The role of hypocretin in driving arousal and goal-oriented behaviors.

The hypocretins (Hcrts), also called orexins, are two neuropeptides secreted by a few thousand neurons restricted to the lateral hypothalamus. The Hcrt peptides bind to two receptors located in nuclei associated with diverse cognitive and physiological functions. Experimental evidence has demonstrated that the physiological roles of hypocretins extend far beyond its initial role in food consumption and has emerged as a key system in the fields of sleep disorders and drug addiction. Here, we discuss recent evidence demonstrating a key role of hypocretin in the motivation for reward seeking in general, and drug taking in particular, and we delineate a physiological framework for this peptidergic system in orchestrating the appropriate levels of alertness required for the elaboration and the execution of goal-oriented behaviors. We propose a general role for hypocretins in mediating arousal, especially when an organism must respond to unexpected stressors and environmental challenges, which serve to shape survival behaviors. We also discuss the limit of the current experimental paradigms to address the question of how a system normally involved in the regulation of vigilance states and hyperarousal may promote a pathological state that elicits compulsive craving and relapse to drug seeking.

Cannabis et conduite automobile [Cannabis and automobile driving]

Cannabis use has increased considerably during the last 15 years. One of the major problems dealing with cannabis use is driving under the influence of drugs. With the exception of ethyl alcohol, the majority of the epidemiological studies have shown that cannabis is the most frequently detected substance in people suspected of driving under the influence of drugs. Experimental studies are therefore needed to assess cannabis effects on driving capability. Many studies indicate that cannabis impairs psychomotor performance. This impairment becomes obvious when high doses of cannabis are taken, when ethyl alcohol or other drugs are simultaneously ingested, or when sustained attention is needed. Moreover, cannabis effects are qualitatively different from those observed after ethyl alcohol consumption. In forensic practice, cannabis impairment of driving performance must be related to cannabinoids blood concentrations. To facilitate the interpretation of cannabinoids blood levels, several models were set up recently. These models must be further improved in order to fit in with all circumstances of cannabis use.

Driving under the influence of cocaine or therapeutic administration of cocaine?

Introduction: In forensic toxicology, cocaine is better known for its powerful stimulating effects of nervous system and its high potential for recreational abuse, than for his therapeutic use. However, cocaine is still use as a topical anesthetic and peripheral vasoconstrictor in surgeries of eye, ear, nose and throat. Last decade, an increase of the presence of cocaine and metabolites in blood samples of drivers suspected to drive under the influence of drugs (DUID) was observed in Switzerland (Augsburger et al., Forensic Sci Int 153 (2005) 11-15; Senna et al., Forensic Sci Int 198 (2010) 11-16). Observed blood concentration ranges of cocaine and benzoylecgonine were 10-925 μg/L and 20-5200 μg/L, respectively. Since 2005, zero-tolerance approach was introduced in the Swiss legislation for different substances, especially cocaine (analytical cutoff: 15 μg/L). Thus, the interpretation often amounts to determine if the concentration is situated above or under the limit. However, it is important for the interpretation to take into account the context and to be critical with the obtained results, at the risk of ending in erroneous conclusions. Methods: Systematical toxicological analyses were performed on blood and urine, if available, for 5 DUID cases, as already published (Augsburger et al., Forensic Sci Int 153 (2005)). Positive results were confirmed and drugs were quantified in biological samples by GCMS, GC-MS/MS or LC-MS/MS. Results: Administration of cocaine after traffic accident was identified in five cases. All people were admitted to the emergency room because of severe trauma. Maxillofacial surgery was done shortly after admission to the emergency room, involving use of nasal application of cocaine (swab). For all cases, use of cocaine swab was not mentioned in the document filled by the police and by medical staff requested for blood and urine sampling. The information was obtained retrospectively after consultation of the medical records, without precise indication of the application time or dose. Case 1. A 83-year old man (pedestrian) was hit by a car. Blood (+11h after the accident): cocaine (16 μg/L), benzoylecgonine (370 μg/L). Urine: cocaine (1700 μg/L), benzoylecgonine (560 μg/L). Case 2. A 84-year old woman (pedestrian) was hit by a car. Blood (+1.5h after the accident): cocaine (230 μg/L), benzoylecgonine (370 μg/L). Urine was not available. Hair (+4 months after the accident): segment 1 (0-2 cm), cocaine not detected; segment 2 (2-4 cm), cocaine: <0.5 ng/mg. Case 3. A 66-year old man was involved in a car/car accident. He died 2 hours and 5 minutes after the crash. Blood (+1.5h after the accident): cocaine and metabolites not detected. Blood (+2h after the accident): cocaine (1750 μg/L), benzoylecgonine (460 μg/L). Blood (post-mortem): cocaine (370 μg/L), benzoylecgonine (200 μg/L). Urine (+1.5h after the accident): cocaine not detected. Case 4. A 57-year old woman on a motor scooter was hit by a car. She died 2 hours and 10 minutes after the crash. Blood (+0.5h after the accident): cocaine and metabolites not detected. Urine (post-mortem): cocaine (<20 μg/L), benzoylecgonine (120 μg/L). Case 5. A 30-year old man was involved in a car accident. Blood (+4h after the accident): cocaine (29 μg/L), benzoylecgonine (< 20 μg/L). Urine (+4h after the accident): cocaine and metabolites not detected. Ethanol (1,32 g/kg) and cannabinoids (THC (2,0 μg/L), THCCOOH (38 μg/L)) were also detected in blood. Conclusion: To our knowledge, this is the first description of DUID cases involving therapeutic use of cocaine after an accident. These results indicate that even if a per se law is effective for prosecution case of DUID, a critical interpretation of the results is always needed, especially if a medical intervention occurs after an accident.

