The inhibition of RasGRF2, but not RasGRF1, alters cocaine reward in mice

Bernardi, Rick E., Olevska, Anastasia, Morella, Ilaria ORCID: https://orcid.org/0000-0001-5691-5400, Fasano, Stefania ORCID: https://orcid.org/0000-0002-3696-7139, Santos, Eugenio, Brambilla, Riccardo ORCID: https://orcid.org/0000-0003-3569-5706 and Spanagel, Rainer 2019. The inhibition of RasGRF2, but not RasGRF1, alters cocaine reward in mice. Journal of Neuroscience 39 (32) , pp. 6325-6338. 10.1523/JNEUROSCI.1120-18.2019

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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(RasGRF1) and 2(RasGRF2), upstream regulators of the Ras-ERK signaling cascade, on cocaine self-administration(SA) in male mice. We first established a role for Ras-ERK signaling in cocaine SA, demonstrating that pERK1/2 is upregulated following SA in C57Bl/6N mice in striatum. We then compared RasGRF1 and RasGRF2 knock-out(KO) mouse lines, demonstrating that cocaine SA in RasGRF2 KO mice was increased relative to wild-type(WT) controls, while RasGRF1 KO and WT mice did not differ. This effect in RasGRF2 mice is likely mediated by the Ras-ERK signaling pathway, as pERK1/2 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, while 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Neuroscience and Mental Health Research Institute (NMHRI) Biosciences
Publisher:	Society for Neuroscience
ISSN:	0270-6474
Date of First Compliant Deposit:	17 June 2019
Date of Acceptance:	4 June 2019
Last Modified:	10 Nov 2024 20:15
URI:	https://orca.cardiff.ac.uk/id/eprint/123479

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