Is the acquired hypothyroidism a risk factor for developing psychiatric disorders?

Hypothyroidism is a prevalent thyroid condition in which the thyroid gland fails to secrete an adequate amount of thyroid hormone into the bloodstream. This condition may develop due to genetic or acquired factors. The most frequent cause of acquired hypothyroidism is chronic autoimmune thyroiditis, also known as Hashimoto's disease. Acquired hypothyroidism is diagnosed when patients present with overt hypothyroidism (also known as clinical hypothyroidism), as they exhibit increased TSH and decreased T3 and T4 serum levels. This article examines the prevalence of psychiatric disorders among patients diagnosed with acquired hypothyroidism with or without Levothyroxine treatment. We discuss the available evidence indicating that acquired hypothyroidism may be a risk factor for psychiatric disorders, and the effectiveness of thyroid treatment in relieving psychiatric symptoms. Additionally, we provide critical details on thyroid hormone cutoff values reported in the literature, their potential clinical importance, and their correlation with psychiatric symptoms. Finally, we examined the various mechanisms by which acquired hypothyroidism can lead to depression. The high rate of comorbidity between hypothyroidism and psychiatric disorders deserves special attention, indicating the importance of consistent monitoring and timely identification of psychiatric symptoms to prevent disease exacerbation and facilitate therapeutic management. On the other hand, several mechanisms underlie the strong association between depression and acquired hypothyroidism. Deeper research into these mechanisms will allow knowledge of the pathophysiology of depression in patients with acquired hypothyroidism and will provide clues to design more precise therapeutic strategies for these patients.

Use of Extracellular Monomeric Ubiquitin as a Therapeutic Option for Major Depressive Disorder.

Major depressive disorder (MDD) is a mood disorder that has become a global health emergency according to the World Health Organization (WHO). It affects 280 million people worldwide and is a leading cause of disability and financial loss. Patients with MDD present immunoendocrine alterations like cortisol resistance and inflammation, which are associated with alterations in neurotransmitter metabolism. There are currently numerous therapeutic options for patients with MDD; however, some studies suggest a high rate of therapeutic failure. There are multiple hypotheses explaining the pathophysiological mechanisms of MDD, in which several systems are involved, including the neuroendocrine and immune systems. In recent years, inflammation has become an important target for the development of new therapeutic options. Extracellular monomeric ubiquitin (emUb) is a molecule that has been shown to have immunomodulatory properties through several mechanisms including cholinergic modulation and the generation of regulatory T cells. In this perspective article, we highlight the influence of the inflammatory response in MDD. In addition, we review and discuss the evidence for the use of emUb contained in Transferon as a concomitant treatment with selective serotonin reuptake inhibitors (SSRIs).

Concomitant Treatment with Doxycycline and Rifampicin in Balb/c Mice Infected with Brucella abortus 2308 Fails to Reduce Inflammation and Motor Disability.

Brucellosis is an infection widely distributed around the world, and in some countries it is considered a public health problem. Brucellosis causes insidious symptoms that make it difficult to diagnose. Infection can also trigger chronic pain and neuropsychiatric complications. Antibiotics are not always effective to eradicate infection, contributing to chronicity. We aimed to investigate the effects of antibiotic treatment on proinflammatory cytokines, neurotransmitters, corticosterone, and behavior in a murine model of infecrion of B. abortus strain 2308. Four study groups were created: (a) control; (b) antibiotic control; (c) infected with B. abortus 2308; and (d) infected and treated with rifampicin and doxycycline. We determined B. abortus 2308 colony-forming units (CFUs), the count of dendritic cells, and macrophages in the spleen; serum levels of cytokines and corticosterone; levels of serotonin, dopamine, epinephrine, and norepinephrine in the brain; and equilibrium, physical strength, anxiety, and hopelessness tests. The infected and treated mice group was compared with the control and infected mice to assess whether treatment is sufficient to recover neuroimmunoendocrine parameters. Our results showed that despite the treatment of brucellosis with rifampicin and doxycycline, antibiotic-treated mice showed a persistence of B. abortus 2308 CFUs, an increased count in macrophage number, and higher circulating levels of corticosterone. Furthermore, the levels of IL-12, IL-6, and TNF-α remained higher. We found a decrease in muscular strength and equilibrium concomitant to changes in neurotransmitters in the hippocampus, cerebellum, and frontal cortex. Our data suggest that the remaining bacterial load after antibiotic administration favors inflammatory, neurochemical, and behavioral alterations, partly explaining the widespread and paradoxical symptomatology experienced by patients with chronic brucellosis.

