Adolescence is a critical developmental period in which the brain emerges from an immature state to adulthood. This process of brain development is associated to greater cognitive capacity but also to altered emotional behaviour, such as anxiety and depressive symptoms; as well as increased sensation-seeking and risk taking behaviour. The proper development of brain and behaviour into adulthood can be negatively affected by external factors such as drug abuse and environmental conditions. This work consists firstly on, studying the impact of binge ethanol, 3, 4-Methylenedioxymethamphetamine (MDMA) and its combination in adolescent mice. Secondly, study the consequences of early-life stressful experiences (social isolation) into adulthood. Main results obtained from the first objective are that the combination of binge ethanol and MDMA induces emotional-like alterations. These alterations can be prevented by antidepressant treatment. In addition, MDMA induces memory impairments that may be associated to oxidative damage to specific proteins in the hippocampus. Neuroinflammation is also present after MDMA treatment, but not after binge ethanol treatment, in mice striatum. Metabolomic studies indicate that brain metabolism is altered after binge ethanol, MDMA or its combination. Even though these are only preliminary results, these alterations might be due to an imbalance in tryptophan metabolism. Regarding the second objective, our findings indicate that social isolation during adolescence induces an altered response to novel and stressful situations. These alterations are probably due to altered HPA axis activity. / L'adolescència és un període crític en el desenvolupament de l’individu en el qual el cervell va d’un estat immadur a l’edat adulta. Aquest procés va acompanyat d’una elevada capacitat cognitiva però també de freqüents alteracions de tipus emocional, com l’ansietat o els símptomes depressius, així com la cerca de sensacions de risc. Un bon desenvolupament del cervell i del comportament es pot veure negativament afectat per factors externs com són l’abús de drogues i les condicions ambientals desfavorables. Aquest projecte consisteix en primer lloc, a estudiar l'impacte de l’alcohol en excés, la 3, 4-Metilendioximetamfetamina (MDMA) i la seva combinació en ratolins adolescents. En segon lloc, estudiar les conseqüències en l’edat adulta d’experiències estressants durant l’adolescència. Els principals resultats obtinguts referents al primer objectiu són que la combinació d'alcohol en excés i MDMA provoca alteracions de tipus emocional. Aquestes alteracions poden ser previngudes pel tractament amb antidepressius. A més, la MDMA indueix un deteriorament de la memòria que pot estar associada amb el dany oxidatiu a proteïnes específiques de l'hipocamp. També s’ha observat una resposta neuroinflamatòria en el cos estriat dels ratolins després del tractament amb MDMA, però no després del tractament amb etanol en excés. Finalment, estudis de metabolòmica indiquen que el metabolisme cerebral es veu alterat després de l’alcohol en excés, la MDMA o la seva combinació. Tot i que només són resultats preliminars, aquestes alteracions poden ser conseqüència d'un desequilibri en el metabolisme del triptòfan. Referent al segon objectiu, els nostres resultats indiquen que l'aïllament social durant l’adolescència indueix una resposta alterada a situacions novelles i estressants. Aquestes respostes anormals són probablement conseqüència d’alteracions en l’activitat de l’eix HPA.

Denna uppsats undersöker ravekulturens nuvarande tillstånd i Stockholm. Ravekulturens primära produkt – den elektroniska musiken (EDM) – som innefattar många olika typer av musikstilar, bland annat techno- och housemusik, har blivit ett allt vanligare inslag inom de reglerade klubb- och festivalverksamheterna. Sedan ravekulturens storhetstid på 1990-talet har rave- och klubbkulturen utvecklats till ett internationellt, om inte globalt, fenomen med demografiska skillnader i förhållande till narkotikabruk, musik- och danstraditioner. Genom Durkheims ritualteori, tillsammans med Collins teori om gruppinteraktion närmas ravekulturen och dess relation till narkotikabruk. Respektive teoretikers begrepp; collective effervescense och emotionell energi, används som verktyg för att erhålla en större förståelse för ravekulturens utveckling och nuvarande läge. För skapa en förståelse av ravekulturens utveckling och nuvarande tillstånd har ett antal nyckelaktörer identifierats, vilka alla besitter stor erfarenhet av ravekulturen. Deras erfarenheter lyfts fram genom semistrukturerade expertintervjuer. Beröringspunkter intervjuerna emellan, samt till teorin har lyfts fram som teman till analysen. Intervjudeltagarna beskriver en ravekultur som i allra högsta grad är levande som har tydliga kopplingar till narkotikabruk, med ecstasy som den primära ravedrogen. Den emotionella energin som skapas på ravens dansgolv lyfts fram som den fundamentala dragningskraft till rave, vilket binder dess deltagare samman genom att etablera ett kollektivt fokus på dansen. Narkotikabruket används som en förstärkare för de gemensamma känslorna, och upprätthåller dansen genom hela nätter. Ravets sociala regler ställs upp för att enskilda deltagare inte ska kunna bryta det kollektiva fokuset genom att ta för stort individuellt utrymme i den sociala sfären. Detta fokus kan också förklara en DJ eller en narkotikalangares särställning inom kulturen eftersom deras roller förstärker fokus genom musiken eller försäljning av narkotika. Det att förklara ravekulturens beståndsdelar utifrån ravets emotionella energi.

