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Preclinical evidence suggests a main role of lysophosphatidic acid (LPA) signaling in anxiogenic responses and drug addiction. To further explore the potential role of the LPA signaling system in sex differences and psychiatric comorbidity in cocaine use disorder (CUD), we conducted a cross-sectional study with 88 patients diagnosed with CUD in outpatient treatment and 60 healthy controls. Plasma concentrations of total LPA and LPA species (16:0, 18:0, 18:1, 18:2 and 20:4) were quantified and correlated with cortisol and tryptophan metabolites [tryptophan (TRP), serotonin (5-HT), kynurenine (KYN), quinolinic acid (QUIN) and kynurenic acid (KYNA)]. We found sexual dimorphism for the total LPA and most LPA species in the control and CUD groups. The total LPA and LPA species were not altered in CUD patients compared to the controls. There was a significant correlation between 18:2 LPA and age at CUD diagnosis (years) in the total sample, but total LPA, 16:0 LPA and 18:2 LPA correlated with age at onset of CUD in male patients. Women with CUD had more comorbid anxiety and eating disorders, whereas men had more cannabis use disorders. Total LPA, 18:0 LPA and 20:4 LPA were significantly decreased in CUD patients with anxiety disorders. Both 20:4 LPA and total LPA were significantly higher in women without anxiety disorders compared to men with and without anxiety disorders. Total LPA and 16:0 LPA were significantly decreased in CUD patients with childhood ADHD. Both 18:1 LPA and 20:4 LPA were significantly augmented in CUD patients with personality disorders. KYNA significantly correlated with total LPA, 16:0 LPA and 18:2 LPA species, while TRP correlated with the 18:1 LPA species. Our results demonstrate that LPA signaling is affected by sex and psychiatric comorbidity in CUD patients, playing an essential role in mediating their anxiety symptoms.<\/jats:p>","DOI":"10.3390\/ijms242115586","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T09:54:08Z","timestamp":1698227648000},"page":"15586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Plasma Lysophosphatidic Acid Concentrations in Sex Differences and Psychiatric Comorbidity in Patients with Cocaine Use Disorder"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3257-8459","authenticated-orcid":false,"given":"Nerea","family":"Requena-Oca\u00f1a","sequence":"first","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina (IBIMA-Plataforma BIONAND), 29590 M\u00e1laga, Spain"},{"name":"Unidad de Gesti\u00f3n Cl\u00ednica de Salud Mental, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3489-1465","authenticated-orcid":false,"given":"Mar\u00eda","family":"Flores-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina (IBIMA-Plataforma BIONAND), 29590 M\u00e1laga, Spain"},{"name":"Unidad de Gesti\u00f3n Cl\u00ednica de Salud Mental, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nuria","family":"Garc\u00eda-Marchena","sequence":"additional","affiliation":[{"name":"Unidad de Gesti\u00f3n Cl\u00ednica de Salud Mental, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"},{"name":"Departamento de Psicobiolog\u00eda y Metodolog\u00eda en Ciencias del Comportamiento, Facultad de Psicolog\u00eda, Universidad Complutense de Madrid, 28223 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5256-8904","authenticated-orcid":false,"given":"Francisco J.","family":"Pav\u00f3n-Mor\u00f3n","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina (IBIMA-Plataforma BIONAND), 29590 M\u00e1laga, Spain"},{"name":"Unidad de Gesti\u00f3n Cl\u00ednica de Salud Mental, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"},{"name":"Unidad de Gesti\u00f3n Cl\u00ednica del Coraz\u00f3n, Hospital Universitario Virgen de la Victoria de M\u00e1laga, 29010 M\u00e1laga, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0011-2817","authenticated-orcid":false,"given":"Carmen","family":"Pedraza","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina (IBIMA-Plataforma BIONAND), 29590 M\u00e1laga, Spain"},{"name":"Departamento de Psicobiolog\u00eda y Metodolog\u00eda de las Ciencias del Comportamiento, Facultad de Psicolog\u00eda, Universidad de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agust\u00edn","family":"Wallace","sequence":"additional","affiliation":[{"name":"Departamento de Psicobiolog\u00eda y Metodolog\u00eda de las Ciencias del Comportamiento, Facultad de Psicolog\u00eda, Universidad de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Estela","family":"Castilla-Ortega","sequence":"additional","affiliation":[{"name":"Departamento de Psicobiolog\u00eda y Metodolog\u00eda de las Ciencias del Comportamiento, Facultad de Psicolog\u00eda, Universidad de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-5795","authenticated-orcid":false,"given":"Fernando","family":"Rodr\u00edguez de Fonseca","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina (IBIMA-Plataforma BIONAND), 29590 M\u00e1laga, Spain"},{"name":"Unidad de Gesti\u00f3n Cl\u00ednica de Salud Mental, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonia","family":"Serrano","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina (IBIMA-Plataforma BIONAND), 29590 M\u00e1laga, Spain"},{"name":"Unidad de Gesti\u00f3n Cl\u00ednica de Salud Mental, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro","family":"Araos","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga y Plataforma en Nanomedicina (IBIMA-Plataforma BIONAND), 29590 M\u00e1laga, Spain"},{"name":"Unidad de Gesti\u00f3n Cl\u00ednica de Salud Mental, Hospital Regional Universitario de M\u00e1laga, 29010 M\u00e1laga, Spain"},{"name":"Departamento de Psicobiolog\u00eda y Metodolog\u00eda de las Ciencias del Comportamiento, Facultad de Psicolog\u00eda, Universidad de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,25]]},"reference":[{"key":"ref_1","unstructured":"EMCDDA (2022). 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