Risperidone Decreases Expression of Serotonin Receptor-2A (5-HT2A) and Serotonin Transporter (SERT) but Not Dopamine Receptors and Dopamine Transporter (DAT) in PBMCs from Patients with Schizophrenia.

Dopamine and serotonin receptors and transporters play an essential role in the pathophysiology of schizophrenia; changes in their expression have been reported in neurons and leukocytes. Each antipsychotic induces a unique pattern in leukocyte function and phenotype. However, the use of polytherapy to treat schizophrenia makes it challenging to determine the specific effects of risperidone on peripheral blood mononuclear cells (PBMCs). The aim of this study was to evaluate the changes in the expression of D3, D5, DAT, 5-HT2A, and SERT in PBMCs from healthy volunteers (HV), drug-naive patients with schizophrenia (PWS), drug-free PWS, and PWS treated with risperidone for up to 40 weeks using quantitative PCR. Our study revealed elevated mRNA levels of D3, DAT, 5-HT2A, and SERT in unmedicated PWS. Treatment with risperidone led to a reduction only in the expression of 5-HT2A and SERT. Furthermore, we observed a moderate correlation between 5-HT2A expression and the positive and negative syndrome scale (PANSS), as well as SERT expression and PANSS scale. We also found a moderate correlation between 5-HT2A and SERT expression and the positive subscale. The duration of risperidone consumption had a significant negative correlation with the expression of 5-HT2A and SERT. Our study introduces the measurement of 5-HT2A and SERT expression in PBMCs as a useful parameter for assessing the response to risperidone in PWS.

Imipramine Administration in Brucella abortus 2308-Infected Mice Restores Hippocampal Serotonin Levels, Muscle Strength, and Mood, and Decreases Spleen CFU Count.

Brucellosis infection causes non-specific symptoms such as fever, chills, sweating, headaches, myalgia, arthralgia, anorexia, fatigue, and mood disorders. In mouse models, it has been associated with increased levels of IL-6, TNF-α, and IFN-γ, a decrease in serotonin and dopamine levels within the hippocampus, induced loss of muscle strength and equilibrium, and increased anxiety and hopelessness. Imipramine (ImiP), a tricyclic antidepressant, is used to alleviate neuropathic pain. This study evaluated the effects of ImiP on Balb/c mice infected with Brucella abortus 2308 (Ba) at 14- and 28-days post-infection. Serum levels of six cytokines (IFN-γ, IL-6, TNF-α, IL-12, MCP-1. and IL-10) were assessed by FACS, while the number of bacteria in the spleen was measured via CFU. Serotonin levels in the hippocampus were analyzed via HPLC, and behavioral tests were conducted to assess strength, equilibrium, and mood. Our results showed that mice infected with Brucella abortus 2308 and treated with ImiP for six days (Im6Ba14) had significantly different outcomes compared to infected mice (Ba14) at day 14 post-infection. The mood was enhanced in the forced swimming test (FST) (p < 0.01), tail suspension test (TST) (p < 0.0001), and open-field test (p < 0.0001). Additionally, there was an increase in serotonin levels in the hippocampus (p < 0.001). Furthermore, there was an improvement in equilibrium (p < 0.0001) and muscle strength (p < 0.01). Lastly, there was a decrease in IL-6 levels (p < 0.05) and CFU count in the spleen (p < 0.0001). At 28 days, infected mice that received ImiP for 20 days (Im20Ba28) showed preservation of positive effects compared to infected mice (Ba28). These effects include the following: (1) improved FST (p < 0.0001) and TST (p < 0.0001); (2) better equilibrium (p < 0.0001) and muscle strength (p < 0.0001); (3) decreased IL-6 levels (p < 0.05); and (4) reduced CFU count in the spleen (p < 0.0001). These findings suggest the potential for ImiP to be used as an adjuvant treatment for the symptoms of brucellosis, which requires future studies.

Modulation of vagal activity may help reduce neurodevelopmental damage in the offspring of mothers with pre-eclampsia.

