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RUOLO DEI RECETTORI NICOTINICI CENTRALI NELL'ADDICTION' E NELLA 'DEPENDENCE' DA NICOTINA: POTENZIALE STRATEGIA FARMACOLOGICA DI NUOVI AGONISTI NICOTINICI PARZIALI
No full textRationale 1: Cigarette smoking is one of the most serious health problems worldwide and people trying to stop smoking have high rates of relapse. Nicotine is the main psychoactive ingredient in cigarettes and its binding to neuronal nicotinic acetylcholine receptors (nAChRs) located in the mesolimbic areas induces reward (Picciotto and Kenney, 2013).
Current first-line pharmacotherapies aiming at encouraging people to stop smoking include nicotine replacement therapy, bupropion hydrochloride and varenicline tartrate. The atypical antidepressant bupropion reduces the severity of nicotine craving during withdrawal, but its long-term beneficial effects on relapse are not clear (Hughes et al., 2007). Cytisine-related varenicline tartrate is a partial agonist of α4β2 and α6β2 nAChR subtypes and a full agonist of α7 and α3β4 nAChRs. Clinical trials indicate that varenicline is effective in decreasing relapse to smoking in humans (Cahill et al., 2011; Gonzales et al., 2006; Joreby et al., 2006; Tonstad et al., 2006; Zierler-Brown and Kyle, 2007) but adverse cardiovascular effects and/or neuropsychiatric events have recently been reported including depression, suicidal ideation, suicide attempts and completed suicide (Freedman, 2007; Moore et al., 2011; Singh et al., 2011).
Aim 1: In search for new drugs that act on nicotine-induced dopamine release, firstly we tested the ability of new nicotinic partial agonists derivated from cytisine, 1,2-bis(cytisin-12-ul)ethane (CC4) and 1,4-bis(cytisin-12-yl)-2-butyne (CC26), compared to nicotine, cytisine and varenicline, to reduce nicotine-induced Conditioned Place Preference (CPP) in zebrafish, a promising animal model for rapidly screening new compounds to induce smoking cessation.
Results 1: Our results demonstrated that CC4, CC26, cytisine and varenicline induced per se CPP with an inverted U-shaped dose-response curve similar to that of nicotine. However, when co-administered with the maximally effective dose of nicotine, they blocked its reinforcing effect. Since very little is known about the pharmacology of the native nicotinic subtypes expressed in zebrafish, we used binding and pharmacological experiments to identify the native nicotinic receptors in adult zebrafish brain by means of subtypes-selective antagonists. The results demonstrated that zebrafish brain expresses two distinct classes of nicotinic receptors: one containing the α7 subunit that binds [125I]-αbungarotoxin with high affinity and another that binds [3H]-epibatidine. We used also three antagonists α-conotoxin MII, methyllycaconitine (MLA) and dihydro-β-erythroidine (DhβE), selective respectively for α6β2, α7 and β2. Mecamilamine, a non selective antagonist, DhβE and MLA blocked the nicotine rewarding effect, demonstrating that nicotine exerted its addictive properties acting on α7 and β2 nAChRs.
Since the results obtained in zebrafish looked promising, CC4 was also tested on rats, to verify if in this animal model it was effective in reducing nicotine rewarding effect. Our results demonstrated that CC4, like cytisine and nicotine, induced CPP and is ICV self-administered with an inverted-U dose response curve. Both models (CPP and ICV self-administration) showed that CC4 is per se slighty reinforcing, although to a lesser extent than nicotine. Moreover, in line with the fact that CC4 is a partial agonist, pre-treatment with non-reinforcing doses of CC4 significantly antagonized the rewarding effects induced by nicotine, both in CPP and in self administration task, without affecting motor functions. These findings indicate that this compound has a selective effect in reducing nicotine addiction-associated behaviours.
Conclusions 1: Our results, obtained in zebrafish and in rats, demonstrated the possible development of CC4 or its derivatives as a new medication specific to tobacco smoking cessation with fewer side effects due to its lack of action on β4 nAChR subtypes.
Rationale 2: In humans, however, the addiction is not just due to nicotine, but at least also to a complex of 4000 substances that constitute cigarette smoke. Recently electronic-cigarette (e-cigarette) has been introduced into the market with the purpose of mimic nicotine inhalation through traditional cigarette, whithout the negative effects of tobacco combustion. However, under now there are no long-term studies about the use of e-cigarette effects. In addition, the way in which nicotine is administered to experimental animals is very different from that used by humans: they do not mimic the route of administration used in the latter case, they are invasive and do not allow to study the effects of cigarette smoke compared to e-cigarette vapour (Cohen and George 2013).
Aim 2: Thus, another aim of our study was to validate a rodent smoking model (tobacco smoke or e-cigarette vapour) and investigate the behavioural and biochemical changes after 7 weeks exposure. Male Balb/C mice were exposed to a mechanical ventilator delivering the smoke of 7 traditional cigarettes (cig) or e-cigarette vapour (e-cig) containing 5.6 mg of nicotine for three 30-minutes session/day for seven weeks. One hour after the last session, a group of animals was sacrified for biochemical assays and another group underwent mecamylamine precipitated or spontaneous withdrawal for behavioural analysis.
