Protective mechanisms in nicotine-induced conditioned place preference and in vivo functional validation of candidate genes using rAAV
Final Report Abstract
Despite an enormous investment in resources (personnel, mouse mutants, backcrossing, GeneChip analysis), we were not able in detailing the reward circuitry and downstream signalling system in nicotine addiction to the extent wished to do in the course of this project. Several issues have to be mentioned: Significant differences in nicotine response were observed in the two widely used substrains C57BL/6N and C57BL/6J. - Published data on the analysis of nicotine- and cocaine-induced CPP in CB1-KO could not be reproduced. - The paradigm of nicotine-induced CPP evokes a high degree in heterogenous (i.e., individual) responses in mice. - Results from GeneChip experiments could not be reproduced using other quantitative detection methods, such as qPCR. On the positive side, due to the fact that the lab further pursued projects aiming at understanding reward circuitry and the role of the endocannabinoid system in addiction behaviour, we have recently succeeded in making a big step forward in detailing why some mice get addicted and others do not (vulnerability versus resilience). In this recent study, we were able to apply the genetic tools intended to use in the past project (AAV-mediated genetic intervention, transcriptomic, mouse mutants of the endocannabinoid system).
Publications
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Circuit specific functions of cannabinoid CB1 receptor in the balance of investigatory drive and exploration. PLoS One. 2011;6(11):e26617
Häring M, Kaiser N, Monory K, Lutz B
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Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons: distinctive sufficiency for hippocampus-dependent and amygdala-dependent synaptic and behavioral functions. J Neurosci. 2013 Jun 19;33(25):10264-77
Ruehle S, Remmers F, Romo-Parra H, Massa F, Wickert M, Wörtge S, Häring M, Kaiser N, Marsicano G, Pape HC, Lutz B
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Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons. Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):13693-8
de Salas-Quiroga A, Díaz-Alonso J, García-Rincón D, Remmers F, Vega D, Gómez-Cañas M, Lutz B, Guzmán M, Galve-Roperh I
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A specific prelimbic-nucleus accumbens pathway controls resilience versus vulnerability to food addiction. Nat Commun. 2020 Feb 7;11(1):782
Domingo-Rodriguez L, Ruiz de Azua I, Dominguez E, Senabre E, Serra I, Kummer S, Navandar M, Baddenhausen S, Hofmann C, Andero R, Gerber S, Navarrete M, Dierssen M, Lutz B, Martín-García E, Maldonado R
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Endocannabinoid LTD in accumbal D1 neurons mediates reward-seeking behavior. iScience. 2020 Mar 27;23(3):100951
Bilbao A, Neuhofer D, Sepers M, Wei SP, Eisenhardt M, Hertle S, Lassalle O, Ramos-Uriarte A, Puente N, Lerner R, Thomazeau A, Grandes P, Lutz B, Manzoni OJ, Spanagel R
