Thesis (Ph. D.)--University of Glasgow, 1997. / Includes bibliographical references. Print version also available.

Thesis (M.S.)--University of Massachusetts Amherst, 2009. / Includes bibliographical references (p. 47-59).

Not available / text

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.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Includes bibliographical references (p. 112-125).

Ecstasy é o nome popular do 3,4-metilenodioximetanfetamina (MDMA), uma droga de abuso utilizada por adultos jovens. Diversos relatos têm mostrado existência de correlações positivas entre o abuso do Ecstasy e o aparecimento de doenças infecciosas. Muitos estudos em modelos animais mostram que o MDMA induz alterações de imunidade inata e adquirida; entretanto pouco se sabe sobre os mecanismos pelos quais estes efeitos ocorrem. Desta forma, buscamos neste trabalho os mecanismos neuroimunes pelos quais o MDMA diminui a atividade de neutrófilos e altera a distribuição de leucócitos nos diferentes compartimentos imunes. Além disso, avaliamos se os efeitos induzidos pelo MDMA afetam a resposta a uma infecção experimental induzida por Listeria monocytogenes. Nossos resultados mostram que 60 minutos após a administração de MDMA na dose 10mg/kg, houve 1) diminuição do burst oxidativo de neutrófilos induzido por SAPI e PMA e, também, da porcentagem e da intensidade da fagocitose dos neutrófilos sanguíneos; 2) diminuição da celularidade total da medula óssea e aumento da mesma no baço, além de diminuição do peso relativo do baço; 3) aumento na porcentagem de neutrófilos e diminuição na porcentagem de linfócitos sanguíneos; e 4) diminuição da expressão de NFB de neutrófilos sanguíneos. O tratamento com metirapona ou RU-486 prévio ao tratamento com MDMA foi capaz de inibir 5) os efeitos observados em todos os parâmetros avaliados na diminuição da atividade de neutrófilos; 6) as alterações das porcentagens de neutrófilos e linfócitos sanguíneos e 7) a diminuição da expressão de NFB. Observamos, ainda, que o tratamento com 6-OHDA ou ICI-118,551 prévio ao tratamento com MDMA 8) não foram capazes de inibir os efeitos induzidos pelo MDMA na atividade de neutrófilos e na contagem diferencial de leucócitos sanguíneos; no entanto, 9) preveniram as alterações de celularidade induzidas por MDMA na medula óssea e no baço, e 10) a diminuição do peso relativo do baço. Por fim, observamos em um modelo de infecção experimental por LM que o MDMA 11) induziu mielosupressão (diminuição do CFU na medula óssea e aumento no baço); 12) diminuiu o número de leucócitos sanguíneos e a celularidade da medula óssea; 13) aumentou a celularidade do baço; 14) diminuiu a produção de citocinas pró-inflamatórias (IL-12p70, TNF, IFN-, IL-6) e quimiocina (MCP-1) nas primeiras 24 h; e 15) aumentou a produção das mesmas citocinas e quimiocina após 72 h da indução da infecção. Desta forma, concluímos que os efeitos induzidos pelo MDMA sobre a atividade de neutrófilos foram provavelmente mediados pela diminuição da expressão de NFB induzido pela ação da corticosterona e que a corticosterona, também está envolvida com as alterações na contagem diferencial de neutrófilos e linfócitos. As catecolaminas periféricas responderam pelas alterações na distribuição de leucócitos entre baço e medula óssea, e diminuição do peso relativo do baço. Além disso, o MDMA pode ser considerado uma droga imunossupressora visto que diminuiu a resistência a uma infecção por LM por mecanismos neuroimunes / Ecstasy is the popular name of 3,4-metylendioxymetamphetamine (MDMA), a drug of abuse mainly used by young adults. Several reports have shown the existence of a positive correlation between Ecstasy abuse and increased susceptibility to infectious diseases. Some studies using animal models report that MDMA induces alterations in both innate and adaptive immunity, however little is known about the mechanisms that generate such alterations. Therefore, we sought for neuroimmune mechanisms that could be involved in the previously reported decreasing on neutrophil activity and alteration in the leukocyte distribution. Moreover, we analyzed the host resistance to Listeria monocytogenes after MDMA treatment. We show that MDMA (10 mg/kg), 60 min