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Cannabinoid CB? receptor-mediated regulation of impulsive-like behaviour in DBA/2 mice.

ABSTRACT: BACKGROUND AND PURPOSE:This study evaluated gene expression differences between two mouse strains, characterized by opposite impulsivity-like traits and the involvement of the cannabinoid CB(2) receptor in the modulation of impulsivity. EXPERIMENTAL APPROACH:Behavioural tests were conducted to compare motor activity, exploration and novelty seeking, attention and cognitive and motor impulsivity (delayed reinforcement task: session duration 30 min; timeout 30 s) between A/J and DBA/2 mice. Expression of genes for dopamine D(2) receptors, CB(1) and CB(2) receptors were measured in the cingulate cortex (CgCtx), caudate-putamen (CPu), accumbens (Acc), amygdala (Amy) and hippocampus (Hipp). Involvement of CB(2) receptors in impulsivity was evaluated in DBA/2 mice with a CB(2) receptor agonist (JWH133) and an antagonist (AM630). KEY RESULTS:DBA/2 mice presented higher motor and exploratory activity, pre-pulse inhibition impairment and higher cognitive and motor impulsivity level than A/J mice. In addition, DBA/2 mice showed lower (CgCtx, Acc, CPu) D(2) receptor, lower (Amy) and higher (CgCtx, Acc, CPu, Hipp) CB(1) receptor and higher (CgCtx, Acc, Amy) and similar (CPu, Hipp) CB(2) receptor gene expressions. Treatment with JWH133 (0.5, 1, 3 mg·kg(-1), i.p.) reduced cognitive and motor impulsivity level, accompanied by CB(2) receptor down-regulation (CgCtx, Acc, Amy) but did not modify other behaviours. In contrast, AM630 (1, 2, 3 mg·kg(-1), i.p.) improved pre-pulse inhibition and reduced novelty seeking behaviour in DBA/2 mice. CONCLUSIONS AND IMPLICATIONS:CB(2) receptors might play an important role in regulating impulsive behaviours and should be considered a promising therapeutic target in the treatment of impulsivity-related disorders.

SUBMITTER: Navarrete F

PROVIDER: S-EPMC3252982 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Cannabinoid CB₂ receptor-mediated regulation of impulsive-like behaviour in DBA/2 mice.

Navarrete Francisco F Pérez-Ortiz José M JM Manzanares Jorge J Manzanares Jorge J

British journal of pharmacology 20120101 1

<h4>Background and purpose</h4>This study evaluated gene expression differences between two mouse strains, characterized by opposite impulsivity-like traits and the involvement of the cannabinoid CB(2) receptor in the modulation of impulsivity.<h4>Experimental approach</h4>Behavioural tests were conducted to compare motor activity, exploration and novelty seeking, attention and cognitive and motor impulsivity (delayed reinforcement task: session duration 30 min; timeout 30 s) between A/J and DBA ...[more]

PMID: 21671903

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Project description:Receptor internalization increases the flexibility and scope of G protein-coupled receptor (GPCR) signaling. CB(1) and CB(2) cannabinoid receptors undergo internalization after sustained exposure to agonists. However, it is not known whether different agonists internalize CB(2) to different extents. Because CB(2) is a promising therapeutic target, understanding its trafficking in response to different agonists is necessary for a complete understanding of its biology. Here we profile a number of cannabinoid receptor ligands and provide evidence for marked functional selectivity of cannabinoid receptor internalization. Classic, aminoalkylindole, bicyclic, cannabilactone, iminothiazole cannabinoid, and endocannabinoid ligands varied greatly in their effects on CB(1) and CB(2) trafficking. Our most striking finding was that (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone (WIN55,212-2) (and other aminoalkylindoles) failed to promote CB(2) receptor internalization, whereas 5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol (CP55,940) robustly internalized CB(2) receptors. Furthermore, WIN55,212-2 competitively antagonized CP55,940-induced CB(2) internalization. Despite these differences in internalization, both compounds activated CB(2) receptors as measured by extracellular signal-regulated kinase 1/2 phosphorylation and recruitment of β-arrestin(2) to the membrane. In contrast, whereas CP55,940 inhibited voltage-gated calcium channels via CB(2) receptor activation, WIN55,212-2 was ineffective on its own and antagonized the effects of CP55,940. On the basis of the differences we found between these two ligands, we also tested the effects of other cannabinoids on these signaling pathways and found additional evidence for functional selectivity of CB(2) ligands. These novel data highlight that WIN55,212-2 and other cannabinoids show strong functional selectivity at CB(2) receptors and suggest that different classes of CB(2) ligands may produce diverse physiological effects, emphasizing that each class needs to be separately evaluated for therapeutic efficacy.

Dataset Information

Cannabinoid CB? receptor-mediated regulation of impulsive-like behaviour in DBA/2 mice.

Publications

Cannabinoid CB₂ receptor-mediated regulation of impulsive-like behaviour in DBA/2 mice.

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