Plasma concentrations of lysophosphatidic acid and the expression of its receptors in peripheral blood mononuclear cells are altered in patients with cocaine use disorders

Abstract

We have recently reported alterations in the plasma concentrations of lysophosphatidic acid (LPA) in patients with substance use disorders. In order to further explore the potential role of the LPA signaling system as biomarker in cocaine use disorders (CUD) we conducted a cross-sectional study with 105 patients diagnosed with CUD and 92 healthy controls. Participants were clinically evaluated and blood samples were collected to determine plasma concentrations of total LPA and LPA species (16:0-, 18:0-, 18:1-, 18:2-, and 20:4-LPA), and the gene expression of LPA1 and LPA2 receptors in peripheral blood mononuclear cells. We found that patients with CUD had significantly lower plasma concentration of the majority of LPA species, while the mRNA expression of LPA1 receptor was found to be higher than controls. Moreover, we found a positive association between plasma concentration of 20:4-LPA and relevant CUD-related variables: age of onset cocaine use and length of cocaine abstinence. The statistical analysis revealed sex differences in concentrations of total LPA and LPA species, and women showed higher LPA concentrations than men. Furthermore, studies in rats of both sexes showed that plasma concentrations of total LPA were also altered after acute and chronic cocaine administration, revealing a sexual dimorphism in these effects. This study found alterations on the LPA signaling system in both, patients with CUD and rats treated with cocaine. Our results demonstrate that LPA signaling is impacted by CUD and sex, which must be taken into consideration in future studies evaluating LPA as a reliable biomarker for CUD.

Plasma Lysophosphatidic Acid Concentrations in Sex Differences and Psychiatric Comorbidity in Patients with Cocaine Use Disorder

“…Thus, LPA receptors have been implicated in neurodevelopmental and neuropsychiatric diseases such as neuropathic pain, ischemic stroke, traumatic brain injury, spinal cord injury, fetal hypoxia, fetal hydrocephalus, schizophrenia and Alzheimer disease [22,27]. Furthermore, sex differences in all LPA species unless for LPA 18:0 and 18:1 have been found in previous studies revealing a robust sexual dimorphism [23,28,29]. On the other hand, because the activation of the LPA receptor has been involved with the release of neurotransmitters (e.g., dopamine) associated with behavior, reward and learning and memory processes, it has been suggested to be implicated in substance use disorders [30][31][32][33].…”

“…Recently, studies in rats showed that plasma levels of total LPA were lower after 30 min of acute and chronic cocaine administration (5 mg/kg for males and 30 mg/kg for females). In addition, total LPA concentrations were lower before 72 h of abstinence in male rats that were exposed to 15 mg/kg every day for two weeks, but abstinence had no impact on total LPA levels in females rats [29]. In contrast, intracerebroventricular infusions of LPA in mice might increase adult-hippocampal neurogenesis that enhances forgetting of cocaineassociated contextual memories [48].…”

“…On the other hand, lower plasma levels of total LPA, LPA 18:2 and LPA 16:0 have been reported in patients with substance use disorders [34]. Especially, decreases in total LPA, 16:0 LPA, 18:1 LPA, 18:2 and 20:4 have been found in CUD patients compared to controls [29]. Furthermore, plasma concentrations of total LPA, 18:1, 18:2 and 20:4 were even more decreased in CUD patients compared to patients with alcohol use disorder [34].…”

“…On the other hand, because the activation of the LPA receptor has been involved with the release of neurotransmitters (e.g., dopamine) associated with behavior, reward and learning and memory processes, it has been suggested to be implicated in substance use disorders [30][31][32][33]. Thus, we have recently found that patients with CUD have significantly lower plasma concentrations of total LPA and some LPA species [29,34], while the mRNA expression of the LPA 1 receptor has been found to be higher than controls [29]. In addition, several preclinical studies have also linked the effects of LPA with anxiety like-behaviors [33].…”