Drugs such as opioids, cocaine and amphetamine elicit most of their addictive effects via activating dopamine and opioid G protein coupled receptors in the striatum. Persistent signaling through these receptors produce a range of molecular adaptations leading to the development of addiction. Our long term goal is to elucidate molecular and cellular mechanisms that regulate signaling in the striatal G protein pathways as a necessary prerequisite to understanding events that lead to substance dependence and designing strategies for the therapeutic correction. In G protein signaling pathways, the surface receptors upon binding to the neurotransmitter activate heterotrimeric G proteins, which in turn regulate functional states of many molecules that shape cellular responses. Increasing evidence indicates that Regulators of G protein Signaling (RGS) proteins play essential roles in modulating G protein signaling. RGS proteins limit G protein activity and thereby control both sensitivity and extent of neurotransmitter signaling. However, our understanding of the role that specific RGS proteins play in shaping G protein signaling that contributes to addiction is fragmented at best. The main purpose of this exploratory proposal is to probe potential involvement of a poorly studied signaling regulator, RGS7 in controlling the effects of addictive drugs. Our preliminary data points to a previously unanticipated role of RGS7 in controlling G protein signaling in the striatum. We have found that: (i) RGS7 is a potent G protein inhibitor acting downstream from the D2 dopamine and ?-opioid receptors, (ii) it undergoes compositional rearrangement induced by changes in neurotransmitter signaling, and (iii) viral-mediated knockdown of RGS7 in the striatum enhances psychomotor sensitization to cocaine. We hypothesize that RGS7 acts in concert with other RGS proteins in the striatum and common binding partners to control behavioral response to opioids and cocaine. The proposed research will test this hypothesis by generating mouse models with selective disruption of RGS7 in striatal circuitry and evaluating their drug induced behavior. It is anticipated that understanding the mechanisms of RGS protein action that naturally counteract excessive GPCR signaling induced by addictive drugs, will be central for the development of effective therapies aimed at curtailing the addiction.
Drug addiction is a disorder of the brain that puts a heavy burden on society. Studies proposed herein are aimed at understanding molecular mechanisms controlling the function of the neuronal signaling systems that mediate the effects of addictive drugs. It is anticipated that the results will facilitate the design of novel strategies for the treatment of drug addiction and neurological diseases.
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|Xie, Keqiang; Colgan, Lesley A; Dao, Maria T et al. (2016) NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum. Curr Biol 26:2992-3003|
|Orlandi, Cesare; Xie, Keqiang; Masuho, Ikuo et al. (2015) Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain. J Biol Chem 290:13622-39|