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- Title
The Inhibition of RasGRF2, But Not RasGRFl, Alters Cocaine Reward in Mice.
- Authors
Bernardi, Rick E.; Olevska, Anastasia; Morelia, Ilaria; Fasano, Stefania; Santos, Eugenio; Brambilla, Riccardo; Spanagel, Rainer
- Abstract
Ras/Raf/MEK/ERK (Ras-ERK) signaling has been implicated in the effects of drugs of abuse. Inhibitors of MEK1/2, the kinases upstream of ERK1/2, have been critical in defining the role of the Ras-ERK cascade in drug-dependent alterations in behavioral plasticity, but the Ras family of small GTPases has not been extensively examined in drug-related behaviors. We examined the role of Ras Guanine Nucleotide Releasing Factor 1 (RasGRFl) and 2 (RasGRF2), upstream regulators of the Ras-ERK signaling cascade, on cocaine selfadministration (SA) in male mice. We first established a role for Ras-ERK signaling in cocaine SA, demonstrating that pERKl/2 is upregulated following SA in C57BL/6N mice in striatum. We then compared RasGRFl and RasGRF2 KO mouse lines, demonstrating that cocaine SA in RasGRF2 KO mice was increased relative to WT controls, whereas RasGRFl KO and WT mice did not differ. This effect in RasGRF2 mice is likely mediated by the Ras-ERK signaling pathway, as pERKl/2 upregulation following cocaine SA was absent in RasGRF2 KO mice. Interestingly, the lentiviral knockdown of RasGRF2 in the NAc had the opposite effect to that in RasGRF2 KO mice, reducing cocaine SA. We subsequently demonstrated that the MEK inhibitor PD325901 administered peripherally prior to cocaine SA increased cocaine intake, replicating the increase seen in RasGRF2 KO mice, whereas PD325901 administered into the NAc decreased cocaine intake, similar to the effect seen following lentiviral knockdown of RasGRF2. These data indicate a role for RasGRF2 in cocaine SA in mice that is ERK-dependent, and suggest a differential effect of global versus site-specific RasGRF2 inhibition.
- Subjects
COCAINE; MICE; PHARMACOLOGY; DRUGS of abuse; GUANINE
- Publication
Journal of Neuroscience, 2019, Vol 39, Issue 32, p6325
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/jneurosci.1120-18.2019