El modulador alostérico negativo de los mGluR5, MPEP, potencia la reinstauración de la preferencia condicionada inducida con priming de cocaína

• Autores: Carmen Manzanedo, Ana Mateos García, José Miñarro López, María Carmen Arenas Fenollar
• Localización: Adicciones: Revista de socidrogalcohol, ISSN 0214-4840, Vol. 32, Nº. 3, 2020, págs. 193-201
• Idioma: español
• DOI: 10.20882/adicciones.1348
• Títulos paralelos:
  • The negative allosteric modulator of mGluR5, MPEP, potentiates the rewarding properties of cocaine in priming-induced reinstatement of CPP
• Enlaces
  • Texto completo
• Resumen
  • español

    La adicción a la cocaína es un trastorno crónico con un alto índice de recaídas; por tanto, es prioritario entender los mecanismos neurales implicados en la búsqueda de la droga durante la recaída para desarrollar farmacoterapias eficaces. El receptor metabotrópico 5 del glutamato (mGluR5) parece estar implicado en la reinstauración inducida por las claves asociadas a la cocaína. El objetivo principal de este estudio fue profundizar en el papel del receptor mGluR5 en la recaída en el consumo de cocaína, evaluando el efecto del MPEP, un modulador alostérico negativo del mGluR5, sobre la reinstauración inducida por un priming de cocaína en el paradigma del condicionamiento de la preferencia de lugar (CPL). Ratones OF1 (48 machos y 48 hembras) fueron condicionados en el paradigma del CPL con cocaína (20 mg/kg) y expuestos a un programa de extinción. Cuando la extinción de la preferencia condicionada fue confirmada, se evaluó la eficacia del MPEP (30 mg/kg) para bloquear las sucesivas reinstauraciones mediante priming de cocaína en el CPL.

    La administración contingente de MPEP con la cocaína en el CPL incrementó la conducta de búsqueda de la droga y el número de reinstauraciones. Además, la administración solo de MPEP produjo reinstauración cruzada en el CPL inducido por cocaína. Por tanto, el MPEP no solo no previno, sino que incrementó las reinstauraciones de la preferencia condicionada inducida por priming de cocaína.

    Estos resultados pueden ayudar a entender el papel del mGluR5 en la recaída al consumo de cocaína.

  • English

    Cocaine addiction is a chronic disorder with high relapse rates;

    therefore, understanding the neuronal mechanisms underlying drug-seeking during relapse is a priority to develop targeted pharmacotherapy. The metabotropic glutamate receptor 5 (mGluR5) seems to be involved in the reinstatement induced by cocaineassociated cues. The main objective of the study was to evaluate the efficacy of MPEP, a negative allosteric modulator of mGluR5, in attenuating or potentiating the reinstatement induced by priming doses of cocaine in the CPP paradigm, ultimately to further knowledge regarding the role of the mGluR5 in relapse into cocaine abuse. OF1 mice (48 female and 48 male) were conditioned in the CPP paradigm with cocaine (20 mg/kg) and were exposed to an extinction program.

    We evaluated the efficacy of MPEP (30 mg/kg) in blocking the successive cocaine-priming reinstatements in the CPP when extinction of the conditioning preference was confirmed. MPEP did not block the reinstatement of priming cocaine-induced CPP, but increased the potential of cocaine for reinstating conditioning preference. The contingent administration of MPEP with cocaine increased the drugseeking behaviour and the number of reinstatements with priming doses of cocaine. Moreover, MPEP produced cross reinstatement of cocaine-induced CPP. Rather than preventing the reinstatements of conditioned preference induced by priming doses of cocaine, MPEP increased them. These findings may help to understand the role of mGluR5 in the relapse into cocaine abuse

