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Deficits in the prefrontal and hippocampal excitatory\/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of \u03b15\u2010containing GABA<jats:sub>A<\/jats:sub> receptors (\u03b15\u2010GABA<jats:sub>A<\/jats:sub>Rs) SH\u2010053\u20102\u2032F\u2010R\u2010CH3 (10\u2009mg\/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH\u2010053\u20102\u2032F\u2010R\u2010CH3 could attenuate these changes. SH\u2010053\u20102\u2032F\u2010R\u2010CH3 was administered intraperitoneally 30\u2009min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self\u2010grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH\u2010053\u20102\u2032F\u2010R\u2010CH3 attenuated the impairments in sociability and cognitive function in male VPA\u2010exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA\u2010exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH\u2010053\u20102\u2032F\u2010R\u2010CH3. Despite sex differences, our findings indicate that \u03b15\u2010GABA<jats:sub>A<\/jats:sub>Rs positive allosteric modulators may effectively attenuate some core ASD symptoms.<\/jats:p>","DOI":"10.1002\/aur.3178","type":"journal-article","created":{"date-parts":[[2024,6,22]],"date-time":"2024-06-22T08:44:10Z","timestamp":1719045850000},"page":"1534-1544","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["An alpha <scp>5\u2010GABA<sub>A<\/sub><\/scp> receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in rats exposed to valproic acid in utero"],"prefix":"10.1002","volume":"17","author":[{"given":"Adriana Jesus","family":"Souza","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Ribeirao Preto Medical School University of S\u00e3o Paulo  Ribeirao Preto Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3971-5770","authenticated-orcid":false,"given":"\u00cdcaro Silva","family":"Freitas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Ribeirao Preto Medical School University of S\u00e3o Paulo  Ribeirao Preto Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dishary","family":"Sharmin","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery University of Wisconsin\u2010Milwaukee  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery University of Wisconsin\u2010Milwaukee  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco S.","family":"Guimar\u00e3es","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Ribeirao Preto Medical School University of S\u00e3o Paulo  Ribeirao Preto Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1033-1850","authenticated-orcid":false,"given":"Felipe V.","family":"Gomes","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Ribeirao Preto Medical School University of S\u00e3o Paulo  Ribeirao Preto 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