The illegal drug ecstasy, chemically known as 3,4-methylenedioxymethamphetamine (MDMA), sometimes contains additional chemicals which can pose health risks to users. This thesis examines strategies that recreational ecstasy users in Victoria, British Columbia utilize to determine the purity of their ecstasy. It also examines why they use these strategies and if they are concerned about impure ecstasy affecting their health because this information can help explain the use of these strategies. I performed a quantitative analysis of data collected by the Centre for Addictions Research of BC’s survey, the Canadian Recreational Drug Use Survey, to determine the strategies participants utilized to minimize potential harms caused by ecstasy use. This analysis revealed that 73.9% of survey participants discussed purity of ecstasy with friends, 33.3% checked drug information websites, 17.4% used an ecstasy testing kit, 2.9% asked harm reduction services for advice, and 0% owned a testing kit. In addition, the data revealed that the participants were more likely to take ecstasy from a friend than a stranger. Next, I developed an interview guide based on these findings and I interviewed 10 female recreational ecstasy users. I chose to interview women only because recreational drug use by women is underrepresented in the drug literature. The most common strategy the women utilized to determine ecstasy purity was to discuss ecstasy with friends. They preferred this strategy because it was a convenient, practical strategy. Also, they perceived their friends to be a trusted source of ecstasy and ecstasy information. Half the women analyzed how they felt after ingesting ecstasy to determine its purity because they believed different chemicals caused different effects. Others assessed the physical characteristics of their ecstasy to try to determine purity because they believed these characteristics could reveal its chemical contents. One participant used an ecstasy testing kit, but the rest cited multiple barriers to their use. Some women also had negative attitudes towards testing kits and felt no social pressure to use them. I asked the participants about their use of ecstasy testing laboratories, but none used this service because they did not know it existed. Overall, none of the women seemed concerned about ecstasy impurity harms. This could be due to four factors. First, their ecstasy use patterns made them feel safe from harms related to ecstasy use. Second, recreational ecstasy use was “normal” amongst young adults in Victoria who attend parties, raves, or clubs. Third, they primarily obtained ecstasy and ecstasy information from trusted friends. Fourth, they had never suffered significant harm caused by ecstasy impurity, even though all of the women believed they had ingested impure ecstasy. / Graduate

