{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T22:33:10Z","timestamp":1767652390652,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T00:00:00Z","timestamp":1693353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Anti-Drug Policies Department, Presidency of the Council of Ministers, Italy","award":["FAR 2021","FAR 2022","RBFR12LDOW","Linea D1"],"award-info":[{"award-number":["FAR 2021","FAR 2022","RBFR12LDOW","Linea D1"]}]},{"name":"University of Ferrara","award":["FAR 2021","FAR 2022","RBFR12LDOW","Linea D1"],"award-info":[{"award-number":["FAR 2021","FAR 2022","RBFR12LDOW","Linea D1"]}]},{"name":"FIRB 2012","award":["FAR 2021","FAR 2022","RBFR12LDOW","Linea D1"],"award-info":[{"award-number":["FAR 2021","FAR 2022","RBFR12LDOW","Linea D1"]}]},{"name":"Catholic University of Rome","award":["FAR 2021","FAR 2022","RBFR12LDOW","Linea D1"],"award-info":[{"award-number":["FAR 2021","FAR 2022","RBFR12LDOW","Linea D1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Gamma-hydroxybutyric acid (GHB) at low dosages has anxiolytic effects and promotes REM sleep and low-wave deep sleep. In the U.S., the legal form of GHB is prescribed to adults suffering from narcolepsy-associated cataplexy; the sodium salt of GHB is reserved for alcohol-addiction treatment. GHB is also a molecule of abuse and recreational use, it is a controlled substance in several countries, so gamma-valerolactone (GVL) has frequently been used as a legal substitute for it. GHB\u2019s abuse profile is most likely attributable to its anxiolytic, hypnotic, and euphoric properties, as well as its widespread availability and inexpensive\/low cost on the illicit market. Methods: Our study is focused on evaluating the potential effects on the mouse brain after repeated\/prolonged administration of GHB and GVL at a pharmacologically active dose (100 mg\/kg) through behavioral study and immunohistochemical analysis using the markers tetraspanin 17 (TSPAN17), aldehyde dehydrogenase 5 (ALDH5A1), Gamma-aminobutyric acid type A receptor (GABA-A), and Gamma-aminobutyric acid type B receptor (GABA-B). Results: Our findings revealed that prolonged administration of GHB and GVL at a pharmacologically active dose (100 mg\/kg) can have effects on a component of the mouse brain, the intensity of which can be assessed using immunohistochemistry. The findings revealed that long-term GHB administration causes a significant plastic alteration of the GHB signaling system, with downregulation of the putative binding site (TSPAN17) and overexpression of ALDH5A1, especially in hippocampal neurons. Our findings further revealed that GABA-A and GABA-B receptors are downregulated in these brain locations, resulting in a greater decrease in GABA-B expression. Conclusions: The goal of this study, from the point of view of forensic pathology, is to provide a new methodological strategy for better understanding the properties of this controversial substance, which could help us better grasp the unknown mechanism underlying its abuse profile.<\/jats:p>","DOI":"10.3390\/ph16091225","type":"journal-article","created":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T09:44:46Z","timestamp":1693388686000},"page":"1225","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Effect of Repeated Administration of \u0263-Valerolactone (GVL) and GHB in the Mouse: Neuroadaptive Changes of the GHB and GABAergic System"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4862-2215","authenticated-orcid":false,"given":"Paolo","family":"Frisoni","sequence":"first","affiliation":[{"name":"Unit of Legal Medicine, AUSL of Ferrara, Via Arturo Cassoli 30, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2973-2446","authenticated-orcid":false,"given":"Giorgia","family":"Corli","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrine","family":"Bilel","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9337-9184","authenticated-orcid":false,"given":"Micaela","family":"Tirri","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura Camilla","family":"Gasparini","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, Institute of Legal Medicine, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8234-5525","authenticated-orcid":false,"given":"Letizia","family":"Alfieri","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Section of Legal Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6459-1669","authenticated-orcid":false,"given":"Margherita","family":"Neri","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Section of Legal Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"De-Giorgio","sequence":"additional","affiliation":[{"name":"Department of Health Care Surveillance and Bioethics, Section of Legal Medicine, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito 1, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8751-2882","authenticated-orcid":false,"given":"Matteo","family":"Marti","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Section of Legal Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy"},{"name":"Collaborative Center for the Italian National Early Warning System, Department of Anti-Drug Policies, Presidency of the Council of Ministers, 00186 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0301-0082(96)00064-0","article-title":"The Gamma-Hydroxybutyrate Signalling System in Brain: Organization and Functional Implications","volume":"51","author":"Maitre","year":"1997","journal-title":"Prog. 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