Maternal Immune Activation (MIA) has been linked to the pathogenesis of pre-eclampsia and adverse neurodevelopmental outcomes in the offspring, such as cognitive deficits, behavioral abnormalities, and mental disorders. Pre-eclampsia is associated with an activation of the immune system characterized by persistently elevated levels of proinflammatory cytokines, as well as a decrease in immunoregulatory factors. The Cholinergic Anti-inflammatory Pathway (CAP) may play a relevant role in regulating the maternal inflammatory response during pre-eclampsia and protecting the developing fetus from inflammation-induced damage. Dysregulation in the CAP has been associated with the clinical evolution of pre-eclampsia. Some studies suggest that therapeutic stimulation of this pathway may improve maternal and fetal outcomes in preclinical models of pre-eclampsia. Modulation of vagal activity influences the CAP, improving maternal hemodynamics, limiting the inflammatory response, and promoting the growth of new neurons, which enhances synaptic plasticity and improves fetal neurodevelopment. Therefore, we postulate that modulation of vagal activity may improve maternal and fetal outcomes in pre-eclampsia by targeting underlying immune dysregulation and promoting better fetal neurodevelopment. In this perspective, we explore the clinical and experimental evidence of electrical, pharmacological, physical, and biological stimulation mechanisms capable of inducing therapeutical CAP, which may be applied in pre-eclampsia to improve the mother's and offspring's quality of life.

Therapeutic treatment with fluoxetine using the chronic unpredictable stress model induces changes in neurotransmitters and circulating miRNAs in extracellular vesicles.

The most widely prescribed antidepressant, fluoxetine (FLX), is known for its antioxidant and anti-inflammatory effects when administered post-stress. Few studies have evaluated the effects of FLX treatment when chronic stress has induced deleterious effects in patients. Our objective was to evaluate FLX treatment (20 mg/kg/day, i.v.) once these effects are manifested, and the drug's relation to extracellular circulating microRNAs associated with inflammation, a hedonic response (sucrose intake), the forced swim test (FST), and corticosterone levels (CORT) and monoamine concentrations in limbic areas. A group of Wistar rats was divided into groups: Control; FLX; CUMS (for six weeks of exposure to chronic, unpredictable mild stress); and CUMS + FLX, a mixed group. After CUMS, the rats performed the FST, and serum levels of CORT and six microRNAs (miR-16, -21, -144, -155, -146a, -223) were analyzed, as were levels of dopamine, noradrenaline, and serotonin in the prefrontal cortex, hippocampus, and hypothalamus. CUMS reduced body weight, sucrose intake, and hippocampal noradrenaline levels, but increased CORT, immobility behavior on the FST, dopamine concentrations in the prefrontal cortex, and all miRNAs except miR-146a expression. Administering FLX during CUMS reduced CORT levels and immobility behavior on the FST and increased the expression of miR-16, -21, -146a, -223, and dopamine. FLX protects against the deleterious effects of stress by reducing CORT and has an antidepressant effect on the FST, with minimally-modified neurotransmitter levels. FLX increased the expression of miRNAs as part of the antidepressant effect. It also regulates both neuroinflammation and serotoninergic neurotransmission through miRNAs, such as the miR-16.

Agomelatine decreases cocaine-induced locomotor sensitisation and dopamine release in rats.

BACKGROUND: Agomelatine is a melatoninergic antidepressant approved to treat the major depressive disorder. Agomelatine exerts its behavioural, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors and the blockade of 5-HT2B and 5-HT2C serotonin receptors. Some studies have reported that the activation of the MT1 and MT2 melatonin receptors decreased cocaine-induced locomotor activity and cocaine self-administration. These findings from another study showed that agomelatine decreased alcohol consumption. This study aimed to evaluate the effects of agomelatine administration on cocaine-induced behavioural (cocaine-induced locomotor activity and cocaine-induced locomotor sensitisation) and neurochemical (dopamine levels) effects. METHODS: Male Wistar rats (250-280 g) received cocaine (10 mg/kg) during the induction and expression of locomotor sensitisation. Agomelatine (10 mg/kg) was administered 30 minutes before cocaine. After each treatment, locomotor activity was recorded for 30 minutes. Dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) by high-performance liquid chromatographic (HPLC) in animals treated with agomelatine and cocaine. Luzindole (30 mg/kg) was administered to block the agomelatine effect. RESULTS: In this study, we found that agomelatine decreased cocaine-induced locomotor activity and the induction and expression of locomotor sensitisation. In addition, agomelatine decreased cocaine-induced dopamine levels. Luzindole blocked the agomelatine-induced decrease in the expression of locomotor sensitisation in rats. CONCLUSION: Our results suggest (1) that agomelatine showed efficacy in decreasing cocaine psychostimulant effects and (2) that agomelatine can be a useful therapeutic agent to reduce cocaine abuse.

