Psychostimulants activate the Ras-mitogen-activated protein kinase (Ras-MAPK) cascade in the limbic reward circuit and thereby trigger a transcription-dependent mechanism underlying enduring synaptic plasticity related to addictive properties of drugs of abuse. The Ras-specific activator, Ras-guanine nucleotide-releasing factor (Ras-GRF), is predominantly expressed at synapses and is thought to actively regulate Ras-MAPK responses to changing synaptic signals. In this study, a possible influence of cocaine on Ras-GRF gene expression at the protein level in the rat striatum was investigated in vivo. A single systemic injection of cocaine induced an increase in Ras-GRF1 protein levels in both the dorsal (caudoputamen) and ventral (nucleus accumbens) striatum. The increase in Ras-GRF1 proteins was dose-dependent and was a delayed and transient event. In contrast to Ras-GRF1, a closely related Ras-GRF2 showed no change in its protein abundance following cocaine administration. These data identify the Ras activator, Ras-GRF1, although not Ras-GRF2, as a susceptible target to cocaine stimulation in striatal neurons.