Acute Effects of Cannabis Smoking on Skills Related to Driving : an fMRI Study

Introduction : Driving is a complex everyday task requiring mechanisms of perception, attention, learning, memory, decision making and action control, thus indicating that involves numerous and varied brain networks. If many data have been accumulated over time about the effects of alcohol consumption on driving capability, much less is known about the role of other psychoactive substances, such as cannabis (Chang et al.2007, Ramaekers et al, 2006). Indeed, the solicited brain areas during safe driving which could be affected by cannabis exposure have not yet been clearly identified. Our aim is to study these brain regions during a tracking task related to driving skills and to evaluate the modulation due to the tolerance of cannabis effects. Methods : Eight non-smoker control subjects participated to an fMRI experiment based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. Half of the active tracking conditions included randomly presented traffic lights as distractors. Subjects were asked to track with a joystick with their right hand and to press a button with their left index at each appearance of a distractor. Four smoking subjects participated to the same fMRI sessions once before and once after smoking cannabis and a placebo in two independent cross-over experiments. We quantified the performance of the subjects by measuring the precision of the behavioural responses (i.e. percentage of time of correct tracking and reaction times to distractors). Functional MRI data were acquired using on a 3.0T Siemens Trio system equipped with a 32-channel head coil. BOLD signals will be obtained with a gradient-echo EPI sequence (TR=2s, TE=30ms, FoV=216mm, FA=90°, matrix size 72×72, 32 slices, thickness 3mm). Preprocessing, single subject analysis and group statistics were conducted on SPM8b. Results were thresholded at p<0.05 (FWE corrected) and at k>30 for spatial extent. Results : Behavioural results showed a significant impairment in task and cognitive test performance of the subjects after cannabis inhalation when comparing their tracking accuracy either to the controls subjects or to their performances before the inhalation or after the placebo inhalation (p<0.001 corrected). In controls, fMRI BOLD analysis of the active tracking condition compared to the passive one revealed networks of polymodal areas in superior frontal and parietal cortex dealing with attention and visuo-spatial coordination. In accordance to what is known of the visual and sensory motor networks we found activations in V4, frontal eye-field, right middle frontal gyrus, intra-parietal sulcus, temporo-parietal junction, premotor and sensory-motor cortex. The presence of distractors added a significant activation in the precuneus. Preliminary results on cannabis smokers in the acute phase, compared either to themselves before the cannabis inhalation or to control subjects, showed a decreased activation in large portions of the frontal and parietal attention network during the simple tracking task, but greater involvement of precuneus, of the superior part of intraparietal sulcus and middle frontal gyrus bilaterally when distractors were present in the task. Conclusions : Our preliminary results suggest that acute cannabis smoking alters performances and brain activity during active tracking tasks, partly reorganizing the recruitment of brain areas of the attention network.

