Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice.

Failure in fear extinction is one of the more troublesome characteristics of posttraumatic stress disorder (PTSD). Cotinine facilitates fear memory extinction and reduces depressive-like behavior when administered 24 h after fear conditioning in mice. In this study, it was investigated the behavioral and molecular effects of cotinine, and other antidepressant preparations infused intranasally. Intranasal (IN) cotinine, IN krill oil, IN cotinine plus krill oil, and oral sertraline were evaluated on depressive-like behavior and fear retention and extinction after fear conditioning in C57BL/6 mice. Since calcineurin A has been involved in facilitating fear extinction in rodents, we also investigated changes of calcineurin in the hippocampus, a region key on contextual fear extinction. Short-term treatment with cotinine formulations was superior to krill oil and oral sertraline in reducing depressive-like behavior and fear consolidation and enhancing contextual fear memory extinction in mice. IN krill oil slowed the extinction of fear. IN cotinine preparations increased the levels of calcineurin A in the hippocampus of conditioned mice. In the light of the results, the future investigation of the use of IN cotinine preparations for the extinction of contextual fear memory and treatment of treatment-resistant depression (TRD) in PTSD is discussed.

Is VEGF a Key Target of Cotinine and Other Potential Therapies Against Alzheimer Disease?

BACKGROUND: The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine that promotes neurogenesis and angiogenesis in the brain. In animal models, it has been shown that environmental enrichment and exercise, two non-pharmacological interventions that are beneficial decreasing the progression of Alzheimer disease (AD) and depressive-like behavior, enhance hippocampal VEGF expression and neurogenesis. Furthermore, the stimulation of VEGF expression promotes neurotransmission and synaptic plasticity processes such as neurogenesis. It is thought that these VEGF actions in the brain, may underly its beneficial therapeutic effects against psychiatric and other neurological conditions. CONCLUSION: In this review, evidence linking VEGF deficit with the development of AD as well as the potential role of VEGF signaling as a therapeutic target for cotinine and other interventions in neurodegenerative conditions are discussed.

Effects of Nicotine Metabolites on Nicotine Withdrawal Behaviors in Mice.

INTRODUCTION: Rodent studies suggest that nicotine metabolites and minor tobacco alkaloids such as nornicotine and cotinine may promote cigarette smoking by enhancing nicotine rewarding and reinforcing effects. However, there is little information on the effects of these minor tobacco alkaloids on nicotine withdrawal. The present studies were conducted to determine whether the minor tobacco alkaloids nornicotine and cotinine exhibit nicotine-like behavioral effects in a mouse model of spontaneous nicotine withdrawal. METHODS: Mice were infused with nicotine or saline for 14 days. Experiments were conducted on day 15, 18-24 hours after minipump removal. Ten minutes prior to testing, nicotine-dependent ICR male mice received an acute injection of nicotine (0.05 and 0.5 mg/kg), nornicotine (2.5 and 25 mg/kg), or cotinine (5 and 50 mg/kg) to determine effects on somatic signs, anxiety-like behaviors, and hyperalgesia spontaneous signs of withdrawal. RESULTS: Nicotine and the minor tobacco alkaloid nornicotine, but not cotinine, produced dose-dependent reversal of nicotine withdrawal signs in the mouse. IMPLICATIONS: The minor tobacco alkaloid and nicotine metabolite nornicotine at high doses have nicotinic like effects that may contribute to tobacco consumption and dependence.

Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome.

