Heteromeric nicotinic receptors are involved in the sensitization and addictive properties of MDMA in mice

We have investigated the effect of nicotinic receptor ligands in the behavioral sensitization (hyperlocomotion) and rewarding properties (conditioned place preference paradigm, CPP) of 3,4-methylenedioxy-methamphetamine (MDMA) in mice. Each animal received intraperitoneal pretreatment with either saline, dihydro-β-erythroidine (DHβE, 1 mg/kg) or varenicline (VAR, 0.3 mg/kg), 15 min prior to subcutaneous saline or MDMA (5 mg/kg), for 10 consecutive days. On day 1, both DHβE and VAR inhibited the MDMA-induced hyperlocomotion. After 10 days of treatment, MDMA induced a hyperlocomotion that was not reduced (rather enhanced) in antagonist-pretreated animals. This early hyperlocomotion was accompanied by a significant increase in heteromeric nicotinic receptors in cortex that was not blocked by DHβE or VAR. Behavioral sensitization to MDMA was highest 2 weeks after the discontinuation of MDMA treatment. This additional increase in sensitivity was prevented in animals pretreated with DHβE or VAR. At this time, MDMA-treated mice showed a significant increase in heteromeric receptors in cortex that was prevented by DHβE and VAR. An involvement of α7 nicotinic receptors in this effect is ruled out. MDMA (10 mg/kg) induced positive CPP that was abolished by DHβE (2 mg/kg) and VAR (2 mg/kg). Moreover, chronic nicotine pretreatment (2 mg/kg, ip, b.i.d., for 14 days) caused MDMA, administered at a low dose (3 mg/kg), to induce CPP, which would otherwise not occur. Finally, present results point out that heteromeric nicotinic receptors are involved in locomotor sensitization and addictive potential induced by MDMA. Thus, varenicline might be a useful drug to treat both tobacco and MDMA abuse at once

Neuropsychopharmacologic and neurotoxicologic effects of the combination of ethanol with mephedrone in adolescent mice

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/103042In the last decade, a new family of synthetic psychostimulant drugs, under the name of cathinones, broke into the market. These drugs are mainly consumed by adolescents and young adults with recreational purposes, in most cases combined with alcoholic drinks. Although a number of works about new cathinones have been recently published, none explored the consequences of such combination. Because adolescence is a crucial period in brain development, we sought to study the effects of the combination of mephedrone plus ethanol in adolescent mice, focusing on psychostimulant and conditioning effects, as well as on neurotoxicity markers. Ethanol increased both locomotor activity and conditioned place preference (CPP) induced by mephedrone. RNA microarray assays after CPP test yielded significant alterations in neuronal plasticity-related genes and a key role of BDNF and dopamine D3 receptors in CPP acquisition was found. Ethanol potentiated the oxidative stress as well as the decreases in dopaminergic and serotonergic markers in frontal cortex and hippocampus respectively, after a binge treatment with mephedrone. Moreover, the drug combination impaired spatial learning and memory, as well as neurogenesis to a higher extent than mephedrone alone

Protracted treatment with MDMA induces heteromeric nicotinic receptor up-regulation in rat brain: an autoradiography study.

Previous studies indicate that 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) can induce heteromeric nicotinic acetylcholine receptor (nAChR, mainly of α4β2 subtype) up-regulation. In this study we treated Sprague-Dawley rats twice-daily for 10 days with either saline or MDMA (7 mg/kg) and killed them on day 11 to perform [125I]epibatidine binding autoradiograms on serial coronal slices. Results showed significant increases in nAChR density in the substantia nigra, ventral tegmental area, nucleus accumbens, olfactory tubercle, anterior caudate-putamen, somatosensory cortex, motor cortex, auditory cortex, retrosplenial cortex, laterodorsal thalamus nuclei, amygdala, postsubiculum and pontine nuclei. These increases ranged from 3% (retrosplenial cortex) to 30 and 33% (amygdala and substantia nigra). No increased α4 subunit immunoreactivity was found in up-regulated areas compared with saline-treated rats, suggesting a post-translational mechanism as occurs with nicotine. The percentage of up-regulation correlated positively with the density of serotonin transporters, according to the serotonergic profile of MDMA. The heteromeric nAChR increase in concrete areas could account, at least in part, for the reinforcing, sensitizing and psychiatric disorders observed after long-term treatment with MDMA