Le modèle de sensibilisation comportementale permet d'étudier les changements neuronaux induits par les drogues. Chez les rongeurs, l'activité locomotrice augmente au fur et à mesure des injections et se maintient à long terme. En parallèle à cette sensibilisation, on observe une sensibilisation neurochimique des transmissions noradrénergique (NA) et sérotoninergique (5-HT) jusqu'à un mois après la dernière injection. Cette sensibilisation neurochimique, qui se traduit par des libérations de NA et de 5-HT potentialisées mesurées au niveau du cortex préfrontal, est commune à toutes les drogues et fortement corrélée à la sensibilisation comportementale. Le but de ce travail était d'identifier les mécanismes qui maintiennent à long terme cette hyper-réactivité. Nous avons tout d'abord montré que la réponse locomotrice potentialisée à l'amphétamine se maintient durant le premier mois de sevrage, et décroit de 60% entre 2 et 4 mois. Toutefois les souris restent plus vulnérables à la drogue et ce, même après de longs sevrages. Nous avons également démontré que l'hyper-réactivité des systèmes se maintient à long terme notamment grâce à une désensibilisation fonctionnelle persistante des récepteurs ?2A- adrénergiques et 5-HT1A, responsables du rétrocontrôle inhibiteur des transmissions NA et 5-HT. On observe une diminution de l'expression des protéines G?i couplées à ces récepteurs, dans le locus coeruleus et dans le raphé dorsal, respectivement. La même altération des rétrocontrôles ayant été mesurée chez les animaux sensibilisés au MDMA, les résultats suggèrent que les récepteurs ?2A-adrénergiques et 5-HT1A pourraient être des cibles indirectes des psychostimulants. / The behavioral sensitization model allows the study of the neuronal changes induced by drugs of abuse. In rodents, the locomotor activity increases progressively with the injections of drug, and stays long-lastingly potentiated. Concurrent with this sensitization, a neurochemical sensitization of noradrenergic and serotonergic transmissions is developed until one month after the last injection. This sensitization, quantified through potentiated noradrenergic and serotonergic releases in the prefrontal cortex, was shown to be common to almost all drugs of abuse and highly correlated to behavioral sensitization. The aim of this study was to identify the mechanisms sustaining this hyper-reactivity. We first showed that the potentiated response persists after the first month of withdrawal, and decreases to 40% of the response after 2 to 4 months of withdrawal. However, all mice remain more vulnerable to the drug, even after long (4 months) withdrawals. We also showed that the systems? hyper-reactivity is sustained in the long term by a functional and persistent desensitization of the ?2A-adrenergic and 5-HT1A receptors, responsible for the inhibitory feed-back of noradrenergic and serotonergic transmissions. We observed a decreased expression of G?i proteins coupled receptors in the locus coeruleus and the dorsal raphe.The same feed-back dysfunctions were found in animals sensitized to MDMA, which suggests that ?2A-adrenergic and 5-HT1A receptors are indirect targets of psychostimulant drugs

3,4-methlenedioxymethamphetamine (MDMA), the main constituent of Ecstasy, is a ring-substituted amphetamine commonly abused in recreational users. High doses of MDMA determined by allometric scaling produce serotonin (5-HT) axon deneveration. Studies suggest that this interspecies scaling does not reflect human use. An 'effects' scale comparing similar behavioral and physiological effects between species has been postulated as more accurate for translational studies. Experiment 1 examined the effects of MDMA on serotonergic forebrain innervation using immunohistochemical labeling targeting the serotonin transporter protein (SERT). Experiments 2 and 3 examined low and high doses of MDMA on spatial memory, prefrontal functioning, and serotonergic neurotoxicity using 'effects' scaling. Long Evans rats were given MDMA regimens of: chronic low dose (daily injections of 1.5 mg/kg for 10 days); binge low dose (2 days of 4 x 1.5 mg/kg spaced 2 hours apart), binge high dose (2 x 7.5 mg/kg sp aced 2 hours apart). Acquisition, retention, and spatial reversal (SR) were measured in a water maze task. A 2.0 mg/kg MDMA drug challenge was then given prior to a serial spatial reversal (SSR) task to assess performance while under the effect of the drug. Attentional set shifting and behavioral flexibility were assessed in an intradimensional extradimensionl (IED) task using odor/texture discriminations. MDMA chronic and binge low doses did not impair water maze or IED performance and produced no reductions in SERT expression. MDMA binge high dose resulted in significant reductions of SERT density in the prefrontal cortex, striatum, cortical mantle, hippocampus, amygdala, and many thalamic nuclei. Despite prominent 5-HT denervation, water maze performance was unaffected. Selective impairment in behavioral flexibility on the IED test was found. / This suggests that low doses of MDMA do not produce long-term deleterious effects. But, high doses of MDMA taken in 'binges' produces widespread loss of forebrain SERT fiber innervation and significant impairments in reversal learning, while leaving attentional set shifting and spatial navigation unscathed. / by Stephanie Brooke Linley. / Thesis (Ph.D.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.