Cotinine is the major metabolite of nicotine and has displayed some capacity for improving cognition in mouse models following chronic administration. We tested if acute cotinine treatment is capable of improving cognition in the mouse model of Fragile X syndrome, Fmr1-/- knockout mice, and if this is related to inhibition by cotinine treatment of glycogen synthase kinase-3ß (GSK3ß), which is abnormally active in Fmr1-/- mice. Acute cotinine treatment increased the inhibitory serine-phosphorylation of GSK3ß and the activating phosphorylation of AKT, which can mediate serine-phosphorylation of GSK3ß, in both wild-type and Fmr1-/- mouse hippocampus. Acute cotinine treatment improved cognitive functions of Fmr1-/- mice in coordinate and categorical spatial processing, novel object recognition, and temporal ordering. However, cotinine failed to restore impaired cognition in GSK3ß knockin mice, in which a serine9-to-alanine9 mutation blocks the inhibitory serine phosphorylation of GSK3ß, causing GSK3ß to be hyperactive. These results indicate that acute cotinine treatment effectively repairs impairments of these four cognitive tasks in Fmr1-/- mice, and suggest that this cognition-enhancing effect of cotinine is linked to its induction of inhibitory serine-phosphorylation of GSK3. Taken together, these results show that nicotinic receptor agonists can act as cognitive enhancers in a mouse model of Fragile X syndrome and highlight the potential role of inhibiting GSK3ß in mediating the beneficial effects of cotinine on memory.

Post-treatment with cotinine improved memory and decreased depressive-like behavior after chemotherapy in rats.

PURPOSE: Most cancer patients treated with systemic adjuvant chemotherapy endure long-lasting side effects including decrease in concentration, forgetfulness and slower thinking, which are globally termed "chemobrain." Cotinine, the main derivative of nicotine, improved visual and spatial working memory and decreased depressive-like behavior in an animal model of chemotherapy-induced cognitive impairment. METHODS: In this study, we investigated the effect of cotinine on weight gain, locomotor activity, cognitive abilities and depressive-like behavior in rats treated with the chemotherapy mix, cyclophosphamide, methotrexate and 5-fluorouracil. Locomotor activity and depressive-like behavior were assessed using the rotarod and Porsolt's tests, respectively. Changes in cognitive abilities were determined using the novel place recognition test. RESULTS: Female rats treated with cotinine after chemotherapy, recovered weight faster, showed superior cognitive abilities and lower levels of depressive-like behavior than chemotherapy, vehicle-treated rats. CONCLUSIONS: This evidence suggests that treatment with cotinine may facilitate the recovery and diminish the cognitive consequences of chemotherapy.

Neuroinflammation: A Therapeutic Target of Cotinine for the Treatment of Psychiatric Disorders?

Neuroinflammation is a common characteristic of several mental health conditions such as major depression, bipolar disorder, post-traumatic stress disorder (PTSD) and schizophrenia (SCHZ). Inflammatory processes trigger and/or further deteriorate mental functions and are regarded as targets for therapeutic drug development. Cotinine is an alkaloid present in tobacco leaves and the main metabolite of nicotine. Cotinine is safe, non-addictive and has pharmacokinetic properties adequate for therapeutic use. Research has shown that cotinine has antipsychotic, anxiolytic, and antidepressant properties and modulates the serotonergic, cholinergic and dopaminergic systems. Consistent with the modulation of these neurotransmitter systems, cotinine behaves as a positive allosteric modulator of the nicotinic acetylcholine receptors (nAChRs) and has anti-inflammatory effects. The decrease in neuroinflammation induced by the stimulation of the cholinergic system seems to be a key element explaining the beneficial effects of cotinine in a diverse range of neurological and psychiatric conditions. This review discusses new evidence of the role of neuroinflammation as a key aspect in bipolar disorder, PTSD and major depression, as well as the potential use of cotinine to reduce neuroinflammation in those conditions.

Nicotine-Derived Compounds as Therapeutic Tools Against Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is an anxiety disorder that develops after experiencing trauma. Actual therapies do not help majority of patients with PTSD. Moreover, extinguished fear memories usually reappear in the individuals when exposed to trauma cues. New drugs to reduce the impact of conditioned cues in eliciting abnormal fear responses are urgently required. Cotinine, the main metabolite of nicotine, decreased anxiety and depressive-like behavior, and enhanced fear extinction in mouse models of PTSD. Cotinine, considered a positive modulator of the α7 nicotinic acetylcholine receptor (α7nAChR), enhances fear extinction in rodents in a manner dependent on the activity of the αnAChRs. Cotinine stimulates signaling pathways downstream of α7nAChR including the protein kinase B (Akt)/glycogen synthase kinase 3ß (GSK3ß) pathway and the extracellular signal-regulated kinases (ERKs). The stimulation of these factors promotes synaptic plasticity and the extinction of fear. In this review, we discuss the hypothesis that cotinine relieves PTSD symptoms and facilitates fear memory extinction by promoting brain plasticity through the positive modulation of presynaptic nAChRs and its effectors in the brain.