Altered neutrophil-to-lymphocyte ratio in sepsis secondary to canine parvoviral enteritis treated with and without an immunomodulator in puppies.

Neutrophil-to-lymphocyte ratio (NLR) is a cheap and easy-to-obtain biomarker that mirrors the balance between innate and adaptive immunity. Cortisol and catecholamines have been identified as major drivers of NLR. High cortisol levels increase neutrophils while simultaneously decreasing lymphocyte counts. Likewise, endogenous catecholamines may cause leukocytosis and lymphopenia. Thus, NLR allows us to monitor patient severity in conditions such as sepsis. Twenty-six puppies with sepsis secondary to canine parvoviral enteritis were treated with and without an immunomodulator. Our group determined the NLR and the plasmatic cortisol levels by chemiluminescence, and norepinephrine (NE) and epinephrine (E) by HPLC during the first 72 h of clinical follow-up. Our results showed that at admission puppies presented an NLR value of 1.8, cortisol of 314.9 nmol/L, NE 3.7, and E 3.3 pmol/mL. Both treatments decreased admission NLR values after 24 h of treatment. However, only the puppies treated with the immunomodulator (I) remained without significant changes in NLR (0.7-1.4) compared to the CT group, and that showed a significant difference (P < 0.01) in their NLR value (0.4-4.6). In addition, we found significant differences in the slope values between the admission and final values of NLR (P < 0.005), cortisol (P < 0.02), and E (P < 0.05) between treatments. Then, our data suggest that the immunomodulator positively affects the number of lymphocytes and neutrophils involved in NLR as well as major drivers like cortisol and epinephrine, which is reflected in clinical parameters and survival.

The Impairment of Blood-Brain Barrier in Alzheimer's Disease: Challenges and Opportunities with Stem Cells.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and its prevalence is increasing. Nowadays, very few drugs effectively reduce AD symptoms and thus, a better understanding of its pathophysiology is vital to design new effective schemes. Presymptomatic neuronal damage caused by the accumulation of Amyloid ß peptide and Tau protein abnormalities remains a challenge, despite recent efforts in drug development. Importantly, therapeutic targets, biomarkers, and diagnostic techniques have emerged to detect and treat AD. Of note, the compromised blood-brain barrier (BBB) and peripheral inflammation in AD are becoming more evident, being harmful factors that contribute to the development of the disease. Perspectives from different pre-clinical and clinical studies link peripheral inflammation with the onset and progression of AD. This review aims to analyze the main factors and the contribution of impaired BBB in AD development. Additionally, we describe the potential therapeutic strategies using stem cells for AD treatment.

Serum anti-neural immunoreactivity in patients with fibromyalgia. Preliminary study.

INTRODUCTION: Fibromyalgia (FM) is a non-degenerative syndrome characterized by generalized, chronic musculoskeletal pain, as well as mood, memory and sleep disorders. OBJECTIVE: To search for serum anti-neural antibodies (ANeuA) in patients with FM (FMP) in order to rule out autoimmune etiology. METHODS: The Fibromyalgia Impact Questionnaire (FIQ) and Beck's depression inventory (BDI) were applied. Immunoreactivity and the target recognized on the sera from FMPs and healthy subjects were analyzed by indirect immunofluorescence and Western blot. RESULTS: Both FIQ and BDI values were significantly altered in FMPs in comparison with those of controls (FIQ, 70 ± 25 vs. 12 ± 12, p < 0.0001; BDI, 17 ± 11 vs. 4 ± 3, p < 0.0002). Only five out of 15 FMP sera had ANeuA specifically directed against neurons from the medial vestibular nucleus of the brainstem. This immunoreactivity was not detected in the sera from the 14 controls. ANeuA recognized a 45 kDa protein. CONCLUSIONS: 30% of FMPs have ANeuA that have not been described before. In future studies, it will be necessary for anti-neural immunoreactivity to be determined in a larger sample and for the role of ANeuAs in the pathophysiology of FM to be established.