after administration: 1) decreases SAPI and PMA-induced oxidative burst and percentage/intensity of phagocytosis of circulating neutrophils; 2) decreases bone marrow cellularity while increases it in the spleen, and also decreases spleen relative weight; 3) increases neutrophil percentage while decreases lymphocyte percentage in the blood; and 4) decreases NFB expression on circulating neutrophils. Metyrapone or RU-486 prior to MDMA treatment abrogates 5) the MDMA effects previously reported on neutrophil activity; 6) alterations in the percentage of circulating neutrophils and lymphocytes, and 7) decreasing of NFB expression. We also show that 6-OHDA or ICI-118,551 prior to MDMA treatment were not able to 8) abrogated the MDMA effects previously reported on neutrophil activity and blood leukocyte differential counts; nevertheless, 9) they abrogated the previously reported alterations on bone marrow and spleen cellularity, and 10) reduction on spleen relative weight. Finally, in a model of host resistance to Listeria monocytogenes we show that MDMA: 11) induces myelosuppression by decreasing CFU on bone marrow while increasing it on spleen; 12) decreases circulating leukocytes and bone marrow cellularity; 13) increases spleen cellularity; 14) decreases pro-inflammatory cytokines production (IL-12p70, TNF, IFN-, IL-6) and chemokine (MCP-1) after 24h of the infection; and 15) increases the production of the pro-inflammatory cytokines and chemokines previously reported after 72h of the infection. Thus, we conclude that the MDMA effects on neutrophil activity were mediated by the reduction of NFB expression, and this effect was induced by corticosterone elevation in the serum. Corticosterone is also involved in the alterations on neutrophil and lymphocyte counts. Catecholamines were shown to be involved in the alterations on leukocyte distribution in the bone marrow and spleen, and in the reduction of relative weight of spleen. Additionally, MDMA reduced the host resistance to Listeria monocytogenes. Therefore, MDMA can be considered an immunosuppressive drug and those effects are mediated by neuroimmune mechanisms

Ecstasy é o nome popular do 3,4-metilenodioximetanfetamina (MDMA), uma droga de abuso utilizada por adultos jovens. Diversos relatos têm mostrado existência de correlações positivas entre o abuso do Ecstasy e o aparecimento de doenças infecciosas. Muitos estudos em modelos animais mostram que o MDMA induz alterações de imunidade inata e adquirida; entretanto pouco se sabe sobre os mecanismos pelos quais estes efeitos ocorrem. Desta forma, buscamos neste trabalho os mecanismos neuroimunes pelos quais o MDMA diminui a atividade de neutrófilos e altera a distribuição de leucócitos nos diferentes compartimentos imunes. Além disso, avaliamos se os efeitos induzidos pelo MDMA afetam a resposta a uma infecção experimental induzida por Listeria monocytogenes. Nossos resultados mostram que 60 minutos após a administração de MDMA na dose 10mg/kg, houve 1) diminuição do burst oxidativo de neutrófilos induzido por SAPI e PMA e, também, da porcentagem e da intensidade da fagocitose dos neutrófilos sanguíneos; 2) diminuição da celularidade total da medula óssea e aumento da mesma no baço, além de diminuição do peso relativo do baço; 3) aumento na porcentagem de neutrófilos e diminuição na porcentagem de linfócitos sanguíneos; e 4) diminuição da expressão de NFB de neutrófilos sanguíneos. O tratamento com metirapona ou RU-486 prévio ao tratamento com MDMA foi capaz de inibir 5) os efeitos observados em todos os parâmetros avaliados na diminuição da atividade de neutrófilos; 6) as alterações das porcentagens de neutrófilos e linfócitos sanguíneos e 7) a diminuição da expressão de NFB. Observamos, ainda, que o tratamento com 6-OHDA ou ICI-118,551 prévio ao tratamento com MDMA 8) não foram capazes de inibir os efeitos induzidos pelo MDMA na atividade de neutrófilos e na contagem diferencial de leucócitos sanguíneos; no entanto, 9) preveniram as alterações de celularidade induzidas por MDMA na medula óssea e no baço, e 10) a diminuição do peso relativo do baço. Por fim, observamos em um modelo de infecção experimental por LM que o MDMA 11) induziu mielosupressão (diminuição do