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

Carmen Manzanedo, Ana Mateos-García, José Miñarro, M. Carmen Arenas

Resumen


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.

 

Palabras clave


MPEP; Cocaína; CPL; Reinstauración; mGluR5.

Texto completo:

PDF PDF (English)

Referencias


Aguilar, M.A., Rodríguez-Arias, M. y Miñarro, J. (2009). Neurobiological mechanisms of the reinstatement of drug-conditioned place preference. Brain Research Review, 59, 253-277. doi:10.1016/j.brainresrev.2008.08.002.

Backstrom, P. y Hyytia, P. (2006). Ionotropic and metabotropic glutamate receptor antagonism attenuates cue-induced cocaine seeking. Neuropsychopharmacology, 31, 778-786. doi:10.1038/sj.npp.1300845.

Backstrom, P. y Hyytia, P. (2007). Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl), 192, 571-580. doi:10.1007/s00213-007-0753-8.

Backstrom, P., Bachteler, D., Koch, S., Hyytia, P. y Spanagel, R. (2004). mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology, 29, 921-928. doi:10.1038/sj.npp.1300381.

Bespalov, A. Y., Dravolina, O. A., Sukhanov, I., Zakharova, E., Blokhina, E., Zvartau, E., … Markou, A. (2005). Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats. Neuropharmacology, 49, Suppl 1, 167-178. doi:10.1016/j.neuropharm.2005.06.007.

Blanco-Gandía, M. C., Aguilar, M. A., Miñarro, J. y Rodríguez-Arias, M. (2018). Reinstatement of Drug-seeking in Mice Using the Conditioned Place Preference Paradigm. Journal of Visualized Experiments: JoVE, 136, 56983. doi: 10.3791/56983.

Bobzean, S. A., Dennis, T. S., Addison, B. D. y Perrotti, L. I. (2010). Influence of sex on reinstatement of cocaine-conditioned place preference. Brain Research Bulletin, 83, 331-336. doi:10.1016/j.brainresbull.2010.09.003.

Bobzean, S. A., Dennis, T. S. y Perrotti, L. I. (2014). Acute estradiol treatment affects the expression of cocaine-induced conditioned place preference in ovariectomized female rats. Brain Research Bulletin, 103, 49-53. doi:10.1016/j.brainresbull.2014.02.002.

Bracci, A., Daza-Losada, M., Aguilar, M., De Feo, V., Miñarro, J. y Rodríguez-Arias, M. (2013). A methanol extract of brugmansia arborea affects the reinforcing and motor effects of morphine and cocaine in mice. Evidence-Based Complementary and Alternative Medicine, 482976. doi:10.1155/2013/482976.

Brown, R. M., Mustafa, S., Ayoub, M. A., Dodd, P. R., Pfleger, K. D. y Lawrence, A. J. (2012). mGlu5 receptor functional interactions and addiction. Frontiers in Pharmacology, 3, 84, 1-9. doi:10.3389/fphar.2012.00084.

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 glycine receptors. Addiction Biology, 16, 591-599. doi:10.1111/j.1369-1600.2011.00343.x.

Cleva, R. M. y Olive, M. F. (2012). mGlu receptors and drug addiction. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling, 1, 281-295.

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 (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology, 38, 1493-1503. doi:10.1016/S0028-3908(99)00082-9.

Georgiou, P., Zanos, P., Ehteramyan, M., Hourani, S., Kitchen, I., Maldonado, R. y Bailey, A. (2015). Differential regulation of mGlu5 R and ΜOPr by priming- and cue-induced reinstatement of cocaine-seeking behaviour in mice. Addiction Biology, 20, 902-912. doi:10.1111/adb.12208.

Herzig, V., Capuani, E. M., Kovar, K. A. y Schmidt, W. J. (2005). Effects of MPEP on expression of food, MDMA- or amphetamine-conditioned place preference in rats. Addiction Biology, 10, 243-249. doi: 10.1080/13556210500223272

Homayoun, H., Stefani, M. R., Adams, B. W., Tamagan, G. D. y Moghaddam, B. (2004). Functional interaction between NMDA and mGLU5 receptors: Effects on working memory, instrumental learning, motor behaviors, and dopamine release. Neuropsychopharmacology, 29, 1259-1269. doi:10.1038/sj.npp.1300417.

Hilderbrand, E. R. y Lasek, A. W. (2014). Sex differences in cocaine conditioned place preference in C57BL/6J mice. Neuroreport, 25, 105-109. doi:10.1097/WNR.0000000000000053.

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 cocaine-taking and cocaine-seeking behavior in rats. Addiction Biology, 19, 195-209. doi:10.1111/adb.12086.

Kumaresan, V., Yuan, M., Yee, J., Famous, K. R., Anderson, S. M., Schmidt, H. D. y Pierce, R. C. (2009). Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking. Behavioral Brain Research, 202, 238-244. doi:10.1016/j.bbr.2009.03.039.

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 Glutamate Receptor 5 Antagonist 2-Methyl-6-(phenylethynyl)-pyridine in squirrel monkeys: comparison with dizocilpine. Journal of Pharmacology and Experimental Therapeutics, 312, 1232-1240. doi:10.1124/jpet.104.078733

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 by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism. ScIeNTIfIc Reports, 8, 3686. doi:10.1038/s41598-018-22087-1.

