{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T16:30:34Z","timestamp":1759336234500,"version":"3.37.3"},"reference-count":64,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003968","name":"Iran National Science Foundation","doi-asserted-by":"publisher","award":["INSF- 96008684"],"award-info":[{"award-number":["INSF- 96008684"]}],"id":[{"id":"10.13039\/501100003968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008257","name":"Tarbiat Modares University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008257","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012330","name":"Cognitive Sciences and Technologies Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>\u0263-aminobutyric acid (<jats:italic>GABA<\/jats:italic>) facilitator valproic acid may be able to curb memory disruption induced by morphine exposure.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Objective<\/jats:title>\n<jats:p>The effects of the <jats:italic>GABA<\/jats:italic> facilitator valproic acid on the behavioral tolerance induced by morphine were investigated. Then hippocampal-dependent tasks named spatial-working and short-term memory procedures using the Y-maze apparatus were examined in morphine tolerant rats. Finally, the changes in the expression of hippocampal <jats:italic>GABA-A<\/jats:italic> receptors underlying morphine tolerance were also examined.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Rats were treated with daily morphine injections, with or without distinct contextual pairing. To examine the effect of valproic acid on morphine tolerance expression, valproic acid was pretreated an hour before morphine. Spatial-working and short-term memory procedures using the Y-maze apparatus were examined in morphine tolerant rats. Afterwards the changes in the expression of hippocampal <jats:italic>GABA\u03b1<\/jats:italic> receptors using the quantitative real-time PCR and western blot techniques to detect <jats:italic>GABAr<\/jats:italic>\u03b1 subunits mRNAs and protein level were studied.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Results<\/jats:title>\n<jats:p>Our results showed that both learned and non-associative morphine tolerance influence short-term memory and the subjacent expression of <jats:italic>GABAr<\/jats:italic>\u03b1 mRNAs and protein level. Despite its attenuating effects on the development and expression of both learned and non-associative morphine tolerance, only associative morphine tolerance-induced memory dysfunction was ameliorated by valproic acid pretreatment. We also found that the expression of <jats:italic>GABAr\u03b11<\/jats:italic>, <jats:italic>\u03b12<\/jats:italic>, <jats:italic>\u03b15<\/jats:italic> subunits mRNAs and <jats:italic>GABA\u03b1<\/jats:italic> protein level were affected heavier in associative morphine tolerant rats.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Our data supports the hypothesis that unconditioned and learned morphine tolerance influences short-term memory and the expression of <jats:italic>GABAr<\/jats:italic>\u03b1 <jats:italic>1<\/jats:italic>, <jats:italic>\u03b12<\/jats:italic>, <jats:italic>\u03b15<\/jats:italic> mRNAs and <jats:italic>GABAr<\/jats:italic>\u03b1 protein level differently, and adds to our understanding of the behavioral and molecular aspects of the learned tolerance to morphine effects.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0253902","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T22:05:40Z","timestamp":1631225140000},"page":"e0253902","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Unconditioned and learned morphine tolerance influence hippocampal-dependent short-term memory and the subjacent expression of GABA-A receptor alpha subunits"],"prefix":"10.1371","volume":"16","author":[{"given":"Ghazaleh","family":"Ghamkharinejad","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4179-5490","authenticated-orcid":true,"given":"Seyed 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