CFU na medula óssea e aumento no baço); 12) diminuiu o número de leucócitos sanguíneos e a celularidade da medula óssea; 13) aumentou a celularidade do baço; 14) diminuiu a produção de citocinas pró-inflamatórias (IL-12p70, TNF, IFN-, IL-6) e quimiocina (MCP-1) nas primeiras 24 h; e 15) aumentou a produção das mesmas citocinas e quimiocina após 72 h da indução da infecção. Desta forma, concluímos que os efeitos induzidos pelo MDMA sobre a atividade de neutrófilos foram provavelmente mediados pela diminuição da expressão de NFB induzido pela ação da corticosterona e que a corticosterona, também está envolvida com as alterações na contagem diferencial de neutrófilos e linfócitos. As catecolaminas periféricas responderam pelas alterações na distribuição de leucócitos entre baço e medula óssea, e diminuição do peso relativo do baço. Além disso, o MDMA pode ser considerado uma droga imunossupressora visto que diminuiu a resistência a uma infecção por LM por mecanismos neuroimunes / Ecstasy is the popular name of 3,4-metylendioxymetamphetamine (MDMA), a drug of abuse mainly used by young adults. Several reports have shown the existence of a positive correlation between Ecstasy abuse and increased susceptibility to infectious diseases. Some studies using animal models report that MDMA induces alterations in both innate and adaptive immunity, however little is known about the mechanisms that generate such alterations. Therefore, we sought for neuroimmune mechanisms that could be involved in the previously reported decreasing on neutrophil activity and alteration in the leukocyte distribution. Moreover, we analyzed the host resistance to Listeria monocytogenes after MDMA treatment. We show that MDMA (10 mg/kg), 60 min after administration: 1) decreases SAPI and PMA-induced oxidative burst and percentage/intensity of phagocytosis of circulating neutrophils; 2) decreases bone marrow cellularity while increases it in the spleen, and also decreases spleen relative weight; 3) increases neutrophil percentage while decreases lymphocyte percentage in the blood; and 4) decreases NFB expression on circulating neutrophils. Metyrapone or RU-486 prior to MDMA treatment abrogates 5) the MDMA effects previously reported on neutrophil activity; 6) alterations in the percentage of circulating neutrophils and lymphocytes, and 7) decreasing of NFB expression. We also show that 6-OHDA or ICI-118,551 prior to MDMA treatment were not able to 8) abrogated the MDMA effects previously reported on neutrophil activity and blood leukocyte differential counts; nevertheless, 9) they abrogated the previously reported alterations on bone marrow and spleen cellularity, and 10) reduction on spleen relative weight. Finally, in a model of host resistance to Listeria monocytogenes we show that MDMA: 11) induces myelosuppression by decreasing CFU on bone marrow while increasing it on spleen; 12) decreases circulating leukocytes and bone marrow cellularity; 13) increases spleen cellularity; 14) decreases pro-inflammatory cytokines production (IL-12p70, TNF, IFN-, IL-6) and chemokine (MCP-1) after 24h of the infection; and 15) increases the production of the pro-inflammatory cytokines and chemokines previously reported after 72h of the infection. Thus, we conclude that the MDMA effects on neutrophil activity were mediated by the reduction of NFB expression, and this effect was induced by corticosterone elevation in the serum. Corticosterone is also involved in the alterations on neutrophil and lymphocyte counts. Catecholamines were shown to be involved in the alterations on leukocyte distribution in the bone marrow and spleen, and in the reduction of relative weight of spleen. Additionally, MDMA reduced the host resistance to Listeria monocytogenes. Therefore, MDMA can be considered an immunosuppressive drug and those effects are mediated by neuroimmune mechanisms

Methylenedioxymethamphetamine (MDMA) popularly known as "Ecstasy" continues to gain popularity as a recreational drug that has been shown to increase serotonin and dopamine levels. The present study has demonstrated that repeated exposure to MDMA produces long-term damage to serotonergic and dopaminergic neurons in various regions of the rat brain.