• Referencias bibliográficas
  • Aguilar, M.A., Rodríguez-Arias, M. y Miñarro, J. (2009). Neurobiological mechanisms of the reinstatement of drug-conditioned place preference....
  • Backstrom, P. y Hyytia, P. (2006). Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking. Neuropsychopharmacology,...
  • Backstrom, P. y Hyytia, P. (2007). Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement...
  • Backstrom, P., Bachteler, D., Koch, S., Hyytia, P. y Spanagel, R. (2004). mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior....
  • Bespalov, A. Y., Dravolina, O. A., Sukhanov, I., Zakharova, E., Blokhina, E., Zvartau, E., … Markou, A. (2005). Metabotropic glutamate receptor...
  • Blanco-Gandía, M. C., Aguilar, M. A., Miñarro, J. y Rodríguez-Arias, M. (2018). Reinstatement of Drug-seeking in Mice Using the Conditioned...
  • Bobzean, S. A., Dennis, T. S., Addison, B. D. y Perrotti, L. I. (2010). Influence of sex on reinstatement of cocaine-conditioned place preference....
  • Bobzean, S. A., Dennis, T. S. y Perrotti, L. I. (2014). Acute estradiol treatment affects the expression of cocaine-induced conditioned place...
  • Bracci, A., Daza-Losada, M., Aguilar, M., De Feo, V., Miñarro, J. y Rodríguez-Arias, M. (2013). A methanol extract of brugmansia arborea affects...
  • Brown, R. M., Mustafa, S., Ayoub, M. A., Dodd, P. R., Pfleger, K. D. y Lawrence, A. J. (2012). mGlu5 receptor functional interactions and...
  • Carroll, M. E. y Lynch, W. J. (2016). How to study sex differences in addiction using animal models. Addiction Biology, 21, 1007-1029. doi:10.1111/adb.12400.
  • Chau, P., Soderpalm, B. y Ericson, M. (2011). The mGluR5 antagonist MPEP elevates accumbal dopamine and glycine levels; interaction with strychnine-sensitive...
  • Cleva, R. M. y Olive, M. F. (2012). mGlu receptors and drug addiction. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling,...
  • EMCDDA. (2016). European Drug Report 2016: Trends and Developments. ISBN: 978-92-9168-890-6.
  • Gasparini, F., Lingenhöhl, K., Stoehr, N., Flor, P. J., Heinrich, M., Vranesic, I, … Kuhn, R. (1999). 2-Methyl-6-(phenylethynyl)-pyridine...
  • Georgiou, P., Zanos, P., Ehteramyan, M., Hourani, S., Kitchen, I., Maldonado, R. y Bailey, A. (2015). Differential regulation of mGlu5 R and...
  • Herzig, V., Capuani, E. M., Kovar, K. A. y Schmidt, W. J. (2005). Effects of MPEP on expression of food, MDMA- or amphetamine-conditioned...
  • Homayoun, H., Stefani, M. R., Adams, B. W., Tamagan, G. D. y Moghaddam, B. (2004). Functional interaction between NMDA and mGLU5 receptors:...
  • Hilderbrand, E. R. y Lasek, A. W. (2014). Sex differences in cocaine conditioned place preference in C57BL/6J mice. Neuroreport, 25, 105-109....
  • Keck, T. M., Zou, M. F., Bi, G. H., Zhang, H. Y., Wang, X. F., Yang, H. J., … Newman, A. H. (2014). A novel mGluR5 antagonist, MFZ 10-7, inhibits...
  • Kumaresan, V., Yuan, M., Yee, J., Famous, K. R., Anderson, S. M., Schmidt, H. D. y Pierce, R. C. (2009). Metabotropic glutamate receptor 5...
  • Lee, B., Platt, D. M., Rowlett, J. K., Adewale, A. S. y Spealman, R. D. (2005). Attenuation of behavioral effects of cocaine by the Metabotropic...
  • Li, X., Peng, X. Q., Jordan, C. J., Li, J., Bi, G. H., He, Y., … Xi, Z. X. (2018). mGluR5 antagonism inhibits cocaine reinforcement and relapse...
  • Manzanedo, C., Aguilar, M. A., Rodríguez-Arias, M. y Miñarro, J. (2001a). Conditioned place preference paradigm could be a model of relapse...
  • Manzanedo, C., Aguilar, M. A., Rodríguez-Arias, M. y Miñarro, J. (2001b). Effects of dopamine with different blockade profiles on morphine-induced...
  • Manzanedo, C., Aguilar, M. A., Miñarro, J. y Rodríguez-Arias, M. (2011). Effects of CNQX and MPEP on sensitization to the rewarding effects...
  • Mateos-García, A., Manzanedo, C., Rodríguez-Arias, M., Aguilar, M. A., Reig-Sanchis, E., Navarro-Francés, C. I., … Arenas, M. C. (2015). Sex...
  • McReynolds, J. R., Peña, D. F., Blacktop J. M. y Mantsch J. R. (2014). Neurobiological mechanisms underlying relapse to cocaine use: contributions...
  • Mihov, Y. y Hasler, G. (2016). Negative allosteric modulators of metabotropic glutamate receptors subtype 5 in addiction: a therapeutic window....
  • Olive, M. F. (2009). Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Current Drug Abuse Reviews, 2, 83-98....
  • Pomierny-Chamiolo, L., Miszkiel, J., Frankowska, M., Bystrowska, B. y Filip M. (2017). Cocaine self-administration, extinction training and...
  • Pomierny-Chamioło, L., Rup, K., Pomierny, B., Niedzielska, E., Kalivas, P. W. y Filip, M. (2014). Metabotropic glutamatergic receptors and...
  • Popik, P. y Wrobel, M. (2002). Morphine conditioned reward is inhibited by MPEP, the mGluR5 antagonist. Neuropharmacology, 43, 1210-1217....
  • Rodríguez-Arias, M., Castillo, A., Daza-Losada, M., Aguilar, M. A. y Miñarro, J. (2009). Effects of extended cocaine conditioning in the reinstatement...
  • Rutten, K., Van der Kam, E. L., De Vry, J., Bruckmann,W. y Tzschentke, T. M. (2011). The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine...
  • Sanchis-Segura, C. y Spanagel, R. (2006). Behavioural assessment of drug reinforcement and addictive features in rodents: an overview. Addiction...
  • Schmidt, H. D. y Pierce, R. C. (2010). Cocaine-induced neuroadaptations in glutamate transmission: potential therapeutic targets for craving...
  • Schmidt, H. D., Kimmey, B. A., Arreola, A. C. y Pierce, R. C. (2015). Group I metabotropic glutamate receptor-mediated activation of PKC gamma...
  • Titomanlio, F., Manzanedo, C., Rodríguez-Arias, M., Mattioli, L., Perfumi, M., Miñarro, J. y Aguilar, M. A. (2013). Rhodiola rosea impairs...
  • Tzschentke, T. M. (2007). Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addiction Biology,...
  • Van der Kam, E. L., De Vry, J. y Tzschentke, T. M. (2009a). 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates ketamine and heroin reward...
  • Van der Kam, E. L., De Vry, J. y Tzschentke, T. M. (2009b). The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) supports...