate that non-nicotine constituents of cigarette smoke do contribute to dependence in both adolescents and adults and emphasize the importance of including smoke constituents with nicotine in animal models of tobacco dependence.

Neurophysiological mechanisms of tobacco relapse (review)

Morbidity and mortality associated with tobacco use re-main a major public health problem. Unfortunately, mo-dern pharmacotherapy for smoking cessation have limited effectiveness, and most smokers repeatedly stop smoking. The better understanding of the neurobiological and neu-rophysiological mechanisms that contribute to the relapse of smoking is necessary for new drugs for the nicotine ad-diction treatment. The review examined preclinical studies aimed at identifying neurotransmitter and neuromodula-tory systems that provide a relapse of nicotine consump-tion. In preclinical studies, the efficacy of regulating extra-cellular neurotransmitters or neurotransmitter receptor activity using antagonists or receptor agonists (both full and partial) has been demonstrated. In particular, it was shown that a drug that selectively binds to acetylcholine receptors containing three α4- and two β2-subunits reduc-es the search for nicotine in rats. It was shown that new pharmacological approaches to reduce the craving for ni-cotine in animal models can be used in the future to re-duce the risks of relapse of nicotine addiction in smokers.

Nicotinic receptors in chronic kidney disease

Tobacco smoking remains the most important modifiable risk factor for improving overall morbidity and mortality. In addition to being a risk factor for cancer, cardiovascular and lung diseases, strong evidence from human and animal studies has demonstrated that cigarette smoking accelerates the progression of chronic kidney disease (CKD). Clinical studies have shown a strong association between cigarette smoking and worsening CKD in patients with diabetes mellitus, hypertension, polycystic kidney disease, and post kidney transplant. Nicotine, in addition to being responsible for the addictive properties of cigarette smoking, also has other important biological effects on a variety of organs and tissues. In humans, nicotine induces transitory increases in blood pressure accompanied by reductions in glomerular filtration rate and effective renal plasma flow. In animals, nicotine increases the severity of renal injury in subjects with diabetic nephropathy, CKD, and acute kidney injury (AKI). These effects of nicotine on the kidney are linked to increased generation of reactive oxygen species and activation of pro-fibrotic pathways. There are several nicotinic acetylcholine receptor (nAChR) subunits which are expressed in the normal kidney, and the specific blockade of α7-subunit ameliorates the effects of nicotine in animal models with CKD. In summary, the clinical and experimental evidence indicates that nicotine, via the activation of specific nAChRs, is partly responsible for the deleterious effects of cigarette smoking in the progression of CKD. Better understanding of these mechanisms may result in the development of novel strategies to ameliorate the effects of cigarette smoking in CKD.

P-36 - Behavioural and biochemical changes induced by co-administration of mephedrone and nicotine in animal model

Male rats will intravenously self-administer (IVSA) the substituted cathinone stimulants (“bath salts”) mephedrone (4-methylmethcathione) and methylone (3,4-methylenedioxymethcathinone) robustly, whereas the IVSA of 3,4-methylenedioxymethamphetamine (MDMA) is inconsistent in many rat models. There are no data available on the self-administration of these drugs in female rats, thus a study was undertaken to contrast them directly. Groups of female Wistar rats were trained to self-administer mephedrone, methylone or MDMA (0.5 mg/kg/inf) under a Fixed-Ratio (FR) 1 schedule of reinforcement for 14 sessions. Following the acquisition interval, animals were evaluated in FR (0.0, 0.125, 0.25, 0.5, 1.0, 2.5 mg/kg/inf) and PR (0.125, 1.0 mg/kg/inf) dose-substitution procedures. The results show that female rats acquired the self-administration of all three compounds with intakes in mephedrone-trained rats that were significantly higher than that of methylone-trained or MDMA-trained rats. In dose-substitution under either FR or PR contingencies, however, the potencies of all three drugs were similar within the original training groups. The mephedrone-trained animals exhibited higher intakes of all drugs during dose-substitution, indicating lasting consequences of the training drug. Abuse liability of these three compounds is therefore predicted to be similar in established stimulant users but may differ in liability if they are primary drugs of initiation.

