RGD Reference Report - Dysregulation of cannabinoid CB1 receptor and associated signaling networks in brains of cocaine addicts and cocaine-treated rodents. - Rat Genome Database

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Dysregulation of cannabinoid CB1 receptor and associated signaling networks in brains of cocaine addicts and cocaine-treated rodents.

Authors: Álvaro-Bartolomé, M  García-Sevilla, J A 
Citation: Álvaro-Bartolomé M and García-Sevilla JA, Neuroscience. 2013 Sep 5;247:294-308. doi: 10.1016/j.neuroscience.2013.05.035. Epub 2013 May 29.
RGD ID: 13792719
Pubmed: PMID:23727505   (View Abstract at PubMed)
DOI: DOI:10.1016/j.neuroscience.2013.05.035   (Journal Full-text)

The endocannabinoid system is implicated in the neurobiology of cocaine addiction. This study evaluated the status of cannabinoid (CB) CB1 and CB2 receptors, the endocytic cycle of CB1 receptors, G protein-coupled receptor regulatory kinases (GRK), and associated signaling (mammalian target of rapamicin (mTOR) and 70kDa ribosomal protein S6 kinase (p70S6K)) in brain cortices of drug abusers and cocaine- and cannabinoid-treated rodents. The main results indicate that in cocaine adddicts, but not in mixed cocaine/opiate or opiate abusers, CB1 receptor protein in the prefrontal cortex (PFC) was reduced (-44%, total homogenate) with a concomitant receptor redistribution and/or internalization (decreases in membranes and increases in cytosol). In cocaine addicts, the reductions of CB1 receptors and GRK2/3/5 (-26% to -30%) indicated receptor desensitization. CB2 receptor protein was not significantly altered in the PFC of cocacine addicts. Chronic cocaine in mice and rats also reduced CB1 receptor protein (-41% and -80%) in the cerebral cortex inducing receptor redistribution and/or internalization. The CB1 receptor agonist WIN55212-2 caused receptor downregulation (decreases in membranes and cytosol) and the antagonists rimonabant and AM281 induced opposite effects (receptor upregulation in membranes and cytosol). Rimonabant and AM281 also behaved as inverse agonists on the activation of mTOR and its target p70S6K. Chronic cocaine in mice was associated with tolerance to the acute activation of mTOR and p70S6K. In long-term cocaine addicts, mTOR and p70S6K activations were not altered when compared with controls, indicating that CB1 receptor signaling was dampened. The dysregulation of CB1 receptor, GRK2/3/5, and mTOR/p70S6K signaling by cocaine may contribute to alterations of neuroplasticity and/or neurotoxicity in brains of cocaine addicts.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Cocaine-Related Disorders  IEP 13792719; 13792719; 13792719protein:decreased expression:prefrontal cortex (human)RGD 
Cocaine-Related Disorders  ISOGRK2 (Homo sapiens)13792719; 13792719protein:decreased expression:prefrontal cortex (human)RGD 
Cocaine-Related Disorders  ISOGRK3 (Homo sapiens)13792719; 13792719protein:decreased expression:prefrontal cortex (human)RGD 
Cocaine-Related Disorders  ISOGRK5 (Homo sapiens)13792719; 13792719protein:decreased expression:prefrontal cortex (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Grk2  (G protein-coupled receptor kinase 2)
Grk3  (G protein-coupled receptor kinase 3)
Grk5  (G protein-coupled receptor kinase 5)

Genes (Mus musculus)
Grk2  (G protein-coupled receptor kinase 2)
Grk3  (G protein-coupled receptor kinase 3)
Grk5  (G protein-coupled receptor kinase 5)

Genes (Homo sapiens)
GRK2  (G protein-coupled receptor kinase 2)
GRK3  (G protein-coupled receptor kinase 3)
GRK5  (G protein-coupled receptor kinase 5)


Additional Information