The role of Rapgef2 in the behavioral effects of Cocaine in the Mouse

Authors

• SC Sweat
• KM Loane
• GL Drossel
• SZ Jiang
• CR Gerfen
• LE Eiden

Abstract

G-protein coupled receptors (GPCRs) activate multiple cyclic AMP sensors (effectors) to regulate neuronal function. Previous studies in our laboratory have shown that the neuritogenic cyclic AMP sensor (NCS), encoded by the Rapgef2 gene, is involved in D1 receptor-mediated activation of ERK in CNS (Jiang et al, 2017). D1-dependent ERK activation, in both forebrain and ventral striatum, is thought to be important for long-term synaptic plasticity and behavior adaptation to exposure to psychomotor stimulants. Tests of cocaine-induced behavioral sensitization (CIBS), which measures neuroplasticity following repeated exposure to cocaine, and conditioned place preference (CPP), which measures the motivation to seek drug reward, were completed with Forebrain Rapgef2 KO and Nucleus Accumbens (NAcc) Rapgef2 KO mice to determine the effect of NCS-Rapgef2 ablation in mouse forebrain or NAcc. Forebrain Rapgef2 KO mice did not demonstrate behavioral differences compared to controls. In contrast, NAcc Rapgef2 KO mice showed significantly reduced cocaine sensitization compared to controls, as well as abolition of CPP. This suggests that Rapgef2, specifically within the NAcc, plays an important role in mediating addiction behavior. Investigators have shown that D1-medium spiny neurons (D1-MSNs) of the NAcc show significant increases in dendritic spine density following cocaine administration, which is sustained following cessation of cocaine treatment (Lee et al, 2006). These findings show that dendritic spines may play a significant role in behavioral changes following chronic drug exposure and susceptibility to drug relapse. Therefore, we are now investigating if Rapgef2 is required for such dendritic spine changes associated with cocaine administration.

Scientific Focus Area: Neuroscience

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