Despite decades of research on amphetamine derivatives, a class of compounds sharing a structural foundation with amphetamine, crucial gaps remain in our understanding of these drugs in a variety of animal species and humans. This dissertation addresses three of these gaps through a multi-level approach involving studies in both humans and mice. Specifically, it focuses on investigating the lack of information regarding: 1) repeated dosing of 3,4-methylenedioxymethamphetamine in humans, 2) methamphetamine/alcohol combinations in humans and 3) methamphetamine/oxycodone combinations in mice. Study 1 involved administering three consecutive doses of 3,4 methylenedioxymethamphetamine to human volunteers at 12- and 24-hour intervals while physiological, behavioral, and subjective measures were collected. Study 2 reanalyzed Kirkpatrick and colleagues (2012a) data to evaluate repeated administrations of methamphetamine and alcohol. The reanalysis focused on quantifying the physiological and subjective effect differences between the first and second administrations, which occurred at a 12-hour interval on the same day, an aspect not previously analyzed or reported by the original authors. Study 3 utilized well-established animal models such as Conditioned Place Preference, Open Field Test, and Novel Object Recognition to evaluate the reward-like and aversive effects of methamphetamine and oxycodone combinations in mice. Study 1 was the first to quantify the effects of multiple 3,4-methylenedioxymethamphetamine doses administered over a 36-hour period of time. Initially, acute 3,4-methylenedioxymethamphetamine produced dose-dependent increases in peak heart rate, blood pressure, and more positive than negative subjective effects. However, by the third dose, many of these effects dissipated, heart rate was no longer elevated, and residual mood effects were minor. Overall, the data do not support the general perception that 3,4-methylenedioxymethamphetamine produces dangerous cardiovascular and residual mood effects in humans following repeated administration. The results of Study 2, again a first in the field, discovered that contrary to expectations, heart rate increases produced by the methamphetamine/alcohol combination were not further increased with repeated dosing, but rather attenuated. In fact, methamphetamine offset alcohol-induced intoxication, even after repeated administration. Study 3 revealed that combining methamphetamine and oxycodone in mice increased reward as measured by Conditioned Place Preference, but not more than either drug alone. However, methamphetamine lengthened the duration of Conditioned Place Preference for the lower oxycodone dose and offset the oxycodone-induced disruptions in novel object recognition performance. One crucial cross-species observation was that methamphetamine mitigated adverse effects such as alcohol-related intoxication and oxycodone cognitive disruption, even after repeated administration. While seemingly beneficial, this observation raises concerns that individuals who combine these drugs may be at risk of underestimating their overall degree of impairment, potentially leading to hazardous activities like driving while intoxicated or engaging in risky behaviors. Sharing this insight is crucial to encourage informed, responsible behavior and safeguard public safety. In conclusion, these studies have significantly enhanced our understanding of two frequently used amphetamine derivatives and their interactions with two commonly used psychoactive drugs—oxycodone and alcohol. Most importantly, we strongly advocate for robust empirical experimentation to counteract misinformation related to 3,4-methylenedioxymethamphetamine and methamphetamine. These endeavors are crucial for developing more precise assessments of the risks and benefits associated with these substances, and for improving drug policies and optimizing public health interventions.

La cocaïna i l’èxtasi (MDMA, 3,4-metilendioximetamfetamina) són drogues psicoestimulants que incrementen l’activitat del sistema nerviós central i perifèric amb efectes com l’augment de l’estat d’alerta, la resistència, la productivitat, la motivació, la locomoció, el ritme cardíac i la pressió sanguínia. Ambdues drogues tenen efectes sobre l’estat d’ànim, tot induint sentiments d’eufòria i provocant plaer i recompensa. El seu consum, principalment per part d’adolescents i adults joves, té conseqüències greus per a la salut, i a la llarga el consum reiterat pot esdevenir crònic donant lloc a abús o dependència. Tant la cocaïna com l’MDMA actuen principalment activant els sistemes de neurotransmissió dopaminèrgica i serotoninèrgica en els circuits neuronals de plaer i de recompensa. La genètica juga un paper molt important en la transició del consum a l’abús i a la dependència: d’una banda totes dues drogues indueixen canvis en l’expressió gènica que estan a la base de les neuroadaptacions