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However, longitudinal studies demonstrate that maternal cannabis exposure results in adverse outcomes in the offspring, with a heightened risk for developing psychopathology. One of the most reported psychiatric outcomes is the proneness to psychotic\u2010like experiences during childhood. How exposure to cannabis during gestation increases psychosis susceptibility in children and adolescents remains elusive. Preclinical research has indicated that in utero exposure to the major psychoactive component of cannabis, delta\u20109\u2010tetrahydrocannabinol (THC), deranges brain developmental trajectories towards vulnerable psychotic\u2010like endophenotypes later in life. Here, we present how prenatal THC exposure (PCE) deregulates mesolimbic dopamine development predisposing the offspring to schizophrenia\u2010relevant phenotypes, exclusively when exposed to environmental challenges, such as stress or THC. Detrimental effects of PCE are sex\u2010specific because female offspring do not display psychotic\u2010like outcomes upon exposure to these challenges. Moreover, we present how pregnenolone, a neurosteroid that showed beneficial properties on the effects elicited by cannabis intoxication, normalizes mesolimbic dopamine function and rescues psychotic\u2010like phenotypes. We, therefore, suggest this neurosteroid as a safe \u201cdisease\u2010modifying\u201d aid to prevent the onset of psychoses in vulnerable individuals. Our findings corroborate clinical evidence and highlight the relevance of early diagnostic screening and preventative strategies for young individuals at risk for mental diseases, such as male PCE offspring.<\/jats:p>","DOI":"10.1111\/jne.13240","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T03:02:56Z","timestamp":1675825376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Sex\u2010specific susceptibility to psychotic\u2010like states provoked by prenatal\n                    <scp>THC<\/scp>\n                    exposure: Reversal by pregnenolone"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5922-2404","authenticated-orcid":false,"given":"Roberto","family":"Frau","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology University of Cagliari  Monserrato Italy"},{"name":"The Guy Everett Laboratory for Neuroscience University of Cagliari  Cagliari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Melis","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology University of Cagliari  Monserrato Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,22]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sby058"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.2147\/NDT.S225643"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.schres.2009.03.005"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scog.2022.100249"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1017\/S2045796019000891"},{"issue":"7","key":"e_1_2_11_7_1","first-page":"413","article-title":"Onset and course of the first schizophrenic episode","volume":"14","author":"Hafner H","year":"1998","journal-title":"Kaohsiung J Med Sci"},{"issue":"2","key":"e_1_2_11_8_1","first-page":"S104","article-title":"Is there a primary prevention of schizophrenic psychiasis?","volume":"69","author":"Klosterk\u00f6tter J","year":"2001","journal-title":"Fortschr Neurol Psychiatr"},{"key":"e_1_2_11_9_1","first-page":"646","article-title":"The concept of basic symptoms in schizophrenic and schizoaffective psychoses","volume":"80","author":"Huber G","year":"1989","journal-title":"Recenti Prog Med"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.comppsych.2007.04.001"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2051-5545.2011.tb00044.x"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbx121"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(99)00289-9"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(00)00137-8"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-7634(03)00012-5"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1461145704004122"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2018.12.231"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2019.0076"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.15946"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-019-0512-2"},{"key":"e_1_2_11_21_1","first-page":"105","article-title":"Mesolimbic dopamine dysregulation as a signature of information processing deficits imposed by prenatal THC exposure. 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