Poly (I:C)-induced maternal immune activation generates impairment of reversal learning performance in offspring.

Maternal immune activation (MIA) induces a variety of behavioral and brain abnormalities in offspring of rodent models, compatible with neurodevelopmental disorders, such as schizophrenia or autism. However, it remains controversial whether MIA impairs reversal learning, a basic expression of cognitive flexibility that seems to be altered in schizophrenia. In the present study, MIA was induced by administration of a single dose of polyriboinosinic-polyribocytidylic acid (Poly (I:C) (5 mg/kg i.p.)) or saline to mouse pregnant dams in gestational day (GD) 9.5. Immune activation was monitored through changes in weight and temperature. The offspring were evaluated when they reached adulthood (8 weeks) using a touchscreen-based system to investigate the effects of Poly (I:C) on discrimination and reversal learning performance. After an initial pre-training, mice were trained to discriminate between two different stimuli, of which only one was rewarded (acquisition phase). When the correct response reached above 80% values for two consecutive days, the images were reversed (reversal phase) to assess the adaptation capacity to a changing environment. Maternal Poly (I:C) treatment did not interfere with the learning process but induced deficits in reversal learning compared to control saline animals. Thus, the accuracy in the reversal phase was lower, and Poly (I:C) animals required more sessions to complete it, suggesting impairments in cognitive flexibility. This study advances the knowledge of how MIA affects behavior, especially cognitive domains that are impaired in schizophrenia. The findings support the validity of the Poly (I:C)-based MIA model as a tool to develop pharmacological treatments targeting cognitive deficits associated with neurodevelopmental disorders.

New insights into the effects of serotonin on Parkinson's disease and depression through its role in the gastrointestinal tract.

Neuropsychiatric and neurodegenerative disorders are frequently associated with gastrointestinal (GI) co-pathologies. Although the central and enteric nervous systems (CNS and ENS, respectively) have been studied separately, there is increasing interest in factors that may contribute to conditions affecting both systems. There is compelling evidence that serotonin (5-HT) may play an important role in several gut-brain disorders. It is well known that 5-HT is essential for the development and functioning of the CNS. However, most of the body's 5-HT is produced in the GI tract. A deeper understanding of the specific effects of enteric 5-HT on gut-brain disorders may provide the basis for the development of new therapeutic targets. This review summarizes current data focusing on the important role of 5-HT in ENS development and motility, with particular emphasis on novel aspects of 5-HT signaling in conditions where CNS and ENS comorbidities are common, such as Parkinson's disease and depressive disorders.

Ethanol and illicit drugs acute use and abuse as risk factors for suicide: A case-control study based on forensic autopsies in the Basque Country, Spain.

INTRODUCTION: Abuse/dependence and acute use of ethanol and illicit drug are considered risk factors for suicide. The risk is also influenced by demographic conditions and/or psychiatric comorbidity. The aim of the study was to test the association between presence of ethanol, illicit substances and prescribed drugs in suicide decedents and controls. MATERIALS AND METHODS: Case-control study of autopsies performed in the Biscay Forensic Pathology Service, Basque Country, Spain from 01/01/2010 to 30/06/2021 in subjects between 15 and 55 years old. Suicide deaths (n=481) with completed autopsy were evaluated. Concurrent natural deaths were chosen as controls (n=330). The risk for suicide according to demographic, toxicological and psychiatric variables was analyzed using logistic regression. RESULTS: Ethanol was present in 21% and illicit drugs, mainly cannabis, cocaine and amphetamine, in 27% of suicide deaths. Illicit drugs were more frequent among males. In 63% of suicide cases, prescribed psychotropic drugs were detected. In a multivariate analysis, the main risk factors for suicide were psychiatric diagnosis of illicit drug abuse/dependence (OR=5.56, 95% CI 2.74-11.30) or another mental disease as mood or psychotic disorders (OR=13.05, 95% CI 8.79-19.37). Acute presence of ethanol (OR=4.22, 95% CI 2.52-7.08), recent use of cocaine (OR=2.52, 95% CI 1.05-6.07) and age <35 years (OR=2.50, 95% CI 1.62-3.87) were also associated with suicide deaths. CONCLUSIONS: The presence of drugs of abuse in suicide deaths of people ≤55 years old is high. Recent use of ethanol and cocaine is significantly associated with an increased suicide risk. Specific prevention strategies against exposition to substances of abuse should be promoted, especially in psychiatric patients.

