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Tolerance plays a critical role in the development of alcohol use disorder (AUD) because it leads to the escalation of drinking and dependence. Understanding the molecular mechanisms underlying alcohol tolerance is therefore important for the development of effective therapeutics and for understanding addiction in general. This review explores the molecular basis of alcohol tolerance in invertebrate models, Drosophila and C. elegans, focusing on synaptic transmission. Both organisms exhibit biphasic responses to ethanol and develop tolerance similar to that of mammals. Furthermore, the availability of several genetic tools makes them a great candidate to study the molecular basis of ethanol response. Studies in invertebrate models show that tolerance involves conserved changes in the neurotransmitter systems, ion channels, and synaptic proteins. These neuroadaptive changes lead to a change in neuronal excitability, most likely to compensate for the enhanced inhibition by ethanol.<\/jats:p>","DOI":"10.3390\/ijms25136838","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T08:50:08Z","timestamp":1718959808000},"page":"6838","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synaptic Mechanisms of Ethanol Tolerance and Neuroplasticity: Insights from Invertebrate Models"],"prefix":"10.3390","volume":"25","author":[{"given":"Aakriti","family":"Bhandari","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Neuroscience Graduate Program, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Seguin","sequence":"additional","affiliation":[{"name":"Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3813-5723","authenticated-orcid":false,"given":"Adrian","family":"Rothenfluh","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Neuroscience Graduate Program, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Neurobiology, University of Utah, Salt Lake City, UT 84112, USA"},{"name":"Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,21]]},"reference":[{"key":"ref_1","unstructured":"(2024, May 30). 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