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Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB 2 receptors

AuthorsAracil-Fernández, Auxiliadora; Trigo, José Manuel; García-Gutiérrez, María Salud; Ortega-Álvaro, Antonio; Ternianov, Alexander; Navarro, Daniela; Robledo, Patricia; Berbel, Pere J.; Maldonado, Rafael; Manzanares, Jorge
Issue Date2012
PublisherNature Publishing Group
CitationNeuropsychopharmacology 37(7): 1749-1763 (2012)
AbstractThe potential involvement of the cannabinoid CB 2 receptors (CB 2 r) in the adaptive responses induced by cocaine was studied in transgenic mice overexpressing the CB 2 r (CB 2 xP) 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 CB 2 r 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-opioid and cannabinoid CB 1 receptors in the NAcc were also studied in both genotypes. CB 2 xP mice showed decreased motor response to acute administration of cocaine (10-20 mg/kg) and cocaine-induced motor sensitization compared with WT mice. CB 2 xP mice presented cocaine-induced conditioned place aversion and self-administered less cocaine than WT mice. CB 2 r 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-opioid receptor gene expression was lower in CB 2 xP than in WT mice. However, both genotypes showed similar changes in TH and-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 CB 2 xP than in cocaine-pretreated WT mice. These results revealed that CB 2 r 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. © 2012 American College of Neuropsychopharmacology.
Identifiersdoi: 10.1038/npp.2012.22
issn: 0893-133X
e-issn: 1740-634X
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