Lack of interactions between prenatal immune activation and Δ9-tetrahydrocannabinol exposure during adolescence in behaviours relevant to symptom dimensions of schizophrenia in rats.

The causality in the association between cannabis use and the risk of developing schizophrenia has been the subject of intense debate in the last few years. The development of animal models recapitulating several aspects of the disease is crucial for shedding light on this issue. Given that maternal infections are a known risk for schizophrenia, here, we used the maternal immune activation (MIA) model combined with THC exposure during adolescence to examine several behaviours in rats (working memory in the Y maze, sociability in the three-chamber test, sucrose preference as a measure, prepulse inhibition and formation of incidental associations) that are similar to the different symptom clusters of the disease. To this end, we administered LPS to pregnant dams and when the offspring reached adolescence, we exposed them to a mild dose of THC to examine their behaviour in adulthood. We also studied several parameters in the dams, including locomotor activity in the open field, elevated plus maze performance and their response to LPS, that could predict symptom severity of the offspring, but found no evidence of any predictive value of these variables. In the adult offspring, MIA was associated with impaired working memory and sensorimotor gating, but surprisingly, it increased sociability, social novelty and sucrose preference. THC, on its own, impaired sociability and social memory, but there were no interactions between MIA and THC exposure. These results suggest that, in this model, THC during adolescence does not trigger or aggravate symptoms related to schizophrenia in rats.

Untargeted metabolomic study by liquid chromatography-mass spectrometry in brain tissues on the effects of combined cocaine and ethanol self-administration in male and female young rats.

The combined use of ethanol and cocaine is frequent among drug-abuse users and leads to further exacerbation of health consequences compared to individual consumption and this is of special concern during the transition to adulthood. Despite its high prevalence, the effect of combined consumption of cocaine and ethanol has been scarcely studied. In this work, we report the first untargeted metabolomic study in brain tissues to contribute to the advancement in the knowledge of the possible neurobiological effects of this polysubstance dependence. Liquid Chromatography coupled to high resolution Mass Spectrometry was employed to analyze three different brain tissues samples, prefrontal cortex, striatum and hippocampus, from male and female young rats exposed intravenously to a self-administration of these drugs. After optimizing the best sample treatment and selecting the chromatographic and detection conditions to find the maximum number of significant features (possible biomarker metabolites), the high resolution of the Orbitrap analyzer used in this work has made it possible to find up to 761 significant features with assigned molecular formula, of which up to 190 were tentatively identified and 44 unequivocally confirmed. The results demonstrated that the altered metabolic pathways are involved in multiple functions: receptor systems, such as the Glutamine-Glutamic acid-GABA axis or the catecholamine pathway, purinergic and pyrimidine pathways, fatty acids or oxidative stress, among others.

Interaction between maternal immune activation and peripubertal stress in rats: impact on cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome.

Substance use disorders are more prevalent in schizophrenia, but the causal links between both conditions remain unclear. Maternal immune activation (MIA) is associated with schizophrenia which may be triggered by stressful experiences during adolescence. Therefore, we used a double-hit rat model, combining MIA and peripubertal stress (PUS), to study cocaine addiction and the underlying neurobehavioural alterations. We injected lipopolysaccharide or saline on gestational days 15 and 16 to Sprague-Dawley dams. Their male offspring underwent five episodes of unpredictable stress every other day from postnatal day 28 to 38. When animals reached adulthood, we studied cocaine addiction-like behaviour, impulsivity, Pavlovian and instrumental conditioning, and several aspects of brain structure and function by MRI, PET and RNAseq. MIA facilitated the acquisition of cocaine self-administration and increased the motivation for the drug; however, PUS reduced cocaine intake, an effect that was reversed in MIA + PUS rats. We found concomitant brain alterations: MIA + PUS altered the structure and function of the dorsal striatum, increasing its volume and interfering with glutamatergic dynamics (PUS decreased the levels of NAA + NAAG but only in LPS animals) and modulated specific genes that could account for the restoration of cocaine intake such as the pentraxin family. On its own, PUS reduced hippocampal volume and hyperactivated the dorsal subiculum, also having a profound effect on the dorsal striatal transcriptome. However, these effects were obliterated when PUS occurred in animals with MIA experience. Our results describe an unprecedented interplay between MIA and stress on neurodevelopment and the susceptibility to cocaine addiction.

Plasma Amino Acid Concentrations in Patients with Alcohol and/or Cocaine Use Disorders and Their Association with Psychiatric Comorbidity and Sex.

(1) Background: Co-occurrence of mental and substance use disorders (SUD) is prevalent, but complicates their clinical courses, and specific biomarkers are required. Amino acids are altered in primary mental disorders; however, little is known about SUD and psychiatric comorbidity. Because most psychiatric disorders and biomarkers show sex differences, we investigated amino acids in men and women with alcohol and/or cocaine use disorders (AUD and/or CUD) and psychiatric comorbidity. (2) Methods: A cross-sectional study was conducted in 295 participants, who were divided into four groups (AUD, n = 60; CUD, n = 41; AUD + CUD, n = 64; and control, n = 130). Participants were clinically assessed, and plasma amino acid concentrations were analyzed in relation to sex, diagnosis of SUD and psychiatric comorbidity (3) Results: In the total sample, there were sex differences, and women showed lower Iso, Leu, Gln and Glu than men. While patients with CUD and AUD + CUD had higher Glu, Gly, Orn and Ser than controls, patients with AUD showed no differences. In SUD, patients with psychiatric comorbidity had lower Orn and higher Ala than non-comorbid patients in the AUD group. (4) Conclusions: There was a dysregulation of plasma amino acids in abstinent patients with SUD. However, our results suggest the importance of considering the clinical characteristics and sex in the validity of amino acids as potential biomarkers for SUD.

Ex vivo 1H-MRS brain metabolic profiling in a two-hit model of neurodevelopmental disorders: Prenatal immune activation and peripubertal stress.

Prenatal infections are environmental risk factors for neurodevelopmental disorders. In addition, traumatic experiences during adolescence in individuals exposed to infections during gestation could increase the risk of schizophrenia. It is of the most crucial importance to discover potential markers of the disease in its early stages or before its onset, so that therapeutic strategies may be implemented. In the present study, we combined a proposed two-hit model of schizophrenia-related symptoms with proton magnetic resonance spectroscopy (1H-MRS) to discover potential biomarkers. To this end, we i.p. injected 100 µg/kg/ml of lipopolysaccharide (LPS) or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to five episodes of stress or handling on alternate days during postnatal days (PND) 28-38. Once the animals reached adulthood (PND70), we evaluated prepulse inhibition (PPI). At PND90, we performed an ex vivo 1H-MRS study in the cortex and striatum. While we did not detect alterations in PPI at the age tested, we found neurochemical disturbances induced by LPS, stress or (more interestingly) their interaction. LPS decreased glucose levels in the cortex and striatum and altered glutamate, glutamine and N-acetylaspartate levels. Glutamate and glutamine levels in the left (but not right) striatum were differentially affected by prenatal LPS exposure in a manner that depended on stress experiences. These results suggest that alterations in the glutamate cycle in the striatum could be used as early markers of developmental disorders.