Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure

摘要

Abstract The nucleus accumbens ( NA c) is a critical brain reward region that mediates the rewarding effects of drugs of abuse, including those of morphine and other opiates. Drugs of abuse induce widespread alterations in gene transcription and dendritic spine morphology in medium spiny neurons ( MSN s) of the NA c that ultimately influence NA c excitability and hence reward‐related behavioral responses. Growing evidence indicates that within the NA c small GTP ases are common intracellular targets of drugs of abuse where these molecules regulate drug‐mediated transcriptional and spine morphogenic effects. The RhoA small GTP ase is among the most well‐characterized members of the Ras superfamily of small GTP ases, and recent work highlights an important role for hippocampal RhoA in morphine‐facilitated reward behavior. Despite this, it remains unclear how RhoA pathway signaling in the NA c is affected by withdrawal from morphine. To investigate this question, using subcellular fractionation and subsequent protein profiling we examined the expression of key components of the RhoA pathway in NA c nuclear, cytoplasmic, and synaptosomal compartments during multiple withdrawal periods from repeated morphine administration. Furthermore, using in?vivo viral‐mediated gene transfer, we determined the consequences of revealed RhoA pathway alterations on NA c MSN dendritic spine morphology. Our findings reveal an important role for RhoA signaling cascades in mediating the effects of long‐term morphine withdrawal on NA c MSN dendritic spine elimination. Open Practices Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/