Study of the interaction between 3,4 methylenedioximethamphetamine and the endocannabinoid system
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Valverde Granados, Olga
Maldonado, Rafael
Maldonado, Rafael
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Touriño Raposo, C. Study of the interaction between 3,4 methylenedioximethamphetamine and the endocannabinoid system. Universitat Pompeu Fabra; 2009. handle: http://hdl.handle.net/10803/7154
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Programa de doctorat en Biomedicina
Abstract
La 3,4-metilendioximetamfetamina (MDMA, èxtasi) i el cannabis són dues drogues les quals es consumeixen conjuntament de manera habitual. Malgrat que tots dos compostos presenten propietats reforçant i potencial addictiu, també tenen propietats farmacològiques oposades. La MDMA es una droga psicoestimulant, la qual causa hiperlocomoció, hipertèrmia, resposted de tipus asiogènic i neurotoxicitat. Per altra banda el Δ9-tetrahydrocannabinol (THC), principal compost psicoactiu del cannabis, posseeix efectes relaxants, hipolocomotors, hipotèrmics i neuroprotectors. Els efectes de la MDMA i el THC al sistema nerviós central es troben mediats per dos mecanismes notablement diferents. La MDMA augmenta els nivells extracel·lulars de dopamina i serotonina, mentre que el THC produeix l'activació del receptor cannabinoide CB1. Cal destacar a més que les interaccions entre els sistemes monoaminèrgic i endocannabinoide s'observa de manera freqüent en l'organisme.<br/>En el present estudi hem explorat la implicació del sistema endocannabinoide i la MDMA en diversos aspectes. Per una banda el receptor cannabinoide CB1 juga un important paper en els efectes hiperlocomotors i hipertèrmics, i en les respostes de tipus ansiogènic produïdes per la MDMA. Curiosament, encara que el receptor CB1 no participa en els efectes recompensants primaris de la MDMA, és imprescindible per que tinguin lloc els seus efectes reforçants. Així mateix, l'alliberació de serotonina per part de la MDMA redueix de manera dosi-depenent la simptomatologia física causada pel síndrome d'abstinència a cannabinoides precipitada per un antagonista del receptor CB1. Finalment, el tractament amb THC era capaç de prevenir la hipertèrmia, activació glial, estrès oxidatiu i pèrdua de terminals causada per la MDMA. Com a conseqüència el THC exerceix un efecte neuroprotector contra la neurotoxicitat induïda per la MDMA.
3,4-methylenedioximethamphetamine (MDMA, ecstasy) and cannabis are two drugs frequently consumed in combination. Despite both compounds have rewarding properties and abuse liability, they show opposite pharmacological properties. On the one hand, MDMA is a psychostimulant drug with hyperlocomotor, hyperthermic, anxiogenic-like and neurotoxic effects. On the other hand, Δ9-tetrahydrocannabinol (THC), the main psychoactive compound of cannabis, has relaxant, hypolocomotor, hypothermic and neuroprotective properties. The effects of MDMA and THC in the central nervous system are mediated by two different mechanisms. MDMA enhances the extracellular levels of dopamine and serotonin, whereas THC activates the CB1 cannabinoid receptor. Likewise, interactions between the monoaminergic and the endogenous cannabinoid system have been frequently observed.<br/>In the current study, we explored the involvement of CB1 cannabinoid receptor on the hyperlocomotor, hyperthermic, anxiogenic-like, rewarding and reinforcing effects of MDMA. We also studied the effect of acute and chronic administration of MDMA on rimonabant-precipitated THC withdrawal syndrome. Furthermore, we explored the neuroprotective effects of THC on MDMA-induced neurotoxicity.<br/>As a result of this study we may conclude that endocannabinoid system and MDMA interact in a wide variety of aspects. CB1 receptor plays an important role on the hyperlocomotor, hyperthermic, and anxiogenic-like effects of MDMA. Interestingly, CB1 receptor is essential for the reinforcing but not the primary rewarding properties of MDMA. In addition, the release of serotonin by MDMA dose-dependently reduced the severity of THC withdrawal syndrome triggered by a CB1 antagonist. Finally, pretreatment with THC prevented the hyperthermia, glial activation, oxidative stress and terminal loss caused by MDMA. Consequently, THC exerts a neuroprotective effect against MDMA-induced neurotoxicity.
3,4-methylenedioximethamphetamine (MDMA, ecstasy) and cannabis are two drugs frequently consumed in combination. Despite both compounds have rewarding properties and abuse liability, they show opposite pharmacological properties. On the one hand, MDMA is a psychostimulant drug with hyperlocomotor, hyperthermic, anxiogenic-like and neurotoxic effects. On the other hand, Δ9-tetrahydrocannabinol (THC), the main psychoactive compound of cannabis, has relaxant, hypolocomotor, hypothermic and neuroprotective properties. The effects of MDMA and THC in the central nervous system are mediated by two different mechanisms. MDMA enhances the extracellular levels of dopamine and serotonin, whereas THC activates the CB1 cannabinoid receptor. Likewise, interactions between the monoaminergic and the endogenous cannabinoid system have been frequently observed.<br/>In the current study, we explored the involvement of CB1 cannabinoid receptor on the hyperlocomotor, hyperthermic, anxiogenic-like, rewarding and reinforcing effects of MDMA. We also studied the effect of acute and chronic administration of MDMA on rimonabant-precipitated THC withdrawal syndrome. Furthermore, we explored the neuroprotective effects of THC on MDMA-induced neurotoxicity.<br/>As a result of this study we may conclude that endocannabinoid system and MDMA interact in a wide variety of aspects. CB1 receptor plays an important role on the hyperlocomotor, hyperthermic, and anxiogenic-like effects of MDMA. Interestingly, CB1 receptor is essential for the reinforcing but not the primary rewarding properties of MDMA. In addition, the release of serotonin by MDMA dose-dependently reduced the severity of THC withdrawal syndrome triggered by a CB1 antagonist. Finally, pretreatment with THC prevented the hyperthermia, glial activation, oxidative stress and terminal loss caused by MDMA. Consequently, THC exerts a neuroprotective effect against MDMA-induced neurotoxicity.
Keywords
tremolor, transportador de dopamina, tirosina hidroxilasa, THC, temperatura corporal, sintasa d'òxid nítric, síndrome d'abstinència, serotonina, rotarod, rimonabant, reforç, recompensa, receptor cannabinoide, Ptosis, proteïna glial fibrilar acídica, preferència de plaça condicionada, piloerecció, pèrdua de terminals, nucli accumbens, neuroprotecció, neurotoxicitat, microglia, microdialisis, MDMA, masticació, laberint en creu elevat, infusió, inflamació, immunohistoquímica, hipotèrmia, hipolocomoció, hipertèrmia, hiperlocomoció, glutamat, èxtasi, estriat, dopamina, diarrea, dependència, DAT, dany neuronal, coordinació motora, CD11b, CB2, CB1, autoadministració, atàxia, astròcits, anxiolític, anxiogènic, ansietat, activitat locomotora, abstinència, 4-metilendioximetamfetamina, 3, Δ9-tetrahydrocannabinol, western blot, Δ9-tetrahydrocannabinol, 3, 4-methylenedioximethamphetamine, abstinence, anxiety, anxiogenic, anxiolytic, astrocytes, ataxia, body temperature
Subjects
615 - Pharmacology. Therapeutics. Toxicology. Radiology
616.8 - Neurology. Neuropathology. Nervous system
616.8 - Neurology. Neuropathology. Nervous system
Publisher
Universitat Pompeu Fabra