i del remodelatge dels circuits neuronals que condueixen al consum crònic, i de l’altra hi ha factors genètics de predisposició a la dependència que poden afavorir el desenvolupament d’aquest fenomen en certs individus. El treball que es presenta en aquesta Tesi Doctoral ha permès identificar variacions en el genoma que predisposen a la dependència de cocaïna, així com alteracions en el transcriptoma de cèl•lules neuronals (in vitro) o de determinades estructures cerebrals (in vivo) causades per l’acció de la cocaïna o de l’MDMA. Així, s’ha estudiat la participació de variants genètiques de susceptibilitat a la dependència de cocaïna mitjançant estudis d’associació de tipus cas–control cobrint sistemes gènics sencers implicats en la neurotransmissió dopaminèrgica i serotoninèrgica, en el control de l’alliberament de neurotransmissors i factors neurotròfics i els seus receptors. S’han avaluat un total 446 variants polimòrfiques en 52 gens, seleccionades mitjançant criteris de cobertura genètica. Els resultats més remarcables són la identificació de dos haplotips de risc per la dependència a cocaïna als gens 5-HT1E i NSF (que codifiquen per un receptor de serotonina i per una proteïna implicada l’alliberament de vesícules de neurotransmissor, respectivament). En el cas de l’haplotip de risc del gen NSF, a més predisposa a la dependència ràpida (en dos o menys anys des de l’inici del consum). També s’ha avaluat l’efecte del tractament agut amb cocaïna sobre l’expressió gènica en cèl•lules humanes SH-SY5Y diferenciades a neurones dopaminèrgiques mitjançant microarrays i l’estudi mostra alteracions en la transcripció de gens implicats en la regulació de la transcripció i expressió gènica, moviment cel•lular i adaptacions neuronals. I finalment, s’ha estudiat l’efecte de l’administració activa i passiva d’MDMA sobre la transcripció gènica en quatre estructures cerebrals de ratolí implicades en el fenomen de recompensa. L’estudi de l’efecte directe del MDMA sobre l’expressió gènica mitjançant la comparació de ratolins que reben una solució salina de forma passiva i ratolins que reben MDMA de forma passiva o activa, mostra alteracions en la transcripció de gens implicats principalment en la funció immunitària i en processos inflamatoris a les quatre estructures cerebrals estudiades. La comparació entre el consum actiu i passiu d’MDMA ha permès identificar canvis d’expressió relacionats amb neuroadaptacions i canvis de plasticitat sinàptica a hipocamp i als nuclis dorsals de rafe. En aquesta última regió cal destacar quatre gens que se sobreexpressen com a conseqüència del consum actiu d’MDMA, tots ells implicats en la plasticitat sinàptica, els canvis en la morfologia de les espines dendrítiques i processos neuronals relacionats amb la memòria i l’aprenentatge: Camk2a, Kalrn, Ddn i Egr3. Aquesta troballa reforçaria la idea que aquesta estructura cerebral podria estar involucrada en el comportament de cerca activa d’MDMA, tot recolzant el potencial addictiu d’aquesta droga. / Cocaine and ecstasy (MDMA, 3,4-metilendioximetamfetamina) are psychostimulant drugs that activate the central and peripheral nervous system increasing alertness, energy and motor activity, motivation, cardiac rate and blood preassure. Both drugs have effects on mood, inducing feelings of well-being, euphoria, pleasure and reward. Cocaine and ecstasy use, mainly used by young people, has serious detrimental health effects, and repeated use can become chronic leading to abuse or dependence. Both drugs exert their main psychostimulant effects by activating the dopaminergic and serotoninergic neurotransmission systems in the brain circuits involved in pleasure and reward. Genetics play an important role in the transition from use to abuse and dependence: on one hand, both drugs induce changes in gene expression that are on the basis of neuroadaptations and neuronal circuit remodeling that lead to the chronic use, on the other hand, there are genetic risk factors that predispose to dependency that can drive the development of addiction in some individuals. The work presented in this Doctoral Thesis has allowed to identify genomic variants that predispose to cocaine dependence, as well as gene expression changes in the transcriptome in in vitro and in vivo models. For this purpose, the participation of susceptibility genetic variants to cocaine dependence have been studied using case-control association studies, covering whole gene systems involved in dopaminergic and serotoninergic neurotransmission, in the control of neurotransmitter release, and also encoding neurotrophic factors and their receptors. It has also been evaluated gene expression changes in a human dopaminergic neuronal model after an acute exposure to cocaine. Finally the effect of active and passive MDMA administration on gene expression in mice has been evaluated in four brain structures involved in reward and reinforcing effects of the drug.