Self-Administered Nicotine Suppresses Body Weight Gain Independent of Food Intake in Male Rats.

The action of nicotine to suppress body weight is often cited as a factor impacting smoking initiation and the failure to quit. Despite the weight-suppressant effects of nicotine, smokers and nonsmokers report equal daily caloric intake. The weight-suppressive effects of nicotine in animal models of smoking are poorly understood. Furthermore, the Food and Drug Administration has authority to implement a policy markedly reducing nicotine levels in cigarettes; such a reduction could reduce smoking behavior, but have detrimental effects on body weight. The aim of this investigation was to examine the effects of self-administered nicotine on body weight and food intake in rats. In Experiment 1, rats with ad libitum access to chow responded for intravenous infusions of nicotine (60 µg/kg/infusion) or saline in daily 1-hour sessions; body weight and 24-hour food intake were measured. Experiment 2 tested the effects of subcutaneous injections of nicotine on food intake. In Experiment 3, rats were food restricted and self-administered nicotine across a range of doses (3.75-60 µg/kg/infusion) while body weight was measured. In Experiment 4, rats self-administered 60 µg/kg/infusion nicotine before reduction to one of several doses (1.875-15 µg/kg/infusion) for 50 days. Self-administered nicotine suppressed weight gain independent of food intake. In food restricted rats, self-administered nicotine dose-dependently suppressed body weight gain. In rats self-administering 60 µg/kg/infusion nicotine, dose reduction increased body weight. Self-administered nicotine, even at low doses, suppressed body independent of food intake; this may have important implications for nicotine reduction policy. The results of the present studies demonstrate that self-administered nicotine suppresses body weight independent of food intake in rats. Further, the present studies establish that self-administered nicotine suppresses body weight even at very low doses and that reduction of nicotine dose results in weight gain. These results have important implications for nicotine reduction policy.

Conditioned place preference and self-administration induced by nicotine in adolescent and adult rats.

Nicotine addiction is a worldwide problem. However, previous studies characterizing the rewarding and reinforcing effects of nicotine in animal models have reported inconsistent findings. It was observed that the addictive effects are variable on different factors (e.g. route, dose, and age). Here, we evaluated the rewarding and reinforcing effects of nicotine in different routes of administration, across a wide dose range, and in different age groups. Two of the most widely used animal models of drug addiction were employed: the conditioned place preference (CPP) and self-administration (SA) tests. Nicotine CPP was evaluated in different routes [intraperitoneal (i.p.) and subcutaneous (s.c.)], doses (0.05 to 1.0 mg/kg) and age [adolescent and adult rats]. Similarly, intravenous nicotine SA was assessed in different doses (0.01 to 0.06 mg/kg/infusion) and age (adolescent and adult rats). In the CPP test, s.c. nicotine produced greater response than i.p. The 0.2 mg/kg dose produced highest CPP response in adolescent, while 0.6 mg/kg in adult rats; which were also confirmed in 7 days pretreated rats. In the SA test, adolescent rats readily self-administer 0.03 mg/kg/infusion of nicotine. Doses that produced nicotine CPP and SA induced blood nicotine levels that corresponded well with human smokers. In conclusion, we have demonstrated that nicotine produces reliable CPP [0.2 mg/kg dose (s.c.)] in adolescents and [0.6 mg/kg dose (s.c.)] in adults, and SA [0.03 mg/kg/infusion] in adolescent rats. Both tests indicate that adolescent rats are more sensitive to the rewarding and reinforcing effects of nicotine.