Cotinine reduces depressive-like behavior and hippocampal vascular endothelial growth factor downregulation after forced swim stress in mice.

Cotinine, the predominant metabolite of nicotine, appears to act as an antidepressant. We have previously shown that cotinine reduced immobile postures in Porsolt's forced swim (FS) and tail suspension tests while preserving the synaptic density in the hippocampus as well as prefrontal and entorhinal cortices of mice subjected to chronic restraint stress. In this study, we investigated the effect of daily oral cotinine (5 mg/kg) on depressive-like behavior induced by repeated, FS stress for 6 consecutive days in adult, male C57BL/6J mice. The results support our previous report that cotinine administration reduces depressive-like behavior in mice subjected or not to high salience stress. In addition, cotinine enhanced the expression of the vascular endothelial growth factor (VEGF) in the hippocampus of mice subjected to repetitive FS stress. Altogether, the results suggest that cotinine may be an effective antidepressant positively influencing mood through a mechanism involving the preservation of brain homeostasis and the expression of critical growth factors such as VEGF. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Evaluation of nicotine and cotinine analogs as potential neuroprotective agents for Alzheimer's disease.

The currently available therapies for Alzheimer's disease (AD) and related forms of dementia are limited by modest efficacy, adverse side effects, and the fact that they do not prevent the relentless progression of the illness. The purpose of the studies described here was to investigate the neuroprotective effects of the nicotine metabolite cotinine as well as a small series of cotinine and nicotine analogs (including stereoisomers) and to compare their effects to the four clinically prescribed AD therapies.

[Cotinine--metabolism, application as a biomarker and the effects on the organism]. / Kotynina--metabolizm, zastosowanie jako biomarker i wplyw na organizm czlowieka.

This review presents the current state of knowledge on cotinine, the major metabolite of nicotine. Special attention is paid to the formation of this compound in the organism, its metabolism, application in diagnostic procedures and evaluation of its in vitro and in vivo activities. For many years, cotinine has been used as a biomarker of exposure to tobacco smoke. Currently, this compound is applied in many other studies including the use of cotinine in the treatment of various diseases. Several years ago, Scott et al. patented therapeutic applications of cotinine in chronic and acute inflammation. Cotinine is an interesting compound with a well-known metabolism; therefore there are suggestions for its application in the diagnosis and treatment of certain diseases. 

Cost-effectiveness of an intensive smoking cessation intervention for COPD outpatients.

INTRODUCTION: To determine the cost-effectiveness of a high-intensity smoking cessation program (SmokeStop Therapy; SST) versus a medium-intensity treatment (Minimal Intervention Strategy for Lung patients [LMIS]) for chronic obstructive pulmonary disease outpatients. METHODS: The cost-effectiveness analysis was based on a randomized controlled trial investigating the effectiveness of the SST compared with the LMIS with 12-month follow-up. The primary outcome measure was the cotinine-validated continuous abstinence rate based on intention to treat. A health care perspective was adopted, with outcomes assessed in terms of (incremental) additional quitters gained, exacerbations prevented, and hospital days prevented. Health care resource use, associated with smoking cessation, was collected at baseline and 12 months after the start of the interventions. Monte Carlo simulations were performed to evaluate the robustness of the results. RESULTS: The average patient receiving SST generated €581 in health care costs, including the costs of the smoking cessation program, versus €595 in the LMIS. The SST is also associated with a lower average number of exacerbations (0.38 vs. 0.60) and hospital days (0.39 vs. 1) per patient and a higher number of quitters (20 vs. 9) at lower total costs. This leads to a dominance of the SST compared with the LMIS. CONCLUSIONS: The high-intensive SST is more cost-effective than the medium-intensive LMIS after 1 year. This is associated with cost savings per additional quitter, prevented exacerbations, and hospital days at lower or equal costs.