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry

Background: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients

Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p <.001. Over 24 months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10 ml/min/1.73 m2 decrease), that was most notable in patients with eGFR <30 ml/min/1.73 m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P <.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Contribution to the study of the mechanisms of action and neuropsychopharmacological effects of MDMA and new β-ketoamphetamines

[spa] Las drogas de abuso son una fuente de gran preocupación, dado que su uso se extiende a todos los estamentos sociales, y puede ocasionar graves consecuencias, tanto agudas como a largo término. La presente tesis doctoral estudia los mecanismos que median la acción de los derivados anfetamínicos, y se divide en dos bloques. Bloque 1: MDMA y su interacción con receptores nicotínicos. Previamente, nuestro grupo ha descrito que la metilendioximetanfetamina (MDMA) es un ligando de los receptores nicotínicos de acetilcolina (nAChRs), concretamente los α4β2 y α7. Además, se ha descrito, in vitro, que la exposición a MDMA regula al alza estos subtipos de receptores. Así pues, quisimos estudiar la implicación de dichos receptores en los efectos sensibilizadores y condicionantes de la MDMA; así mismo, determinamos si la regulación al alza ocurre también in vivo. A través de estudios de autoradiografía mapeamos las zonas específicas del cerebro susceptibles a este fenómeno. Finalmente, determinamos la implicación de los nAChRs α4β2 en la sensibilización y condicionamiento a la MDMA. Bloque 2: ß-cetoanfetaminas y su interacción con etanol y otros psicoestimulantes. Recientemente, una nueva familia de derivados anfetamínicos, llamada catinonas sintéticas, ha aparecido en el mercado ilegal. Las catinonas más populares son la mefedrona y la metilendioxipirovalerona (MDPV). Nuestro grupo de investigación ha contribuido a la caracterización de los mecanismos moleculares de estos compuestos, así como a la determinación de sus propiedades farmacocinéticas y potencial neurotóxico. Estos compuestos son usados comúnmente en conjunción con etanol, del cual se sabe que potencia los efectos psicoestimulantes de otras sustancias, tales como la MDMA y la cocaína. Por este motivo, decidimos explorar, a fondo, las consecuencias de la administración simultánea de mefedrona o MDPV y etanol, centrándonos en los efectos sobre la actividad locomotora, condicionamiento, neuroplasticidad y farmacocinética.[eng] Drugs of abuse are a matter of great concern, as their use is widespread in all stratums of society, and can entail both acute and long-term negative consequences. For this reason, our research group is devoted to investigating the mechanisms underlying the action of amphetamine derivatives, as this is a family of drugs that is widely used, especially among adolescents and young adults. The present doctoral thesis is divided into two blocks, each of which focuses on a separate research line, based on different antecedents and with different working hypotheses. Block 1: MDMA and its interaction with nicotinic receptors Previously, our group had described that methylenedioxymethamphetamine (MDMA) is a ligand for two of the main nicotinic acetylcholine receptor (nAChRs) subtypes, namely α4β2 and α7. Furthermore, after exposure to MDMA, receptor density has been found to be increased in PC-12 cells. Given that α4β2 and α7 nAChRs play an important role in reward, movement and memory processes, these findings warranted further research on the in-vivo implications they could entail. For this reason, we sought to study whether α4β2 nAChRs were implicated in the sensitizing and conditioning effects of MDMA. Furthermore, we determined whether α4β2 nAChR up-regulation takes place in-vivo. Through autoradiography studies, we mapped the specific brain areas in which up-regulation takes place, and postulated an underlying mechanism for this process. Finally, we determined the involvement of α4β2 nAChR up-regulation in MDMA-induced sensitization and conditioning. In summary, α4β2 nAChRs were found to be involved in the sensitizing and conditioning properties of MDMA. Furthermore, α4β2 nAChR up-regulation was confirmed in-vivo, a phenomenon that was found to have positive effects on sensitization and conditioning to MDMA. Block 2: β-Ketoamphetamines and their interaction with ethanol and other psychostimulants Recently, a new family of amphetamine derivatives, named synthetic cathinones, has broken into the illegal market, mephedrone and methylenedioxypyrovalerone (MDPV) being the most popular. Our research group has contributed to the characterization of the molecular mechanism of these compounds, as well as their pharmacokinetics and neurotoxic potential. These compounds are commonly used concomitantly with ethanol, which is known to enhance the effects elicited by other psychostimulants, such as MDMA and cocaine. For this reason, we sought to explore, in depth, the consequences of the simultaneous administration of each of these two cathinone derivatives (i.e. mephedrone and MDPV) in combination with ethanol, focusing on the effects on locomotor activity, drug conditioning, neuroplasticity, neurotoxicity, and pharmacokinetics. Furthermore, given that MDPV shares mechanism of action with cocaine, we performed preliminary assays investigating the potential interrelation between these two psychostimulants. In summary, ethanol was found to enhance the psychostimulant and conditioning effects of mephedrone. In this sense, a unique role was found for D3 receptors and BDNF in the mediation of conditioning to mephedrone. Furthermore, the combination with ethanol was also shown to increase the sings of neuronal damage associated to the administration of mephedrone. An opposite effect was revealed for MDPV: ethanol co-administration caused a reduction in locomotor activity and drug conditioning. Finally, MDPV was found to cause sensitization by itself and cross-sensitization with cocaine