En treballs anteriors del nostre grup de recerca es va demostrar que l’antagonista específic del receptor nicotínic α7, metillicaconitina (MLA), inhibia in vitro la producció d’espècies reactives d’oxigen (EROS) i protegia de la neurotoxicitat in vivo induïda per metamfetamina (METH) i per la 3,4-metilendioxi-N-metamfetamina (MDMA). En aquesta tesi, es descriu un nou mecanisme d’acció dels derivats amfetamínics. Mitjançant assajos de fixació de radiolligands, es va comprovar que ambdós derivats amfetamínics competien amb els radiolligands específics dels receptors nicotínics α7 ([3H]Metillicaconitina), i dels heteromèrics ([3H]Epibatidina), el que indicava que en les cèl•lules PC12, el nostre model experimental, i també en una preparació de cervell total de ratolí, aquestes substàncies interaccionaven directament amb els receptors nicotínics. L’MDMA mostrava més afinitat per ambdós subtipus de receptors. Està descrit que el tractament crònic amb nicotina provoca un augment en la densitat de receptors nicotínics tan in vivo com in vitro en cèl•lules PC12. Ambdós derivats amfetamínics van provocar una regulació a l’alça dels dos subtipus de receptors ja a les 6 hores de pretractament. A la vegada, in vivo, l’MDMA i la Nicotina van provocar la regulació a l’alça que va ser potenciada per la seva associació en determinades zones cerebrals on s’expressen cada subtipus de nAChR. De l’estudi dels mecanismes implicats en aquesta regulació a l’alça, mitjançant inhibidors a diferents nivells, es va concluir que, igual com passa amb la nicotina, es produeixen a nivell postraduccional. A nivell funcional, vam determinar que aquests derivats amfetamínics eren capaços d’activar els receptors nicotínics i, d’acord amb les hipòtesis de treballs anteriors, induir una entrada de calci i de sodi que podria estar implicada en els esdeveniments que comportarien la seva neurotoxicitat. Per una banda, l’MDMA i la METH es van comportar com agonistes parcials dels nAChR α7 induïnt un increment de Ca2+ citosòlic. Per altra banda, l’MDMA es va comportar com antagonista dels nAChR heteromèrics i la METH com agonista parcial induint l’entrada de Na+ de la mateixa manera, el qual explicaria diferències a nivell de dependència, ja que els nAChR α4β2 estan implicats en la via mesolímbica o de recompensa. Paral•lelament a l’increment de fixació de radiolligands, es va determinar que la preincubació amb MDMA indueix un increment en la resposta per activació de receptors nicotínics, demostrant que l’ MDMA també indueix regulació a l’alça funcional. Alhora, es va observar que la preincubació de les cèl•lules durant 24 hores amb MDMA dona lloc a un increment perllongat dels nivells basals de Ca2+, el qual indica que l’MDMA inhibeix la desensibilització dels receptors i fa que entri calci durant un temps més llarg. Aquesta entrada persistent podria estar implicada en fenòmens de neurotoxicitat ja que va seguida de l’activació de vies dependents de calci com la calpaïna i la caspasa-3. / During the last years, our emphasis has focused in the study of the neurotoxic effects of MDMA and methamphetamine (METH) on central nervous system and their pharmacological prevention. It has been demonstrated that these amphetamine derivatives produce oxygen species (ROS) in an in vitro model of synaptosomes. In previous works, we demonstrated that blockade of alpha7 nicotinic receptors with methyllycaconitine (MLA) prevented ROS production induced by MDMA and METH, consequently the alpha7 receptor would be involved in the neurotoxicity induced by these drugs. Studies at molecular level, using radioligand binding assays, showed the interaction of METH and MDMA with homomeric alpha7 nAChR and heteromeric subtypes of nicotinic receptors, such as aplha4 beta2. In addition, we investigated the effects of pretreatment with METH and MDMA on nAChR densities. We used PC 12 cells as an experimental model due to the fact other authors have similarly utilised them to evaluate the neurotoxicity of amphetamines. Moreover, they not only express nAChR, including the alpha7 subtype, but also provide an in vitro model for the up-regulation of nAChR, which occurs in vivo following chronic exposure to nicotine. In recent works, we demonstrated in vitro that Ca2+ chelation with EGTA prevented the production of reactive oxygen species (ROS) to a similar extent as nAChR blockade. This indicates that calcium influx, probably through alpha7 nAChR, is a key step in this process. Consequently, one of the objectives of this work was to use a fluorimetric method to investigate the effect of MDMA on Ca2+ and Na+ levels in cultured PC12 cells and the involvement of different nAChR subtypes and other cell pathways related to Ca2+ mobilization. In addition, we used electrophysiology in transfected Xenopus oocytes to corroborate the effects on alpha7 and alpha4 beta2 nAChR. Moreover, pretreatment with MDMA induced functional upregulation by potentiating the effects of specific nAChR agonists or whether it provoked a persistent Ca2+ increase, leading to calpain, caspase 3, NFκB, GSK-3 and Cyt C activation, which was involved in toxicity.