Cotinine, a neuroactive metabolite of nicotine: potential for treating disorders of impaired cognition.

The pharmacological effects of the tobacco-derived alkaloid nicotine have been widely studied in humans and animals for decades. However, relatively little attention has been given to the potential actions of its major metabolite, cotinine. After nicotine consumption the duration of cotinine's presence in blood and brain greatly exceeds that of nicotine. Therefore, cotinine could mediate the more protracted pharmacological effects of nicotine. The studies described in this report were thus designed to further investigate certain neuropharmacological actions of cotinine. Behavioral tests (e.g., delayed matching-to-sample) were conducted in aged rhesus monkeys to assess the effects of cotinine on working memory and attention. In rats a prepulse inhibition (PPI) procedure was used to assess the effects of the compound on auditory gating - a method for predicting the potential antipsychotic properties of drugs. Cotinine exhibited significant effectiveness in these tasks. The drug was also cytoprotective in differentiated PC-12 cells with a potency equivalent to that of nicotine. The effects of chronic cotinine treatment on the expression of nicotinic and muscarinic acetylcholine receptors in rat brain were measured by [125I]epibatidine, [125I]alpha-bungarotoxin ([125I]BTX), [3H]pirenzepine ([3H]PRZ), and [3H]AFDX-384 ([3H]AFX) autoradiography. Unlike nicotine, cotinine failed to upregulate the expression of brain nicotinic receptors. Based on its relative safety in man, cotinine should prove useful in the treatment of diseases of impaired cognition and behavior without exhibiting the toxicity usually attributed to nicotine.

Individualizing nicotine replacement therapy for the treatment of tobacco dependence: a randomized trial.

BACKGROUND: Despite the well-documented efficacy and different pharmacokinetic and pharmacodynamic properties of different forms of nicotine replacement therapy, empirical data are insufficient to guide practitioners in selecting a particular form of treatment for individual patients with tobacco dependence. OBJECTIVE: To evaluate the comparative efficacy of transdermal nicotine and nicotine nasal spray and identify predictors of treatment outcome. DESIGN: Randomized, open-label clinical trial with a 6-month follow-up period. SETTING: 2 university-based smoking cessation research programs. PARTICIPANTS: 299 treatment-seeking smokers who were followed for 6 months after the target quit date. INTERVENTION: Behavioral group counseling and 8 weeks of therapy with nicotine nasal spray or transdermal nicotine. MEASUREMENTS: Demographic characteristics, smoking history, depression symptoms, and body mass index were measured at baseline. Smoking practices were biochemically verified at the end of treatment and at 6 months after the target quit date. RESULTS: Abstinence rates for the transdermal nicotine and nicotine nasal spray groups were not significantly different at 6-month follow-up (15.0% vs. 12.2%, respectively; P > 0.2). Interactions in abstinence rates for subgroups of smokers were statistically significant (P < 0.05). Smokers who had low to moderate dependence levels, were not obese, and were white achieved higher abstinence rates with transdermal nicotine, whereas smokers who were highly dependent, obese, or members of minority groups achieved higher abstinence rates with nasal spray. LIMITATIONS: The subgroup findings need confirmation in additional large studies before they are routinely applied. CONCLUSIONS: Ethnicity, weight, and level of nicotine dependence may help identify smokers who have greater or lesser abstinence rates with either transdermal or nasal spray nicotine.

Effects of cotinine on cigarette self-administration.

Previous studies have shown that cotinine, a metabolite of nicotine, antagonizes some of the effects of nicotine. One study showed that cotinine eliminates the beneficial effects of the nicotine patch in reducing cigarette withdrawal symptoms. The purpose of this study was to examine the effects of various doses of cotinine on cigarette self-administration. Subjects were randomly assigned to one of three doses of cotinine fumarate (40, 80 and 160 mg) and placebo, each for a period of 10 days, in a randomized order. Outcome variables included measures of nicotine intake and subjective responses to smoked cigarettes. Results showed no differences in the number of cigarettes smoked, carbon monoxide levels, and weights of cigarette butts across the various doses of cotinine and placebo. However, higher nicotine serum levels were observed in the 160 mg cotinine fumarate condition compared to placebo and to 40 mg cotinine fumarate. No systematic effects of cotinine on subjective responses to cigarettes were observed. Cotinine appears potentially to have a selective modulatory effect on nicotine withdrawal symptoms but not on cigarette smoking.

