Neurobiological substrates involved in the behavioural alterations induced by MDMA and THC administration in mice
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Robledo, Patricia
Maldonado, Rafael
Maldonado, Rafael
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360 p.
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Citation
Viñals Álvarez, X. Neurobiological substrates involved in the behavioural alterations induced by MDMA and THC administration in mice. Universitat Pompeu Fabra; 2015. handle: http://hdl.handle.net/10803/384324
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Doctoral program
Programa de doctorat en Biomedicina
Abstract
El cànnabis i l’èxtasi són dues drogues d’ús recreatiu, les quals usualment es solen consumir de forma conjunta. Degut al seu ús combinat, resulta difícil esclarir les conseqüències que té cada droga a nivell neurobiològic. En aquesta tesi hem investigat els mecanismes neurals involucrats en les respostes conductuals produïdes per l’administració de MDMA (èxtasi) i THC (principi actiu del cànnabis) en models animals. L’administració repetida de MDMA produeix alteracions en la motivació per obtenir menjar apetitós, però és necessària l’administració repetida d’altes dosis que produeixen efectes neurotòxics per produir una manca de flexibilitat cognitiva i dèficits transitoris en la memòria de treball. L’administració de dosis neurotòxiques de MDMA produeix una disminució en els nivells de transportador de dopamina així com un dèficit en l’alliberació d’aquest transmissor. Així doncs, aquests resultats suggereixen que les alteracions en les funcions executives provocades per la MDMA estan associades als canvis observats en la neurotransmissió dopaminèrgica. Per altra banda, mitjançant l’ús de ratolins transgènics als quals els manquen els receptors 2A de serotonina hem revelat que aquests receptors modulen les respostes induïdes pel THC. Aquests animals són menys sensibles als efectes amnèsics, ansiolítics i pro-socials del THC i a més presenten un menor síndrome d’abstinència a aquesta substància. En canvi, l’absència de 5-HT2A no modifica les propietats antinociceptives, hipotèrmiques, hipolocomotores i ansiogèniques del THC, ni tampoc redueix els efectes reforçants de l’agonista cannabinoide WIN 55,212-2. Mitjançant estudis moleculars in vitro i assajos ex vivo hem descobert i caracteritzat els heteromers CB1-5-HT2A, els quals presenten unes propietats de senyalització específiques. Pertorbant la formació dels heteromers mitjançant pèptids específics hem aconseguit abolir els efectes amnèsics del THC, mantenint les seves propietats antinociceptives. Aquesta troballa suggereix la possibilitat d’utilitzar els heteromers CB1-5-HT2A com a diana per dissociar els efectes terapèutics del THC dels efectes indesitjables induïts per la seva administració.
Cannabis and ecstasy are popular recreational drugs that are often consumed together. Hence, the combined use of both drugs makes it difficult to elucidate their selective contribution in the neurobiological alterations observed in this population. We investigated the neural mechanisms underlying the behavioural effects of MDMA (ecstasy) and THC administration separately using animal models. Repeated administration of neurotoxic and non-neurotoxic doses of MDMA induced alterations in the motivation for palatable food, while only neurotoxic doses of MDMA induced durable resistance to extinction and cognitive flexibility, and transient deficits in working memory. A decrease in striatal DAT binding, and lower levels of stimulated dopamine release were observed following repeated neurotoxic doses of MDMA. These findings suggest that MDMA induces alterations in executive functioning that are associated with changes in striatal dopaminergic neurotransmission. In transgenic mice lacking 5-HT2A receptors, we found a decrease in the amnesic, anxiolytic, and pro-social-like effects of THC, as well as the manifestations of THC withdrawal syndrome. In contrast, 5-HT2A receptor deletion did not modulate the acute hypolocomotor, hypothermic, anxiogenic and antinociceptive effects of THC or the reinforcing effects of the cannabinoid agonist, WIN 55,212-2. In vitro molecular assays and ex vivo studies in mouse brain slices revealed the formation of CB1-5-HT2A heteromers with specific signaling properties. The disruption of this heteromer with specific transmembrane interference peptides selectively abrogated the memory impairments caused by THC exposure, but not its antinociceptive properties. These findings suggest that the potential therapeutic properties of cannabinoids can be dissociated from their unfavourable side-effects by targeting the CB1-5-HT2A heteromer.
Cannabis and ecstasy are popular recreational drugs that are often consumed together. Hence, the combined use of both drugs makes it difficult to elucidate their selective contribution in the neurobiological alterations observed in this population. We investigated the neural mechanisms underlying the behavioural effects of MDMA (ecstasy) and THC administration separately using animal models. Repeated administration of neurotoxic and non-neurotoxic doses of MDMA induced alterations in the motivation for palatable food, while only neurotoxic doses of MDMA induced durable resistance to extinction and cognitive flexibility, and transient deficits in working memory. A decrease in striatal DAT binding, and lower levels of stimulated dopamine release were observed following repeated neurotoxic doses of MDMA. These findings suggest that MDMA induces alterations in executive functioning that are associated with changes in striatal dopaminergic neurotransmission. In transgenic mice lacking 5-HT2A receptors, we found a decrease in the amnesic, anxiolytic, and pro-social-like effects of THC, as well as the manifestations of THC withdrawal syndrome. In contrast, 5-HT2A receptor deletion did not modulate the acute hypolocomotor, hypothermic, anxiogenic and antinociceptive effects of THC or the reinforcing effects of the cannabinoid agonist, WIN 55,212-2. In vitro molecular assays and ex vivo studies in mouse brain slices revealed the formation of CB1-5-HT2A heteromers with specific signaling properties. The disruption of this heteromer with specific transmembrane interference peptides selectively abrogated the memory impairments caused by THC exposure, but not its antinociceptive properties. These findings suggest that the potential therapeutic properties of cannabinoids can be dissociated from their unfavourable side-effects by targeting the CB1-5-HT2A heteromer.
Keywords
MDMA, THC, Sistema serotonèrgic, Sistema encocannabinoide, Farmacologia conductual, Serotonergic system, Endocannabinoid system, Behavioural pharmacology
Subjects
616.8 - Neurology. Neuropathology. Nervous system
Publisher
Universitat Pompeu Fabra