Perception of damaging effects of smoking, and brief cessation counselling by doctors : a comparison between native Swiss and immigrants

Résumé Une étude prospective ouverte a été menée parmi les patients venant pour la première fois, sans rendez-vous et en urgence, dans une policlinique urbaine (où plus de la moitié des patients sont d'origine étrangère) pour déterminer si les connaissances sur les méfaits du tabac sont identiques chez les immigrés et les Suisses, si le niveau d'intégration influence les connaissances et si les médecins du service donnent des conseils aussi souvent aux fumeurs Suisses qu'aux fumeurs étrangers. 226 fumeurs ont participé à l'étude, 105 Suisses (46.5%) et 121 étrangers (53,5%). 32.2% (95% IC [24.4%; 41.1%]) des migrants et 9.6% [5.3% ; 16.8%] des Suisses ne pouvaient pas mentionner un effet nocif du tabac. Après ajustement pour l'âge, l'analyse multivariée montre que le risque d'ignorer les méfaits du tabac est plus élevé pour les personnes ne maîtrisant pas la langue locale que pour celles la maîtrisant (odds ratio (OR)=7.5 [3.6; 15.8], p<0,001), et est plus élevé pour les hommes que pour les femmes (OR=4.3 [1.9 10.0], p<0.001). Un conseil pour arrêter de fumer a été donné avec une égale fréquence aux immigrants (31.9% [24.2% ; 40.1%]) et aux Suisses (29% [21.0% ; 38.5%]). Les patients ne maîtrisant pas la langue locale n'ont pas reçu moins de conseil que ceux la maîtrisant (0R-1.1 [0.6 ; 2.1], p=0.812). En conclusion, le niveau de connaissances des méfaits du tabac est moins bon chez les hommes immigrés non intégrés ou qui ne maîtrisent pas la langue locale. Un conseil sur l'arrêt du tabac n'est donné qu'à une minorité, mais à égale fréquence à tous les patients du service, quelle que soit leur nationalité. Abstract An open prospective study was conducted among the patients visiting an urban medical policlinic for the first time without an appointment to assess whether the immigrants (who represent more than half of our patients) are aware of the health effects of smoking, whether the level of acculturation influences knowledge, and whether doctors give similar advice to Swiss and foreign smokers. 226 smokers, 105 Swiss (46.5%), and 121 foreign-born (53.5%), participated in the study. 32.2% (95% CI [24.4%; 41.1%]) of migrants and 9.6% [5.3%; 16.8%] of Swiss patients were not aware of negative effects of smoking. After adjustment for age, the multivariate model showed that the estimated odds of "ignorance of health effects of smoking" was higher for people lacking mastery of the local language compared with those mastering it (odds ratio (OR) = 7.5 [3.6; 15.8], p <0.001), and higher for men (OR 4.3 [1.9; 10.0], p <0.001). Advice to stop smoking was given with similar frequency to immigrants (31.9% [24.2%; 40.8%] and Swiss patients (29.0% [21.0%; 38.5%]). Non-integrated patients did not appear to receive less counselling than integrated patients (OR = 1.1 [0.6; 2.1], p 0.812). We conclude that the level of knowledge among male immigrants not integrated or unable to speak the local language is lower than among integrated foreign-born and Swiss patients. Smoking cessation counselling by a doctor was only given to a minority of patients, but such counselling seemed irrespective of nationality.