Cotinine: effects with and without nicotine.

The purpose of this study was to examine the effects of the metabolite of nicotine, cotinine, in comparison to the effects of the nicotine patch, and a combination thereof during cigarette abstinence. More specifically, this study examined the effects of cotinine on physiological measures, subjective measures assessing craving, withdrawal symptoms and mood, and performance measures. A between-subject, 2 x 2 factorial design was used, with the daily administration of a 15-mg nicotine patch (Nicotrol) versus placebo patch as one factor and 80 mg of oral cotinine fumarate versus placebo drug as the other factor. Baseline measures were obtained while the subjects smoked cigarettes on an ad lib basis for 1 week. Subjects (n = 106) were then randomly assigned to one of four treatment conditions and for the next 14 days were required to be abstinent from cigarettes and take the study drugs. Cotinine administration, with or without nicotine patch, produced serum cotinine concentrations 3 4 times higher than during ad lib smoking. Results showed a reduction of self-reported tobacco withdrawal symptoms using the nicotine patch alone. Cotinine alone had no effect on withdrawal symptoms. However, when nicotine patch was combined with cotinine, the beneficial effect of the nicotine patch on withdrawal symptoms was absent. Therefore, cotinine appears to antagonize the effects of nicotine in the alleviation of withdrawal symptoms at concentrations higher than that attained from normal smoking. This effect does not appear to be mediated by changes in nicotine disposition.

Aiding reduction of smoking with nicotine replacement medications: hope for the recalcitrant smoker?

OBJECTIVE: To assess the effect of the various nicotine replacement therapies (NRT) on smoking reduction. DESIGN: During an initial sampling week, the subjects familiarised themselves with nicotine gum, patch, nasal spray, vaporiser (vapour inhaler) and sublingual tablet. A crossover design was used during the next four study weeks; during two of these weeks the subjects could select one nicotine replacement product of their choice to use, whereas during the other two they were randomly assigned a product to use. SUBJECTS: 143 men and women smoking an average of 22.6 (SD 7.0) cigarettes per day and exhibiting a Fagerström Tolerance Questionnaire (FTQ) score of 7.0 (SD 1.9). INTERVENTIONS: Subjects were asked to use as much NRT as they wished, yet to smoke enough to feel comfortable. MAIN OUTCOME MEASURES: Self-reported cigarette consumption, exhaled carbon monoxide (CO), withdrawal symptom score, cotinine plasma levels and motivation to quit were monitored over a period of five weeks. RESULTS: Self-reported smoking declined steadily over the five weeks, from 22.6 (SD 7.0) to 10.4 (SD 1.0) (P<0.001) cigarettes daily (54% decrease), with the biggest drop (37%) during the first product-sampling week. Smoking reduction was greater on average during the weeks when the subjects could choose their nicotine product than when products were assigned. CO readings decreased from 22.7 (SD 8.5) to 14.8 (SD 8.4) ppm (P<0.001) confirming a reduction in smoking (35% decrease), although cotinine levels remained steady, suggesting that subjects were titrating nicotine to their original levels. Withdrawal scores decreased over time (32% decrease, P<0.001), showing that there was no discomfort associated with the smoking reduction, and motivation to quit was enhanced by the treatment in most subjects (93%). CONCLUSIONS: NRT for aiding smoking reduction appeared to be safe, was associated with a clinically significant reduction in smoke exposure over a five-week follow up, and increased motivation to stop smoking. A smoking reduction procedure may help the very recalcitrant smoker gain confidence and increase the control over his/her smoking behaviour. More controlled research is needed to follow up these promising results.