Detection of Genetic Association and a Functional Polymorphism of Dynamin 1 Gene with Nicotine Dependence in European and African Americans

Although it has been documented that dynamin 1 gene (DNM1) is significantly modulated by nicotine in animal models, its association with nicotine dependence (ND) in human population remained to be unexplored. To determine whether DNM1 is associated with ND, in this study, we genotyped seven single-nucleotide polymorphisms (SNPs) within this gene in 602 nuclear families of either African-American (AA) or European-American (EA) origin. Individual SNP-based association analysis revealed a significant association of SNP rs3003609 with Smoking Quantity (SQ; P = 0.0031) and Heaviness of Smoking Index (HSI; P = 0.0042) in the EA sample. Furthermore, our haplotype-based association analyses indicated that haplotypes T-G-T, formed by rs2502731-rs2229917-rs3003609 (at a frequency of 54%), G-T-A, formed by rs2229917-rs3003609-rs16930313 (at a frequency of 52%), and T-A-G, formed by rs3003609-rs16930313-rs7022174 (at a frequency of 52%) are significantly associated with SQ (Z = −2.44~−2.92; P = 0.015~0.0055) and HSI (Z = −2.52~−2.67; P = 0.012~0.0076) in the EA sample. In the AA sample, another haplotype, G-T-A, formed by rs7875406-rs2502731-rs2229917, at a frequency of 12% was significantly associated with SQ (Z = −2.58; P = 0.0098). Finally, by using in vitro gene expression assays, we demonstrated that the T allele of rs3003609 in the exon 9 of DNM1 significantly decreases the expression of dynamin 1, by 27.1% at the mRNA and 22.0% at the protein level, suggesting that rs3003609 represents a functional polymorphism affecting DNM1 expression and may partly contributed to the observed association of the gene with ND in our samples. Taken together, our findings indicate that dynamin 1 is likely involved in the etiology of ND and represents a plausible candidate for further investigation in independent samples.

Current status of immunologic approaches to treating tobacco dependence: Vaccines and nicotine-specific antibodies

In contrast to current pharmacotherapies, immunologic approaches to treating tobacco dependence target the drug itself rather than the brain. This approach involves the use of nicotine-specific antibodies that bind nicotine in serum, resulting in a decrease in nicotine distribution to the brain and an increase in nicotine's elimination half-life. This review summarizes the literature examining the effects of immunologic interventions on the pharmacokinetics and behavioral effects of nicotine in animal models, as well as recent phase I and II clinical trials in humans. Studies using various vaccines and nicotine-specific antibodies in rodents have shown that immunization can significantly reduce the behavioral effects of nicotine that are relevant to tobacco dependence (eg, nicotine self-administration). These findings provide proof of principle that immunologic interventions could have utility in the treatment of tobacco dependence. Thus far, phase I clinical trials of nicotine vaccines have not produced any serious adverse events in humans and have produced dose-dependent increases in serum antibody levels. Although preliminary data from these small trials suggest that vaccination can facilitate abstinence from tobacco use, more advance trials are needed. By acting outside the nervous system, immunologic approaches are less likely to produce the adverse side effects associated with current medications. In addition, the unique mechanism of action of immunotherapy makes it particularly suitable for combination with other pharmacological approaches. Taken together, the work completed to date provides substantial evidence that immunologic interventions could play an important role in future treatment strategies for tobacco dependence.

Nicotinic Receptor Modulation for Neuroprotection and Enhancement of Functional Recovery Following Brain Injury or Disease

Despite the well-known adverse health effects of tobacco smoking, numerous studies have shown that nicotine, the principal pharmacologically active alkaloid in tobacco smoke, exerts neuroprotective properties in several animal models of neurodegeneration. Furthermore, cigarette smoking appears to significantly reduce the risk of developing Parkinson's disease in human subjects. We review the animal and human studies that investigated possible neuroprotective actions of nicotine and other nicotinic receptor agonists and antagonists. We demonstrate that nicotine is not neuroprotective in all animal models of neurodegenerative disease. In fact, C57Bl/6 mice pretreated with nicotine have an increased sensitivity to 3-nitropropionic acid, a neurotoxin used in mice to mimic some aspects of Huntington's disease. The actions of nicotine on dopamine release may explain the variable effects of nicotine in animal models of Parkinson's and Huntington's diseases. Finally, we focus on some future directions for studies that evaluate neuroprotective properties of nicotinic agonists and antagonists.