Die Arbeit untersucht verschiedene Möglichkeiten, wie die Substanzgestützte Psychotherapie im deutschen Rechtssystem legalisiert werden kann. Es stellen sich zwei grundlegende Fragen: in welcher juristischen Form soll die Substanzgestützte Psychotherapie geregelt werden und wie detailliert muss eine solche Regelung sein? Zunächst wird die Vorgeschichte der Psychedelika in der Psychiatrie kurz dargestellt. Erörtert wird, warum ihre Wiedereinführung vorteilhaft sein könnte. Die beiden Substanzen Psilocybin und MDMA - die derzeit aussichtsreichsten Kandidaten - werden vorgestellt und der aktuelle Stand der Diskussion umrissen. Es wird aufgezeigt, welche weiteren Probleme, neben der Verschreibbarkeit bisher verbotener Substanzen, auf dem Weg zur Legalisierung gelöst werden müssen: Abgrenzung zu anderen Verfahren, Balance zwischen Patientenschutz/ Standardisierung und Therapiefreiheit, Finanzierung über die gesetzlichen Krankenkassen, Zuständigkeit des Staates versus ärztliche Selbstverwaltung. Anhand von Beispielen aus dem In- und Ausland werden verschiedene Wege der Regelung dargestellt und in ihren Vor- und Nachteilen diskutiert. Unterschieden wird zwischen Varianten einer “kleinen Lösung” mit geringen Eingriffen auf Gesetzesebene und weitgehend untergesetzlicher Normierung und einer “großen Lösung” mit einem neuen Substanzgestützte-Psychotherapie-Gesetz. Für die kleine Lösung werden die Regelungen für verschiedene schon in Gebrauch befindliche Psychopharmaka sowie für die Substitutionstherapie opiatabhängiger Patienten herangezogen. Schließlich wird der Versuch unternommen, aus diesen Untersuchungen den Entwurf eines deutschen Substanzgestützte-Psychotherapie-Gesetzes abzuleiten. Die Argumente für und gegen die unterschiedlichen Möglichkeiten der Normierung werden zusammengeführt und in einen größeren gesellschaftlichen Rahmen gestellt. Die möglichen Vorteile einer großen (gesetzlichen) Lösung gegenüber den verschiedenen kleinen Varianten werden abschließend herausgearbeitet.

No description available.

No description available.

We previously found that intermittent administration of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) to adolescent male rats protected against the behavioral and serotonergic neurotoxic effects of a subsequent MDMA binge. Similar results have been reported for the dopamine (DA) neurotoxin methamphetamine (METH). The present study tested the hypothesis that intermittent adolescent MDMA exposure would protect against the DA neurotoxic effects of a METH binge. Male Sprague-Dawley rats were injected s.c. with MDMA (10 mg/kg x 2; 4-h interdose interval) or saline every fifth day from postnatal day (PD) 35 through PD 60. The animals were then challenged with either a low- or high-dose METH binge (4 or 8 mg/kg x 4; 2- h interdose interval) or saline on PD 67. Activity was measured 1 day after the binge, and regional serotonin transporter (SERT) and dopamine transporter (DAT) expression were analyzed at PD 74 by radioligand binding. All animals treated with METH on the challenge day became hyperthermic, independent of pretreatment conditions. Both MDMA-pretreated and drug-naïve rats also showed a dose-dependent hypoactivity 24 h after the first dose of the METH binge. The SERT binding results indicated that adolescent pretreatment with MDMA provided full or partial protection (depending on the brain region) against the serotonergic deficits produced by METH in previously drug-naïve animals. In contrast, MDMA pretreatment failed to protect against METH-induced decreases in striatal DAT binding. These results suggest that the neuroprotective 2 effects of adolescent MDMA pretreatment are confined to the serotonergic system, possibly reflecting a selective upregulation of antioxidant mechanisms in that system.