title: Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB₂ receptors.
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.
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avenida Ramón y Cajal s/n, Alicante, Spain.
authors.forename: Auxiliadora
authors.initials: A
authors.lastname: Aracil-Fernández
authors.forename: José M
authors.initials: JM
authors.lastname: Trigo
authors.forename: María S
authors.initials: MS
authors.lastname: García-Gutiérrez
authors.forename: Antonio
authors.initials: A
authors.lastname: Ortega-Álvaro
authors.forename: Alexander
authors.initials: A
authors.lastname: Ternianov
authors.forename: Daniela
authors.initials: D
authors.lastname: Navarro
authors.forename: Patricia
authors.initials: P
authors.lastname: Robledo
authors.forename: Pere
authors.initials: P
authors.lastname: Berbel
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism; D009714:Nucleus Accumbens / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D012646:Self Administration; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D043885:Receptor, Cannabinoid, CB2; D017450:Receptors, Opioid, mu; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D004298:Dopamine