Manzanedo, C., Aguilar, M. A., Rodríguez-Arias, M. y Miñarro, J. (2001a). Conditioned place preference paradigm could be a model of relapse to opiates. Neuroscience Research Communications, 28, 23-29.

Manzanedo, C., Aguilar, M. A., Rodríguez-Arias, M. y Miñarro, J. (2001b). Effects of dopamine with different blockade profiles on morphine-induced place preference in male mice. Behavioral Brain Research, 121, 189-197. doi:10.1016/S0166-4328(01)00164-4.

Manzanedo, C., Aguilar, M. A., Miñarro, J. y Rodríguez-Arias, M. (2011). Effects of CNQX and MPEP on sensitization to the rewarding effects of morphine. European Journal of Pharmacology, 654, 42-46. doi:10.1016/j.ejphar.2010.11.037.

Mateos-García, A., Manzanedo, C., Rodríguez-Arias, M., Aguilar, M. A., Reig-Sanchis, E., Navarro-Francés, C. I., … Arenas, M. C. (2015). Sex differences in the long-lasting consequences of adolescent ethanol exposure for the rewarding effects of cocaine in mice. Psychopharmacology (Berl), 232, 2995-3007. doi:10.1007/s00213-015-3937-7.

McReynolds, J. R., Peña, D. F., Blacktop J. M. y Mantsch J. R. (2014). Neurobiological mechanisms underlying relapse to cocaine use: contributions of CRF and noradrenergic systems and regulation by glucocorticoids. Stress, 17:1, 22-38. doi:10.3109/10253890.2013.872617.

Mihov, Y. y Hasler, G. (2016). Negative allosteric modulators of metabotropic glutamate receptors subtype 5 in addiction: a therapeutic window. International Journal of Neuropsychopharmacology, 19, 1-11. doi:10.1093/ijnp/pyw002.

Olive, M. F. (2009). Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Current Drug Abuse Reviews, 2, 83-98. doi:10.2174/1874473710902010083.

Pomierny-Chamiolo, L., Miszkiel, J., Frankowska, M., Bystrowska, B. y Filip M. (2017). Cocaine self-administration, extinction training and drug-induced relapse change metabotropic glutamate mGlu5 receptors expression: Evidence from radioligand binding and immunohistochemistry assays. Brain Research, 1655, 66-76. doi:10.1016/j.brainres.2016.11.014.

Pomierny-Chamioło, L., Rup, K., Pomierny, B., Niedzielska, E., Kalivas, P. W. y Filip, M. (2014). Metabotropic glutamatergic receptors and their ligands in drug addiction. Pharmacology & Therapeutics, 142, 281-305. doi:10.1016/j.pharmthera.2013.

Popik, P. y Wrobel, M. (2002). Morphine conditioned reward is inhibited by MPEP, the mGluR5 antagonist. Neuropharmacology, 43, 1210-1217. doi:10.1016/S0028-3908(02)00309-X.

Rodríguez-Arias, M., Castillo, A., Daza-Losada, M., Aguilar, M. A. y Miñarro, J. (2009). Effects of extended cocaine conditioning in the reinstatement of place preference. Physiology & Behavior, 96, 620-630. doi:10.1016/j.physbeh.2008.

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 (MPEP) potentiates conditioned place preference induced by various addictive and non-addictive drugs in rats. Addiction Biology, 16, 108-115. doi:10.1111/j.1369-1600.2010.00235.x.

Sanchis-Segura, C. y Spanagel, R. (2006). Behavioural assessment of drug reinforcement and addictive features in rodents: an overview. Addiction Biology, 11, 2-38. doi:10.1111/j.1369-1600.2006.00012.x.

Schmidt, H. D. y Pierce, R. C. (2010). Cocaine-induced neuroadaptations in glutamate transmission: potential therapeutic targets for craving and addiction. Annals of the New York Academy of Sciences, 1187, 35-75. doi:10.1111/j.1749-6632.2009.05144.x.

Schmidt, H. D., Kimmey, B. A., Arreola, A. C. y Pierce, R. C. (2015). Group I metabotropic glutamate receptor-mediated activation of PKC gamma in the nucleus accumbens core promotes the reinstatement of cocaine seeking. Addiction Biology, 20, 285-296. doi:10.1111/adb.12122.

Titomanlio, F., Manzanedo, C., Rodríguez-Arias, M., Mattioli, L., Perfumi, M., Miñarro, J. y Aguilar, M. A. (2013). Rhodiola rosea impairs acquisition and expression of conditioned place preference induced by cocaine. Evidence-Based Complementary and Alternative Medicine, 697632. doi:10.1155/2013/697632.

Tzschentke, T. M. (2007). Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addiction Biology, 12, 227-462. DOI: 10.1111/j.1369-1600.2007.00070.x

Van der Kam, E. L., De Vry, J. y Tzschentke, T. M. (2009a). 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates ketamine and heroin reward as assessed by acquisition, extinction, and reinstatement of conditioned place preference in the rat. European Journal of Pharmacology, 606, 94-101. doi:10.1016/j.ejphar.2008.12.042.

Van der Kam, E. L., De Vry, J. y Tzschentke, T. M. (2009b). The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) supports intravenous self-administration and induces conditioned place preference in the rat. European Journal of Pharmacology, 607, 114-20. doi:10.1016/j.ejphar.2009.01.049.




DOI: https://doi.org/10.20882/adicciones.1156

Enlaces refback

  • No hay ningún enlace refback.