Aptitude à la conduite, pathologies psychiatriques et psychotropes chez la personne âgée [Driving ability, mental illness and psychotropic medication in the elderly].

Fitness to drive in elderly drivers is most commonly discussed with a focus on cognitive impairment. Therefore, this article is focussing on mental illness and the use of psychotropic drugs in elderly drivers, which can both interfere with fitness to drive. Based on a detailed literature review and on clinical judgement, we propose signposts and "red flags" to judge the individual risks. Health professionals dealing with elderly patients should in particular be aware of the dangers related to cumulative risks and need to inform the patients appropriately. For medico-legal reasons the information provided to patients must be written down in the medical record. Individual counselling is important as fitness to drive is a complex topic.

Participation in a population-based physical activity programme as an aid for smoking cessation: a randomised trial.

OBJECTIVES: Exercise combined with nicotine therapy may help smoking cessation and minimise weight gain after quitting. Low participation in vigorous-intensity physical activity programmes precludes their population-wide applicability. In a randomised controlled trial, we tested whether a population-based moderate-intensity physical activity programme increases quit rates among sedentary smokers receiving nicotine therapy. METHODS: Participants (n=481; 57% male; mean age, 42.2 years (SD 10.1); mean cigarette consumption, 27 (SD 10.2) per day) were offered a nine-week smoking cessation programme consisting of a weekly 15-minute counselling session and the prescription of nicotine replacement therapy. In addition, participants in the physical activity group (n=229) also took part in a programme of moderate-intensity physical activity implemented at the national level, and offering nine weekly 60-minute sessions of physical activity. To ensure equal contact conditions, participants in the control group (n=252) attended weekly 60-minute health behaviour education sessions unrelated to physical activity. The primary outcome was continuous CO-verified smoking abstinence rates at 1-year follow-up. RESULTS: Continuous smoking abstinence rates were high and similar in the physical activity group and the control group at the end of the intervention (47% versus 46%, p=0.81) and at 1-year follow-up (27% versus 29%, p=0.71). The mean weight gain after one year was 4.4 kg and 6.2 kg among sustained quitters of the physical activity and control groups, respectively (p=0.06). CONCLUSION: Participation in a population-based moderate-intensity physical activity programme for 9 weeks in addition to a comprehensive smoking cessation programme did not significantly increase smoking cessation rates. A non-significant reduction in weight gain was observed among participants who quit smoking in the physical activity group. TRIAL REGISTRATION: ClinicalTrials.gov; US National Institutes for Health (available online at http://clinicaltrials.gov/; CLINICAL TRIAL REGISTRATION NUMBER: NCT00521391).

