Abstract
The potential involvement of the cannabinoid CB2 receptors (CB2r) in the adaptive responses induced by cocaine was studied in transgenic mice overexpressing the CB2r (CB2xP) and in wild-type (WT) littermates. For this purpose, the acute and sensitized locomotor responses to cocaine, conditioned place preference, and cocaine intravenous self-administration were evaluated. In addition, we assessed whether CB2r were localized in neurons and/or astrocytes, and whether they colocalized with dopamine D1 and D2 receptors (D1Dr and D2Dr). Dopamine (DA) extracellular levels in the nucleus accumbens (NAcc), and gene expression of tyrosine hydroxylase (TH) and DA transporter (DAT) in the ventral tegmental area (VTA), and μ-opioid and cannabinoid CB1 receptors in the NAcc were also studied in both genotypes. CB2xP mice showed decreased motor response to acute administration of cocaine (10–20 mg/kg) and cocaine-induced motor sensitization compared with WT mice. CB2xP mice presented cocaine-induced conditioned place aversion and self-administered less cocaine than WT mice. CB2r were found in neurons and astrocytes and colocalized with D2Dr in the VTA and NAcc. No significant differences in extracellular DA levels in the NAcc were observed between genotypes after cocaine administration. Under baseline conditions, TH and DAT gene expression was higher and μ-opioid receptor gene expression was lower in CB2xP than in WT mice. However, both genotypes showed similar changes in TH and μ-opioid receptor gene expression after cocaine challenge independently of the pretreatment received. Importantly, the cocaine challenge decreased DAT gene expression to a lesser extent in cocaine-pretreated CB2xP than in cocaine-pretreated WT mice. These results revealed that CB2r are involved in cocaine motor responses and cocaine self-administration, suggesting that this receptor could represent a promising target to develop novel treatments for cocaine addiction.
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Acknowledgements
This research was supported by ‘Instituto de Salud Carlos III’ (RETICS, RD06/0001/1004), ‘Plan Nacional Sobre Drogas’ (PNSD 2007/061), Fundación para la Investigación en Salud Castilla La Mancha, FISCAM), and ‘Ministerio de Ciencia e Innovación’ (#SAF 2008-01106 and #SAF 2011-23420) to JM; by ‘Instituto de Salud Carlos III’ (RETICS, RD06/001/001), ‘Ministerio de Ciencia e Innovación’ (#SAF2007-64062), and Generalitat de Catalunya (#2009SGR00731 and the ICREA Academia award) to RM; and by the ‘Ministerio de Ciencia e Innovación’ (#SAF2009-10689) to PB Postdoctoral fellows AO-A and AT are supported by FISCAM, and JMT by ‘Becas para estancias cortas de especialización e investigación en psiquiatría y psicología de la infancia y adolescencia o en neurociencias’ Fundación Alicia Koplowitz. AA-F (predoctoral fellow) and Analía Rico (AR, technician) are supported by RETICS. MSG-G is a predoctoral fellow supported by ‘Ministerio de Ciencia e Innovación’. DN is a predoctoral FPI fellow. We thank AR for his excellent technical assistance, and Dulce Real for her contribution in the microdialysis and HPLC experiments. The partial support of FEDER funds (EU) is also acknowledged.
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Aracil-Fernández, A., Trigo, J., García-Gutiérrez, M. et al. Decreased Cocaine Motor Sensitization and Self-Administration in Mice Overexpressing Cannabinoid CB2 Receptors. Neuropsychopharmacol 37, 1749–1763 (2012). https://doi.org/10.1038/npp.2012.22
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