The Inhibition of RasGRF2, But Not RasGRF1, Alters Cocaine Reward in Mice

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 selfadministration (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 KO mouse lines, demonstrating that cocaine SA in RasGRF2 KO mice was increased relative to WT controls, whereas 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, 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.

A Novel Precision Approach to Overcome the “Addiction Pandemic” by Incorporating Genetic Addiction Risk Severity (GARS) and Dopamine Homeostasis Restoration

“…We encourage clinicians to research and understand the importance of a molecular framework to explain the current underpinnings of endorphinergic/dopaminergic mechanisms related to opioid deficiency syndrome and a generalized reward processing deficiency [ 19 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. Along these same lines, many RDS subtypes have also been linked to hypodopaminergia using sophisticated imaging techniques [ 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 ].…”

Comparative Proteomic Analysis of tPVAT during Ang II Infusion

“…The Ras-ERK pathway is largely known for its regulation of cell proliferation, differentiation, survival, and drug-mediated behaviors. A recent study found that RasGRF2 (RAS protein-specific guanine nucleotide-releasing factor 2) mediates cocaine self-administration (SA) in mice via an ERK-dependent mechanism [ 49 ]. Our study discovered that RasGRF2 was up-regulated after Ang II infusion and could serve as a novel target for Ang II action, and the RasGRF2-Ras-ERK signal axis may play an important role in Ang II-mediated tPVAT pathogenesis.…”

Nicotine self-administration and ERK signaling are altered in RasGRF2 knockout mice

“…We recently demonstrated that cocaine self-administration (SA) was increased in RasGRF2 knock-out (KO) mice relative to their wild-type littermates (WT), which we attributed to a decrease in cocaine reinforcement and compensatory increase in intake to achieve similar putative reward (Bernardi et al, 2019). Importantly, these alterations in cocaine intake were accompanied by an attenuation of the cocaine-induced increase in pERK in the ventral and dorsal striatum in RasGRF2 KO mice.…”

“…The extracellular signal-regulated kinases (ERK) cascade (Ras/ Raf/MEK/ERK; Ras-ERK), a member of the mitogen-activated protein kinase (MAPK) family, is an important signaling pathway linking signals from cell surface receptors with changes in gene expression (Grewal et al, 1999;Orton et al, 2005). This pathway has been implicated in the acute and long-term effects of drugs of abuse, including cocaine and other psychostimulants (Valjent et al, 2006;Papale et al, 2016;Bernardi et al, 2019), alcohol (Sanna et al, 2002;Faccidomo et al, 2009;Agoglia et al, 2015;Faccidomo et al, 2015), and nicotine (Brunzell et al, 2003;Valjent et al, 2004;Valjent et al, 2005;Wilar et al, 2019), likely regulating striatal drug-dependent synaptic plasticity (Girault et al, 2007;Cerovic et al, 2013). In terms of nicotine, administration (0.4 mg/kg) in mice has been demonstrated to increase the phosphorylation of ERK1/2 (pERK1/2) in the ventral and dorsal striatum (Valjent et al, 2004;Valjent et al, 2005; but see Brunzell et al, 2003), mesolimbic dopamine structures that have both been shown to mediate neuroadaptations associated with drug dependence (Koob and Volkow, 2010;Lobo and Nestler, 2011).…”