{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:45:50Z","timestamp":1791837950243,"version":"4.3.4"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"6","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,3,13]]},"abstract":"<jats:p>\n                    Protracted administration of diazepam elicits tolerance, whereas\n discontinuation of treatment results in signs of dependence. Tolerance\n to the anticonvulsant action of diazepam is present in an early phase\n (6, 24, and 36 h) but disappears in a late phase (72\u201396 h) of\n withdrawal. In contrast, signs of dependence such as decrease in\n open-arm entries on an elevated plus-maze and increased susceptibility\n to pentylenetetrazol-induced seizures were apparent 96 h (but not\n 12, 24, or 48 h) after diazepam withdrawal. During the first\n 72 h of withdrawal, tolerance is associated with changes in the\n expression of GABA\n                    <jats:sub>A<\/jats:sub>\n                    (\u03b3-aminobutyric acid type A) receptor\n subunits (decrease in \u03b3\n                    <jats:sub>2<\/jats:sub>\n                    and \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    ; increase\n in \u03b1\n                    <jats:sub>5<\/jats:sub>\n                    ) and with an increase of mRNA expression of the\n most abundant form of glutamic acid decarboxylase (GAD),\n GAD\n                    <jats:sub>67<\/jats:sub>\n                    . In contrast,\n                    <jats:sc>dl<\/jats:sc>\n                    -\u03b1-amino-3-hydroxy-5-methylisoxazole-4-propionic acid\n (AMPA) receptor GluR1 subunit mRNA and cognate protein, which are\n normal during the early phase of diazepam withdrawal, increase by\n approximately 30% in cortex and hippocampus in association with the\n appearance of signs of dependence 96 h after diazepam withdrawal.\n Immunohistochemical studies of GluR1 subunit expression with\n gold-immunolabeling technique reveal that the increase of GluR1 subunit\n protein is localized to layer V pyramidal neurons and their apical\n dendrites in the cortex, and to pyramidal neurons and in their\n dendritic fields in hippocampus. The results suggest an involvement of\n GABA-mediated processes in the development and maintenance of tolerance\n to diazepam, whereas excitatory amino acid-related processes\n (presumably via AMPA receptors) may be involved in the expression\n of signs of dependence after withdrawal.\n                  <\/jats:p>","DOI":"10.1073\/pnas.051628698","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:41:48Z","timestamp":1027680108000},"page":"3483-3488","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":79,"title":["Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to benzodiazepines"],"prefix":"10.1073","volume":"98","author":[{"given":"Emanuela","family":"Izzo","sequence":"first","affiliation":[{"name":"Psychiatric Institute, Department of Psychiatry, College of\r Medicine, University of Illinois, Chicago, IL 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