Results 2: Mice submitted to cig or e-cig showed an increase in α4β2 nicotinic receptor subtypes in cerebral cortex, nucleus accumbens and hippocampus. To quantify the amount of nicotine intake and its metabolism, after 1, 4 and 7 weeks of exposure the urinary cotinine levels (the main nicotine metabolite) were quantified: Chronic intermittent exposure to cig or e-cig induces a similar increase of urinary cotinine concentrations (in a range of 700 ng/ml). During cig smoke or e-cig vapour exposure we monitored body weight and food intake: mice exposed to cig showed a significant progressive reduction across the weeks accompanied by a decrease in food intake while only a mild decrease in these parameters was shown in e-cig group. At the end of the exposure, we measured nicotine and cotinine levels in the brain of exposure animals: mice exposed to cig showed an increase in cotinine level, in contrast, mice exposed to e-cig showed an increase in cerebral nicotine level. To verify that our exposure method produces nicotine dependence we precipitated withdrawal syndrome with mecamylamine (1 mg/kg, s.c.), a non selective antagonist: mice submitted to cig or e-cig showed a significant increase in withdrawal-precipitated symptoms. However e-cig group showed a less severe withdrawal syndrome. There was also a reduction of motor function only in cig exposed mice probably due to the presence of severe signs. Finally we monitored spontaneous withdrawal syndrome from 24 hours to 90 days after the end of exposure. In comparison with the control group, both groups exposed to cig or e-cig showed impaired spatial memory (evaluated using the spatial object recognition task) and a progressive increase in anxiety-like behavior (evaluated using elevated plus maze test and marble burying test) starting from 24 hour to at least 90 days after spontaneous withdrawal. Finally, after 60 days e-cig animals and after 90 days cig group, showed a depressive-like behaviour, measured with Tail Suspension test and Sucrose Preference test.
Conclusions 2: In conclusion, we propose an innovative procedure for investigating the short- and long- term alterations induced by exposure to tobacco smoke and, for the first time, we describe the short- and long- term effects of e-cig. Finally, this rodent model is also most suitable for testing new compounds for smoking cessation, such as CC4, whose effectiveness has already been tested on zebrafish and rats.
Future: We propose to investigate the effect of CC4 on nicotine dependence in both cig and e-cig exposed animals.
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3. Cahill K, Stead LF, Lancaster T; “Nicotine receptor partial agonists for smoking cessation” The Cochrane database of systematic reviews CD006103, 2011
4. Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, Watsky EJ, Gong J, Williams KE, Reeves KR; “Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial” JAMA: the journal of the American Medical Association 296: 47-55, 2006
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Abuse potential of methylenedioxymethamphetamine (MDMA) and its derivatives in zebrafish: role of serotonin 5HT2-type receptors
No full textRationale: The synthetic phenethylamines are recreational drugs known to produce psychostimulant effects. However, their abuse potential has not been widely studied. Objectives: Here, we investigated the rewarding and the hallucinatory effects of 2,5-dimetoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA) in comparison with the classical 3,4-methylenedioxymethamphetamine (MDMA). In addition, the role of serotonin 5-HT2-like receptor on the abovementioned effects was evaluated. Methods: Zebrafish were intramuscularly (i.m.) treated with a wide range of doses of DOB (0.1–20 mg/kg), PMA (0.0005–2 mg/kg), or MDMA (0.5–160 mg/kg). Animals were submitted to a conditioned place preference (CPP) task, to investigation of the rewarding properties, and to the evaluation of hallucinatory behavior in terms of appearance of a trance-like behavior. The serotonin 5-HT2 subtype receptor antagonist ritanserin (0.025–2.5 mg/kg) in association with the maximal effective dose of MDMA, DOB, and PMA was given i.m., and the effect on CPP or hallucinatory behavior was evaluated. Results: MDMA and its derivatives exhibited CPP in a biphasic fashion, being PMA the most potent. This effect was accompanied, for DOB (2 mg/kg) and PMA (0.1 mg/kg), by a trance-like hallucinatory behavior. MDMA at a high dose as 160 mg/kg did not induce any hallucinatory behavior. Ritanserin significantly blocked the rewarding and hallucinatory effects suggesting the involvement of serotonin 5HT2 subtype receptor. Conclusion: Collectively, these findings demonstrate for the first time that the rewarding properties of DOB and PMA are accompanied by hallucinatory behavior through a serotonergic system and reinforce zebrafish as an emerging experimental model for screening new hallucinogens
Zebrafish: an animal model to study nicotinic drugs on spatial memory and visual attention
No full textNeuronal nicotinic acetylcholine receptors (nAChRs) are involved in learning and memory in both humans and animals. For their physical characteristics, including small size, easiness to grow, and robustness of the species, zebrafish (Danio rerio) is rapidly becoming a popular model in bio-behavioral studies. Zebrafish are also easy to manipulate for researchers who are not practical users of traditional animal models. Here we describe two cognitive tasks which are sensitive to nicotinic drugs in a similar manner as rodents. Spatial memory is studied using a T-maze apparatus, where animals choose between two arms one of which contains a reservoir that offers a favorable habitat. Each fish receives two training trials at an interval of 24 h. The difference between the running time taken to reach the reservoir (and stay for at least 20 s) obtained during the first and the second trial is a measure of memory of the spatial location of reward. Visual attention is studied using a virtual object recognition test (VORT) where two geometrical 2D virtual shapes are presented stationary on two iPod screens. Shape recognition is scored in terms of exploration time whenever the zebrafish approach to the iPod area and direct their heads towards the shapes. To elucidate the involvement of nicotinic subtype receptors on memory, different selective nAChRs compounds (agonists and antagonists) are given through intraperitoneal (i.p.) route. All the compounds are tested also on swimming behavior to ascertain their possible interference with motor function. Here, we propose zebrafish as a useful tool to rapidly screen new nicotinic compounds active on cognitive disorders
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Different attentional abilities among inbred mice strains using Virtual Object Recognition task (VORT): SNAP25+/- mice as a model of attentional deficit
No full textVariations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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