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.

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

“…In contrast, microinjections of the same doses of JWH133 into a dorsal brain region adjacent to the VTA failed to alter cocaine self-administration, suggesting an effect produced by activation of CB 2 Rs in the VTA, not in adjacent structures. This is consistent with our previous findings that systemic or local administration of JWH133 into the nucleus accumbens inhibits cocaine self-administration (22), and that transgenic up-regulation of brain CB 2 Rs attenuates cocaine self-administration and cocaine-induced increased locomotion (19). The present findings are also congruent with recent reports that brain CB 2 Rs have important roles in other DArelated functions and/or CNS disorders (12,25,51,52).…”

“…This finding is supported by recent studies demonstrating that systemic administration of the CB 2 R agonist O-1966 inhibited cocaine-induced conditioned place preference in WT mice, but not in CB 2 −/− mice (23), and that increased CB 2 R expression in mouse brain attenuates cocaine self-administration and cocaine-enhanced locomotion (19). In addition, brain CB 2 Rs may be involved in several DA-related CNS disorders, such as Parkinson's disease (24), schizophrenia (25), anxiety (26), and depression (27).…”

“…More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9-14). Immunoblot and immunohistochemistry (IHC) assays detected CB 2 R immunoreactivity or immunostaining in various brain regions (13,(15)(16)(17)(18)(19)(20). The specificities of the detected CB 2 R protein and CB 2 -mRNA remain questionable, however, owing to a lack of controls using CB 1 −/− and CB 2 −/− mice in most previous studies (21).…”

Role of CB2 Cannabinoid Receptors in the Rewarding, Reinforcing, and Physical Effects of Nicotine

“…Previous studies suggest a relevant role of CB2r on opiates, cocaine, and ethanol addiction behavior (Adamczyk et al, 2012;Aracil-Fernandez et al, 2012;Onaivi et al, 2008b). To explore the role of CB2r in the rewarding properties of nicotine, CB2KO mice were exposed to the CPP following an unbiased procedure.…”

“…Another study showed that activation of CB2r is involved in cocaine-induced reinstatement of cocaine-seeking behavior, although its activity is not necessary for the rewarding effects of cocaine (Adamczyk et al, 2012). In addition, latest results from our group suggest that overexpression of CB2r (CB2xP mice) decreases cocaine motor responses and cocaine self-administration (Aracil-Fernandez et al, 2012).…”