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

Resumen

[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 ?4?2 y ?7. 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 ?4?2 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 ?4?2 and ?7. Furthermore, after exposure to MDMA, receptor density has been found to be increased in PC-12 cells. Given that ?4?2 and ?7 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 ?4?2 nAChRs were implicated in the sensitizing and conditioning effects of MDMA. Furthermore, we determined whether ?4?2 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 ?4?2 nAChR up-regulation in MDMA-induced sensitization and conditioning. In summary, ?4?2 nAChRs were found to be involved in the sensitizing and conditioning properties of MDMA. Furthermore, ?4?2 nAChR up-regulation was confirmed in-vivo, a phenomenon that was found to have positive effects on sensitization and conditioning to MDMA. Block 2: ?-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.