INTRODUCCIÓN: La fibromialgia (FM) es un síndrome no degenerativo caracterizado por dolor musculoesquelético crónico y generalizado; así como por alteraciones anímicas, de memoria y sueño. OBJETIVO: Buscar anticuerpos antineurales (AANeu) séricos en pacientes con FM para descartar etiología autoinmune. MÉTODOS: Se aplicó el Cuestionario de Impacto en Fibromialgia (FIQ) y el Inventario de Depresión de Beck (BDI). La inmunorreactividad y el blanco reconocido por los sueros de pacientes con FM y sujetos sanos se analizó con inmunofluorescencia indirecta y Western blot. RESULTADOS: Los valores de FIQ y BDI estuvieron significativamente alterados en los pacientes con FM, en comparación con los de los controles (FIQ, 70 ± 25 versus 12 ± 12, p < 0.0001; BDI, 17 ± 11 versus 4 ± 3, p < 0.0002). Solo cinco de 15 sueros de pacientes con FM tuvieron AANeu dirigidos específicamente contra las neuronas del núcleo vestibular medio del tronco encefálico; estos no se detectaron en los 14 sueros de los controles. Los AANeu reconocieron una proteína de 45 kDa. CONCLUSIONES: El 30 % de los pacientes con FM tiene AANeu no descritos antes. Será necesario evaluar la inmunorreactividad antineural en una muestra más grande y determinar el papel de los AANeu en la fisiopatología de la FM.

Screening of SERT and p11 mRNA Levels in Airline Pilots: A Translational Approach.

Airline pilots are frequently exposed to numerous flights per week, changes in their circadian rhythms, and extended periods away from home. All these stressors make pilots susceptible to developing psychiatric disorders. Recently, emphasis has been placed on the need for molecular tests that help in the diagnosis of depression. The genes SLC6A4 and S100A10 encode serotonin transporter (SERT) and p11 protein, respectively. Their expression has been frequently associated with stress and depression. In this work, we quantified, by quantitative PCR, the expression of SERT and p11 in peripheral mononuclear cells of airline pilots compared to patients with depression and healthy volunteers. Moreover, by mass spectrometry, we quantified the serum serotonin levels in the same three groups. We found that SERT and p11 were overexpressed in the mononuclear cells of airline pilots and depressed patients compared to healthy volunteers. Although serum serotonin was not different between healthy volunteers and airline pilots, a decreasing trend was observed in the latter. As expected, serum serotonin in the patients was significantly lower. Alterations in SERT and p11 in airline pilots could be related to professional stress, a condition that could potentially affect their long-term mental health.

Inmunorreactividad antineural sérica en pacientes con fibromialgia. Estudio preliminar / Serum anti-neural immunoreactivity in patients with fibromyalgia. Preliminary study

Resumen Introducción: La fibromialgia (FM) es un síndrome no degenerativo caracterizado por dolor musculoesquelético crónico y generalizado; así como por alteraciones anímicas, de memoria y sueño. Objetivo: Buscar anticuerpos antineurales (AANeu) séricos en pacientes con FM para descartar etiología autoinmune. Métodos: Se aplicó el Cuestionario de Impacto en Fibromialgia (FIQ) y el Inventario de Depresión de Beck (BDI). La inmunorreactividad y el blanco reconocido por los sueros de pacientes con FM y sujetos sanos se analizó con inmunofluorescencia indirecta y Western blot. Resultados: Los valores de FIQ y BDI estuvieron significativamente alterados en los pacientes con FM, en comparación con los de los controles (FIQ, 70 ± 25 versus 12 ± 12, p < 0.0001; BDI, 17 ± 11 versus 4 ± 3, p < 0.0002). Solo cinco de 15 sueros de pacientes con FM tuvieron AANeu dirigidos específicamente contra las neuronas del núcleo vestibular medio del tronco encefálico; estos no se detectaron en los 14 sueros de los controles. Los AANeu reconocieron una proteína de 45 kDa. Conclusiones: El 30 % de los pacientes con FM tiene AANeu no descritos antes. Será necesario evaluar la inmunorreactividad antineural en una muestra más grande y determinar el papel de los AANeu en la fisiopatología de la FM.