Neuropsychopharmacologic and neurotoxicologic effects of the combination of ethanol with mephedrone in adolescent mice

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/103042In the last decade, a new family of synthetic psychostimulant drugs, under the name of cathinones, broke into the market. These drugs are mainly consumed by adolescents and young adults with recreational purposes, in most cases combined with alcoholic drinks. Although a number of works about new cathinones have been recently published, none explored the consequences of such combination. Because adolescence is a crucial period in brain development, we sought to study the effects of the combination of mephedrone plus ethanol in adolescent mice, focusing on psychostimulant and conditioning effects, as well as on neurotoxicity markers. Ethanol increased both locomotor activity and conditioned place preference (CPP) induced by mephedrone. RNA microarray assays after CPP test yielded significant alterations in neuronal plasticity-related genes and a key role of BDNF and dopamine D3 receptors in CPP acquisition was found. Ethanol potentiated the oxidative stress as well as the decreases in dopaminergic and serotonergic markers in frontal cortex and hippocampus respectively, after a binge treatment with mephedrone. Moreover, the drug combination impaired spatial learning and memory, as well as neurogenesis to a higher extent than mephedrone alone

Neuropsychopharmacologic and neurotoxicologic effects of the combination of ethanol with mephedrone in adolescent mice

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/103042In the last decade, a new family of synthetic psychostimulant drugs, under the name of cathinones, broke into the market. These drugs are mainly consumed by adolescents and young adults with recreational purposes, in most cases combined with alcoholic drinks. Although a number of works about new cathinones have been recently published, none explored the consequences of such combination. Because adolescence is a crucial period in brain development, we sought to study the effects of the combination of mephedrone plus ethanol in adolescent mice, focusing on psychostimulant and conditioning effects, as well as on neurotoxicity markers. Ethanol increased both locomotor activity and conditioned place preference (CPP) induced by mephedrone. RNA microarray assays after CPP test yielded significant alterations in neuronal plasticity-related genes and a key role of BDNF and dopamine D3 receptors in CPP acquisition was found. Ethanol potentiated the oxidative stress as well as the decreases in dopaminergic and serotonergic markers in frontal cortex and hippocampus respectively, after a binge treatment with mephedrone. Moreover, the drug combination impaired spatial learning and memory, as well as neurogenesis to a higher extent than mephedrone alone