5-HT2A receptor-mediated Gαq/11 activation in psychiatric disorders: A postmortem study.

OBJECTIVES: Serotonin-2A (5-HT2A) receptors play an important role in the regulation of many brain functions that are disturbed in patients with such psychiatric diseases as mood disorders and schizophrenia. The objective of this study was to evaluate 5-HT2A receptor-mediated signalling pathway through Gαq/11 activation in psychiatric patients by using post-mortem brain samples. METHODS: Functional activation of Gαq/11 proteins coupled to 5-HT2A receptors was determined by means of [35S]GTPγS binding/immunoprecipitation assay in post-mortem prefrontal cortex of psychiatric patients diagnosed as bipolar disorder (BP), major depressive disorder (MDD), and schizophrenia, and individually matched controls. The effects of antipsychotic treatment as well as suicide were also analysed. RESULTS: There was no significant difference in maximum percent increase (%Emax) or slope factor among the four groups. The negative logarithm of concentration eliciting the half-maximal effect (pEC50) was significantly reduced in BP and schizophrenia patients as compared to controls. These alterations were attributable to antipsychotic medication. The pEC50 values in 'non-suicide' group of schizophrenia, but not in 'suicide' group, were significantly reduced as compared with controls. CONCLUSIONS: Altered 5-HT2A receptor-mediated signalling pathway through Gαq/11 proteins in prefrontal cortex might be apparently involved in pathophysiology and pharmacotherapy of BP and schizophrenia. In schizophrenic patients, these alterations as a result of successful treatment with antipsychotic agents may help in prevention of suicidal behaviour.

Diez años de investigación traslacional colaborativa en enfermedades mentales: el CIBERSAM / CIBERSAM: Ten years of collaborative translational research in mental disorders

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El sistema noradrenérgico en la neurobiología de la depresión / The noradrenergic system in the neurobiology of depression

Introducción: Los tratamientos antidepresivos delos que se dispone en la actualidad se encuentran aún muy lejos de ser óptimos. Por un lado hay un porcentaje de pacientes que no responden a los tratamientos y además hay un período de retraso de unas 3-4 semanas entre el inicio del tratamiento y la aparición del efecto terapéutico. El conocimiento dela neurobiología de la enfermedad resulta imprescindible para el desarrollo de nuevos tratamientos. Objetivo: Revisar las bases neurobiológicas de uno de los sistemas diana de los fármacos antidepresivos, el sistema noradrenérgico. Desarrollo: se describe la anatomía y la función del núcleo noradrenérgico más importante, el locus coeruleus, su interacción con los demás sistemas de neurotransmisión, así como el papel de los receptores adrenérgicos alfa2 en el mecanismo de acción de los fármacos antidepresivos. Conclusiones: El estudio profundo de los sistemas de neurotransmisión diana de los antidepresivos es el mejor abordaje como fuente de conocimiento para el diseño de nuevas estrategias antidepresivas. Los receptores adrenérgicos alfa2 parecen tener un papel muy relevante en el mecanismo de acción de estos fármacos. Además, los antidepresivos tanto de perfil noradrenérgico como serotoninérgico son capaces de modular el sistema noradrenérgico, lo que evidencia que ambos sistemas son modulados conjuntamente en el SNC (AU)

Introduction: Currently available antidepressant drugs are far from optimal. On the one hand, approximately 30% patients are treatment-resistant, while on the other, there is a 3-4 week delay between the start of treatment and the onset of therapeutic effects. Knowledge of the neurobiology of depression is essential for the development of new therapeutic strategies. Objective: The present article aims to review the neurobiological bases of the noradrenergic system, one of the main targets of antidepressant drugs. Development: we describe current knowledge of the anatomy and function of the most important noradrenergic nucleus, the locus coeruleus, and its interaction with different neurotransmission systems, as well as of the role of alfa2-adrenoceptors in the mechanism of action of antidepressant drugs. Conclusions: Study of neurotransmission targets for antidepressants seems to be the most effective approach for the design of new antidepressant drugs. In this context, the alfa2-adrenoceptors play a major role in the mechanism of action of these agents. In addition, antidepressants, whether with a noradrenergic or a serotonergic profile, are able to modulate the noradrenergic system, demonstrating that both systems are modulated at the same time in the central nervous system (AU)