The Small G Protein H-Ras in the Mesolimbic System Is a Molecular Gateway to Alcohol-Seeking and Excessive Drinking Behaviors
Copyright policy )The Small G Protein H-Ras in the Mesolimbic System Is a Molecular Gateway to Alcohol-Seeking and Excessive Drinking Behaviors
Uncontrolled consumption of alcohol is a hallmark of alcohol abuse disorders; however, the central molecular mechanisms underlying excessive alcohol consumption are still unclear. Here, we report that the GTP binding protein, H-Ras in the nucleus accumbens (NAc) plays a key role in neuroadaptations that underlie excessive alcohol-drinking behaviors. Specifically, acute (15 min) systemic administration of alcohol (2.5 g/kg) leads to the activation of H-Ras in the NAc of mice, which is observed even 24 h later. Similarly, rat operant self-administration of alcohol (20%) also results in the activation of H-Ras in the NAc. Using the same procedures, we provide evidence suggesting that the exchange factor GRF1 is upstream of H-Ras activation by alcohol. Importantly, we show that infection of mice NAc with lentivirus expressing a short hairpin RNA that targets the H-Ras gene produces a significant reduction of voluntary consumption of 20% alcohol. In contrast, knockdown of H-Ras in the NAc of mice did not alter water, quinine, and saccharin intake. Furthermore, using two-bottle choice and operant self-administration procedures, we show that inhibiting H-Ras activity by intra-NAc infusion of the farnesyltransferase inhibitor, FTI-276, produced a robust decrease of rats' alcohol drinking; however, sucrose consumption was unaltered. Finally, intra-NAc infusion of FTI-276 also resulted in an attenuation of seeking for alcohol. Together, these results position H-Ras as a central molecular mediator of alcohol's actions within the mesolimbic system and put forward the potential value of the enzyme as a novel target to treat alcohol use disorders.
Male, Sucrose, 150, Cardiovascular, Farnesyltranstransferase [MESH], Choice Behavior, Transgenic, Alcohol Use and Health, Substance Misuse, Mice, Methionine, MESH: Animals, Mice, Transgenic [MESH], NEU] Life Sciences/Neurons and Cognition [[SDV], Proto-Oncogene Proteins p21(ras) [MESH], MESH: ras-GRF1, [SDV.MHEP.PHY] Life Sciences/Human health and pathology/Tissues and Organs, Mice [MESH], ras-GRF1 [MESH], MESH: Nucleus Accumbens, MESH: Ethanol, Alcohol Drinking, Basic Behavioral and Social Science, MESH: Choice Behavior, Sucrose [MESH], Binge Drinking, Proto-Oncogene Proteins p21(ras), Choice Behavior [MESH], Rats, Long-Evans, MESH: Farnesyltranstransferase, MESH: Phosphorylation, Ethanol, ras-GRF1, Binge Drinking [MESH], MESH: Sucrose, MHEP:PHY] Life Sciences/Human health and pathology/Tissues and Organs [[SDV], MESH: Alcohol Drinking, Medical and Health Sciences, Oral and gastrointestinal, Nucleus Accumbens, MESH: Binge Drinking, NEU] Sciences du Vivant/Neurosciences [[SDV], Rats, Long-Evans [MESH], Phosphorylation, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Ethanol [MESH], Alcohol Drinking [MESH], Alcoholism, Animals [MESH], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Biotechnology, MESH: Rats, MESH: Mice, Transgenic, Male [MESH], Mice, Transgenic, MESH: Proto-Oncogene Proteins p21(ras), MESH: Rats, Long-Evans, Behavioral and Social Science, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Farnesyltranstransferase, Phosphorylation [MESH], Rats [MESH], MESH: Mice, [SDV.NEU] Life Sciences/Neurons and Cognition, Neurology & Neurosurgery, Psychology and Cognitive Sciences, Methionine [MESH], Long-Evans, MESH: Male, MHEP:PHY] Sciences du Vivant/Médecine humaine et pathologie/Physiologie [[SDV], Rats, Good Health and Well Being, MESH: Methionine, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Nucleus Accumbens [MESH], mesh: mesh:Binge Drinking, mesh: mesh:Phosphorylation, mesh: mesh:Nucleus Accumbens, mesh: mesh:ras-GRF1, mesh: mesh:Farnesyltranstransferase, mesh: mesh:Rats, mesh: mesh:Mice, mesh: mesh:Alcohol Drinking, mesh: mesh:Rats, Long-Evans, mesh: mesh:Proto-Oncogene Proteins p21(ras), mesh: mesh:Methionine, mesh: mesh:Ethanol, mesh: mesh:Male, mesh: mesh:Animals, mesh: mesh:Choice Behavior, mesh: mesh:Sucrose, mesh: mesh:Mice, Transgenic
Male, Sucrose, 150, Cardiovascular, Farnesyltranstransferase [MESH], Choice Behavior, Transgenic, Alcohol Use and Health, Substance Misuse, Mice, Methionine, MESH: Animals, Mice, Transgenic [MESH], NEU] Life Sciences/Neurons and Cognition [[SDV], Proto-Oncogene Proteins p21(ras) [MESH], MESH: ras-GRF1, [SDV.MHEP.PHY] Life Sciences/Human health and pathology/Tissues and Organs, Mice [MESH], ras-GRF1 [MESH], MESH: Nucleus Accumbens, MESH: Ethanol, Alcohol Drinking, Basic Behavioral and Social Science, MESH: Choice Behavior, Sucrose [MESH], Binge Drinking, Proto-Oncogene Proteins p21(ras), Choice Behavior [MESH], Rats, Long-Evans, MESH: Farnesyltranstransferase, MESH: Phosphorylation, Ethanol, ras-GRF1, Binge Drinking [MESH], MESH: Sucrose, MHEP:PHY] Life Sciences/Human health and pathology/Tissues and Organs [[SDV], MESH: Alcohol Drinking, Medical and Health Sciences, Oral and gastrointestinal, Nucleus Accumbens, MESH: Binge Drinking, NEU] Sciences du Vivant/Neurosciences [[SDV], Rats, Long-Evans [MESH], Phosphorylation, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Ethanol [MESH], Alcohol Drinking [MESH], Alcoholism, Animals [MESH], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Biotechnology, MESH: Rats, MESH: Mice, Transgenic, Male [MESH], Mice, Transgenic, MESH: Proto-Oncogene Proteins p21(ras), MESH: Rats, Long-Evans, Behavioral and Social Science, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Farnesyltranstransferase, Phosphorylation [MESH], Rats [MESH], MESH: Mice, [SDV.NEU] Life Sciences/Neurons and Cognition, Neurology & Neurosurgery, Psychology and Cognitive Sciences, Methionine [MESH], Long-Evans, MESH: Male, MHEP:PHY] Sciences du Vivant/Médecine humaine et pathologie/Physiologie [[SDV], Rats, Good Health and Well Being, MESH: Methionine, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Nucleus Accumbens [MESH], mesh: mesh:Binge Drinking, mesh: mesh:Phosphorylation, mesh: mesh:Nucleus Accumbens, mesh: mesh:ras-GRF1, mesh: mesh:Farnesyltranstransferase, mesh: mesh:Rats, mesh: mesh:Mice, mesh: mesh:Alcohol Drinking, mesh: mesh:Rats, Long-Evans, mesh: mesh:Proto-Oncogene Proteins p21(ras), mesh: mesh:Methionine, mesh: mesh:Ethanol, mesh: mesh:Male, mesh: mesh:Animals, mesh: mesh:Choice Behavior, mesh: mesh:Sucrose, mesh: mesh:Mice, Transgenic
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