Abstract Introduction: Fibromyalgia (FM) is a non-degenerative syndrome characterized by generalized, chronic musculoskeletal pain, as well as mood, memory and sleep disorders. Objective: To search for serum anti-neural antibodies (ANeuA) in patients with FM (FMP) in order to rule out autoimmune etiology. Methods: The Fibromyalgia Impact Questionnaire (FIQ) and BECK’s depression inventory (BDI) were applied. Immunorreactivity and the target recognized on the sera from FMPs and healthy subjects were analyzed by indirect immunofluorescence and Western blot. Results: Both FIQ and BDI values were significantly altered in FMPs in comparison with those of controls (FIQ, 70 ± 25 vs. 12 ± 12, p < 0.0001; BDI, 17 ± 11 vs. 4 ± 3, p < 0.0002). Only five out of 15 FMP sera had ANeuA specifically directed against neurons from the medial vestibular nucleus of the brainstem. This immunoreactivity was not detected in the sera from the 14 controls. ANeuA recognized a 45 kDa protein. Conclusions: 30% of FMPs have ANeuA that have not been described before. In future studies, it will be necessary for anti-neural immunoreactivity to be determined in a larger sample and for the role of ANeuAs in the pathophysiology of FM to be established.

NeuroImmunoEndocrinology: A brief historic narrative.

Although no precise moment or unique event marks its birth, neuroimmunoendocrinology arguably shares a great deal of history with other medical and biologic disciplines. It originated from empirical observations and suppositions that failed to prevail upon the existing axioms. Despite the widespread resistance to embracing novel ideas, the seeming defeats inspired visionary researchers. Those pioneers managed to systematize the emerging knowledge and were able to contribute to science with real foundations. In consequence, new concepts and ideas arose in physiology, anatomy, endocrinology and early immunology. Together, they gave rise to a budding approach on the integration between the nervous, immune and endocrine systems. Then, neuroimmunoendocrinology emerged as a discipline integrating an intricate system with multidirectional functions and interactions that allow for responding to internal and external threats. Such response is mediated by cytokines, hormones and neurotransmitters, involved in different physiologic mechanisms of the organism homeostasis. Neuroimmunoendocrinology is no longer an area of scientific skepticism; on the contrary, it has cemented its position as a biomedical discipline worldwide for the past 70 years. Now, it offers a better understanding of pathologic processes.

Behavioral and Neurochemical Shifts at the Hippocampus and Frontal Cortex Are Associated to Peripheral Inflammation in Balb/c Mice Infected with Brucella abortus 2308.

Brucellosis is a zoonosis affecting 50,000,000 people annually. Most patients progress to a chronic phase of the disease in which neuropsychiatric symptoms upsurge. The biological processes underlying the progression of these symptoms are yet unclear. Peripheral inflammation mounted against Brucella may condition neurochemical shifts and hence unchained neuropsychiatric disorders. Our work aimed at establishing whether neurological, behavioral, and neurochemical disarrays are circumstantially linked to peripheral inflammation uprise secondary to Brucella abortus 2308 infections. We then evaluated, in control and Brucella-infected mice, skeletal muscle strength, movement coordination, and balance and motivation, as well as dopamine, epinephrine, norepinephrine, and serotonin availability in the cerebellum, frontal cortex, and hippocampus. Serum levels of proinflammatory cytokines and corticosterone in vehicle-injected and -infected mice were also estimated. All estimates were gathered at the infection acute and chronic phases. Our results showed that infected mice displayed motor disabilities, muscular weakness, and reduced motivation correlated with neurochemical and peripheral immunological disturbances that tended to decrease after 21 days of infection. The present observations support that disturbed peripheral inflammation and the related neurochemical disruption might lead to mood disorders in infected mice. Future experiments must be aimed at establishing causal links and to explore whether similar concepts might explain neurological and mood disorders in humans affected by brucellosis.

Melatonin decreases cocaine-induced locomotor sensitization and cocaine-conditioned place preference in rats.

