PMID- 30925704 OWN - NLM STAT- MEDLINE DCOM- 20190729 LR - 20200225 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 7 DP - 2019 Mar 28 TI - Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age. LID - 10.3390/ijms20071556 [doi] LID - 1556 AB - Ras homolog enriched in striatum (Rhes) is a protein that exerts important physiological functions and modulates psychostimulant drug effects. On this basis, the object of this study was to assess 3,4-methylenedioxymethamphetamine (MDMA) effects on microglial (CD11b) and astroglial (GFAP) activation and on dopamine neuron degeneration (TH) in wild-type (WT) and Rhes knockout (KO) male and female mice of different ages. Motor activity was also evaluated. Adult (3 months) MDMA-treated mice displayed an increase in GFAP-positive cells in striatum (STR), whereas the substantia nigra pars compacta (SNc) was affected only in male mice. In these mice, the increase of CD11b was more extensive including STR, SNc, motor cortex (CTX), ventral tegmental area (VTA), and nucleus accumbens (NAc). MDMA administration also affected TH immunoreactivity in both STR and SNc of male but not female WT and Rhes KO mice. In middle-aged mice (12 months), MDMA administration further increased GFAP and CD11b and decreased TH immunoreactivity in STR and SNc of all mice. Finally, MDMA induced a higher increase of motor activity in adult Rhes KO male, but not female mice. The results show that Rhes protein plays an important role on MDMA-mediated neuroinflammation and neurodegeneration dependent on gender and age, and confirm the important role of Rhes protein in neuroinflammatory and neurodegenerative processes. FAU - Costa, Giulia AU - Costa G AD - Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy. giulia.costa83@gmail.com. FAU - Porceddu, Pier Francesca AU - Porceddu PF AD - Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy. fra8714@hotmail.it. FAU - Serra, Marcello AU - Serra M AD - Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy. marcelloserra92@gmail.com. FAU - Casu, Maria Antonietta AU - Casu MA AD - Institute of Translational Pharmacology, UOS of Cagliari, National Research Council of Italy, Scientific and Technological Park of Sardinia POLARIS, 09010 Pula, Italy. mariaantonietta.casu@ift.cnr.it. FAU - Schiano, Valentina AU - Schiano V AD - Laboratory of Behavioral Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy. schiano@ceinge.unina.it. FAU - Napolitano, Francesco AU - Napolitano F AD - Laboratory of Behavioral Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy. napolitano@ceinge.unina.it. AD - Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", 80131 Naples, Italy. napolitano@ceinge.unina.it. FAU - Pinna, Annalisa AU - Pinna A AUID- ORCID: 0000-0002-4911-1735 AD - Neuroscience Institute, National Research Council of Italy, Cittadella Universitaria, 09042 Monserrato, Italy. apinna@unica.it. FAU - Usiello, Alessandro AU - Usiello A AD - Laboratory of Behavioral Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy. usiello@ceinge.unina.it. AD - Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, 81100 Caserta, Italy. usiello@ceinge.unina.it. FAU - Morelli, Micaela AU - Morelli M AD - Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy. morelli@unica.it. AD - Neuroscience Institute, National Research Council of Italy, Cittadella Universitaria, 09042 Monserrato, Italy. morelli@unica.it. AD - National Institute of Neuroscience (INN), University of Cagliari, 09100 Cagliari, Italy. morelli@unica.it. LA - eng GR - Legge Regionale 7 Agosto 2007, N.7, annualita 2008 and 2010/Regione Autonoma della Sardegna/ GR - Pr. 2015R9ASHT, PI Prof. Micaela Morelli/PRIN 2015/ PT - Journal Article DEP - 20190328 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Hallucinogens) RN - EC 3.6.1.- (GTP-Binding Proteins) RN - EC 3.6.1.- (Rasd2 protein, mouse) RN - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine) MH - Age Factors MH - Animals MH - Dopaminergic Neurons/*drug effects/pathology MH - Female MH - GTP-Binding Proteins/*genetics MH - Gene Deletion MH - Hallucinogens/*adverse effects MH - Inflammation/*chemically induced/genetics/pathology MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - N-Methyl-3,4-methylenedioxyamphetamine/*adverse effects MH - Neurodegenerative Diseases/*chemically induced/genetics/pathology MH - Sex Factors PMC - PMC6480667 OTO - NOTNLM OT - MDMA OT - Rhes knockout mice OT - astrocytes OT - dopamine OT - microglia OT - neurodegeneration OT - psychosis COIS- The authors declare that they have no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2019/03/31 06:00 MHDA- 2019/07/30 06:00 PMCR- 2019/04/01 CRDT- 2019/03/31 06:00 PHST- 2019/02/15 00:00 [received] PHST- 2019/03/21 00:00 [revised] PHST- 2019/03/24 00:00 [accepted] PHST- 2019/03/31 06:00 [entrez] PHST- 2019/03/31 06:00 [pubmed] PHST- 2019/07/30 06:00 [medline] PHST- 2019/04/01 00:00 [pmc-release] AID - ijms20071556 [pii] AID - ijms-20-01556 [pii] AID - 10.3390/ijms20071556 [doi] PST - epublish SO - Int J Mol Sci. 2019 Mar 28;20(7):1556. doi: 10.3390/ijms20071556.