Determinants of smoking and cessation in older women

Résumé Introduction : Le tabagisme est le facteur de risque le plus important dans 7 des 14 premières causes de décès chez les personnes de plus de 65 ans. De nombreuses études ont démontré les bénéfices sur la santé d'un arrêt du tabagisme même à un âge avancé. Malgré cela, peu d'actions préventives sont entreprises dans cette population. Le but de ce travail est d'analyser les caractéristiques du tabagisme et de l'arrêt du tabagisme spécifiquement chez les fumeuses d'âge avancé afin de mieux les aider dans leur désir d'arrêter. Méthode : Nous avons évalué les caractéristiques tabagiques au sein d'une étude prospective de 7'609 femmes vivant en Suisse, âgées de plus de 70 ans et physiquement autonomes (étude Semof s'intéressant à la mesure de l'ostéoporose par ultrason osseux). Un questionnaire sur les habitudes tabagiques a été envoyé aux 486 fumeuses éligibles de la cohorte. Leurs stades de dépendance nicotinique et de motivation ont été évalués à l'aide respectivement des scores «Heavy Smoking Index» et « Prochaska ». Les participantes ayant cessé de fumer pendant le suivi ont été questionnées sur, les motivations, les raisons et les méthodes de leur arrêt. Résultats : 424 femmes ont retourné le questionnaire (taux de réponse de 87%) parmi lesquelles 372 ont répondu de façon complète permettant leur inclusion. L'âge moyen s'élevait à 74,5 ans. La consommation moyenne était de 12 cigarettes par jour, sur une moyenne de 51 ans avec une préférence pour les cigarettes dites « légères » ou « light ». Un peu plus de la moitié des participantes avait une consommation entre 1 et 10 cigarettes par jour et la grande majorité (78%) présentait un score de dépendance faible. Les raisons du tabagisme les plus fréquemment évoquées étaient la relaxation, le plaisir et l'habitude. Les principaux obstacles mentionnés : arrêter à un âge avancé n'a pas de bénéfice, fumer peu ou des cigarettes dites light n'a pas d'impact sur la santé et fumer n'augmente pas le risque d'ostéoporose. Le désir d'arrêter était positivement associé avec un début tardif du tabagisme, une éducation plutôt modeste et la considération que d'arrêter est difficile. Durant le suivi de 3 ans, 57 femmes sur 372 (15%) ont arrêté de-fumer avec succès. Le fait d'être une fumeuse occasionnelle (moins de 1 cigarette par jour) et de considérer que d'arrêter de fumer n'est pas difficile était associés à un meilleur taux d'arrêt du tabagisme. Seuls 11% des femmes ayant stoppé la cigarette signalaient avoir reçu des conseils de leur médecin. Conclusion : ces données illustrent le comportement tabagique spécifique des fumeuses d'âge avancé (consommation et dépendance plutôt faibles) et suggèrent que les interventions médicales pour l'aide à l'arrêt du tabagisme devraient intégrer ces caractéristiques. La volonté d'arrêter est associée à un niveau d'éducation plutôt modeste. Les obstacles les plus fréquemment mentionnés sont basés sur des appréciations erronées de l'impact du tabagisme sur la santé.

Nicotine gum treatment before smoking cessation: a randomized trial.

BACKGROUND: New ways of improving the efficacy of nicotine therapy need to be explored. We tested whether starting nicotine polacrilex gum treatment 4 weeks before the quit date improved smoking abstinence rates compared with starting treatment on the quit date. METHODS: An open randomized trial of 314 daily smokers (mean, 23.7 cigarettes/d) enrolled through the Internet and by physicians in Switzerland from November 2005 to January 2007. In the precessation treatment group, participants received nicotine polacrilex gum (4 mg, unflavored) by mail for 4 weeks before and 8 weeks after their target quit date, and they were instructed to decrease their cigarette consumption by half before quitting. In the usual care group, participants received the same nicotine gum for 8 weeks after their quit date and were instructed to quit abruptly. Instructions were limited to a booklet sent by mail and access to a smoking cessation Web site. Results are expressed as self-reported abstinence rates at the end of treatment and as biochemically verified smoking abstinence (cotinine plus carbon monoxide) after 12 months. RESULTS: Eight weeks after the target quit date, self-reported 4-week abstinence rates were 41.6% in the precessation treatment group and 44.4% in the usual care group (P = .61). One year after the target quit date, biochemically verified 4-week smoking abstinence rates were 20.8% in the precessation treatment group and 19.4% in the usual care group (P = .76). CONCLUSION: Starting nicotine gum treatment 4 weeks before the target quit date was no more effective than starting treatment on the quit date.

Conseit aux fumeurs: mise à jour épidémiologique et clinique [Smoking cessation intervention: 2006 update]

Recent Swiss reports confirmed that several chemical products added to cigarettes may increase the level of dependence and therefore the consumption of cigarettes. Observational studies demonstrated the association between smoking and type II diabetes, that smoking one to four cigarettes daily increases significantly the risk of disease and that the relative risk of breast cancer among non smoking women exposed to passive smoking is increased by 30%. The safety of nicotine replacement therapy for patients with cardiovascular disorders has been confirmed. Among new pharmacological approaches, varenicline, rimonabant, topiramate and nicotine vaccine all appear promising.

Change in physical activity after smoking cessation: the Coronary Artery Risk Development in Young Adults (CARDIA) study.

