The potential therapeutic roles of Rho GTPases in substance dependence

Abstract

Rho GTPases family are considered to be molecular switches that regulate various cellular processes, including cytoskeleton remodeling, cell polarity, synaptic development and maintenance. Accumulating evidence shows that Rho GTPases are involved in neuronal development and brain diseases, including substance dependence. However, the functions of Rho GTPases in substance dependence are divergent and cerebral nuclei-dependent. Thereby, comprehensive integration of their roles and correlated mechanisms are urgently needed. In this review, the molecular functions and regulatory mechanisms of Rho GTPases and their regulators such as GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in substance dependence have been reviewed, and this is of great significance for understanding their spatiotemporal roles in addictions induced by different addictive substances and in different stages of substance dependence.

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

“…These pathways have been implicated in synaptic remodeling and the plasticity of dendritic spines in NAc, particularly during cocaine withdrawal. The activity of the PDZ-RHOGEF/RAP1B pathway was observed to revert during the protracted stages of withdrawal ( 54 , 58 ).…”

DNA methylation signatures in the prefrontal cortex of alcohol-naïve nonhuman primates predict risk for future ethanol drinking.

“…TrkB) and regulators (protein kinases, PKA and PKC), and their downstream mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways as key biochemical cascades linking activation of NMDA receptors and calcium in ux with phosphorylation and tra cking of AMPA receptors during synaptic plasticity 153 . Drugs of abuse stimulate signaling pathways that activate these molecules, leading to altered gene transcription and protein synthesis, which contribute to the long-term changes in synaptic function and neural networks that lead to addiction (see 154 ).…”

Substance Addiction Rehabilitation Drugs

“…Dopaminergic neurons in the nucleus accumbens (NAc) and the ventral tegmental area (VTA) play an important role in the perception of rewarding stimuli, such as the rewards related with substance addiction [13,17]. After cocaine treatments, the extracellular dopamine (DA) contents increased dramatically.…”

“…Repeated morphine administration activated the astrocytes, while rosuvastation suppressed this activation [98]. Rosuvastatin reversed the morphine tolerance also by inhibiting Rho GTPases activation [17,[97][98][99][100]. However, a clinical trial of simvastatin on smoking cessation found that a 3-month simvastatin administration did not improve smoking cessation significantly compared with the placebo group [101].…”