AIMS: To estimate physical activity trajectories for people who quit smoking, and compare them to what would have been expected had smoking continued. DESIGN, SETTING AND PARTICIPANTS: A total of 5115 participants in the Coronary Artery Risk Development in Young Adults Study (CARDIA) study, a population-based study of African American and European American people recruited at age 18-30 years in 1985/6 and followed over 25 years. MEASUREMENTS: Physical activity was self-reported during clinical examinations at baseline (1985/6) and at years 2, 5, 7, 10, 15, 20 and 25 (2010/11); smoking status was reported each year (at examinations or by telephone, and imputed where missing). We used mixed linear models to estimate trajectories of physical activity under varying smoking conditions, with adjustment for participant characteristics and secular trends. FINDINGS: We found significant interactions by race/sex (P = 0.02 for the interaction with cumulative years of smoking), hence we investigated the subgroups separately. Increasing years of smoking were associated with a decline in physical activity in black and white women and black men [e.g. coefficient for 10 years of smoking: -0.14; 95% confidence interval (CI) = -0.20 to -0.07, P < 0.001 for white women]. An increase in physical activity was associated with years since smoking cessation in white men (coefficient 0.06; 95% CI = 0 to 0.13, P = 0.05). The physical activity trajectory for people who quit diverged progressively towards higher physical activity from the expected trajectory had smoking continued. For example, physical activity was 34% higher (95% CI = 18 to 52%; P < 0.001) for white women 10 years after stopping compared with continuing smoking for those 10 years (P = 0.21 for race/sex differences). CONCLUSIONS: Smokers who quit have progressively higher levels of physical activity in the years after quitting compared with continuing smokers.

Cytochrome P450 1A2 activity and inducibility: impact of smoking, smoking cessation and genetic polymorphisms

Aims: Cytochrome P4501A2 (CYP1A2) is involved in the metabolism of severaldrugs (clozapine, olanzapine, theopylline, caffeine, etc) and is induced by smoking.This can result in decreased plasma levels of drugs metabolized by thisisoenzyme, causing a decrease in therapeutic response. After quitting smoking,increased plasma levels can lead to adverse effects of the concerned drugs, such asconfusion and seizures, described under clozapine treatment. The present studyaimed to examine the variation of CYP1A2 activity in a large group of smokersbefore and after smoking cessation. Moreover, we aimed to determine whethergenetic polymorphisms of CYP1A2 gene could influence the inducibility ofCYP1A2. Methods: CYP1A2 activity was determined by the paraxanthine/caffeineratio in 194 smokers and in 118 of them being abstinent during a 4-weekperiod. Participants were genotyped for CYP1A2*1F (rs762551), *1D(rs35694136) and *1C (rs2069514) polymorphisms. Results: Smokers had higherCYP1A2 activity (1.55-fold; p < 0.0001). Individual change of CYP1A2 activityafter smoking cessation ranged from 1.0-fold (no change) to 7.3-fold decreasedactivity. In five participants with low initial CYP1A2 activity, an increase wasobserved after smoking cessation. During smoking, CYP1A2*1F (p = 0.005), CYP1A2*1D (p = 0.014), the number of cigarettes/day (p = 0.012), contraceptives use(p < 0.001) and - 163A/- 2467T/- 3860G haplotype (p = 0.002) influencedCYP1A2 activity, while after quitting smoking, CYP1A2*1F (p = 0.017) and contraceptives(p = 0.05) did. No influence of CYP1A2 polymorphisms on the inducibilityof CYP1A2 was observed. Conclusion: Higher CYP1A2 activity wasmeasured in smokers, but with a large interindividual variability of its inductionby smoking. Careful clinical management with the help of therapeutic drug monitoringis therefore needed for patients receiving drugs which are metabolized byCYP1A2, who stop or start smoking. Unidentified genetic variations in theCYP1A2 gene and/or in other genes controlling CYP1A2 activity and other environmentalfactors could be responsible of the observed differences in CYP1A2enzymatic activity and inducibility.