Melatonin is a hormone that produces behavioral, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors. Melatonin receptors participate in the modulation of the reinforcing effects of cocaine. Some studies report that dosing of melatonin decreases cocaine-induced locomotor activity and cocaine self-administration and that luzindole, an MT1, and MT2 melatonin receptor antagonist, blocks the melatonin-dependent decrease in cocaine-induced locomotor activity. The objective of this study was to evaluate the effect of acute or chronic dosing of melatonin on the induction and expression of cocaine-induced locomotor sensitization and cocaine-CPP in rats. Male Wistar rats received cocaine during the induction and expression of locomotor sensitization. Melatonin was administered 30 min before cocaine. After each treatment, locomotor activity was recorded for 30 min. Additionally, dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFc), and the ventral tegmental area (VTA) by HPLC in animals treated with melatonin and cocaine. Melatonin decreased cocaine-induced locomotor sensitization and intracellular dopamine levels, as well as cocaine-CPP. Luzindole blocked the melatonin-induced decrease in the expression of locomotor sensitization in rats. These data suggest that melatonin may be a useful therapeutic agent to reduce cocaine abuse; additionally, they suggest that MT1 and MT2 receptors could be therapeutic targets, useful for the treatment of drug abuse disorder.

Experimental Pulmonary Tuberculosis in the Absence of Detectable Brain Infection Induces Neuroinflammation and Behavioural Abnormalities in Male BALB/c Mice.

Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.

Serum levels of chemokines in adolescents with major depression treated with fluoxetine.

BACKGROUND: Major depressive disorder (MDD) is a global health issue that affects 350 million people of all ages. Although between 2% and 5.6% of affected individuals are adolescents, research on young patients is limited. The inflammatory response contributes to the onset of depression, and in adult MDD patients, symptom severity has been linked to chemokine levels. AIM: To determine the differences in circulatory levels of chemokines in healthy volunteers (HVs) and adolescents with MDD, and assess the changes induced by fluoxetine consume. METHODS: The 22 adolescents with MDD were monitored during the first 8 wk of clinical follow-up and clinical psychiatric evaluation was done using the Hamilton depresión rating scale (HDRS). The serum levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1ß, interleukin (IL)-8, interferon gamma-induced protein (IP)-10, and eotaxin were measured in patients and HVs. RESULTS: In all cases, significant differences were detected in circulating chemokine levels between patients before treatment and HVs (P < 0.0001). All chemokines decreased at 4 wk, but only MCP-1 and IL-8 significantly differed (P < 0.05) between 0 wk and 4 wk. In the patients, all chemokines rose to their initial concentrations by 8 wk vs 0 wk, but only IP-10 did so significantly (P < 0.05). All patients experienced a significant decrease in HDRS scores at 4 wk (P < 0.0001) and 8 wk (P < 0.0001) compared with 0 wk. CONCLUSION: Despite the consumption of fluoxetine, patients had significantly higher chemokine levels, even after considering the improvement in HDRS score. The high levels of eotaxin, IP-10, and IL-8 partially explain certain aspects that are affected in MDD such as cognition, memory, and learning.

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics.

Atypical antipsychotics (AAP) or second-generation antipsychotics are the clinical option for schizophrenia treatment during acute psychoses, but they are also indicated for maintenance during lifetime, even though they are being used for other psychiatric conditions in clinical practice such as affective disorders and autism spectrum disorder, among others. These drugs are differentiated from typical antipsychotics based on their clinical profile and are a better choice because they cause fewer side effects regarding extrapyramidal symptoms (EPS). Even though they provide clear therapeutic benefits, AAP induce peripheral effects that trigger phenotypic, functional, and systemic changes outside the Central Nervous System (CNS). Metabolic disease is frequently associated with AAP and significantly impacts the patient's quality of life. However, other peripheral changes of clinical relevance are present during AAP treatment, such as alterations in the immune and endocrine systems as well as the intestinal microbiome. These less studied alterations also have a significant impact in the patient's health status. This manuscript aims to revise the peripheral immunological, endocrine, and intestinal microbiome changes induced by AAP consumption recommended in the clinical guidelines for schizophrenia and other psychiatric disorders.

Alterations in the Levels of Growth Factors in Adolescents with Major Depressive Disorder: A Longitudinal Study during the Treatment with Fluoxetine.

Major depressive disorder (MDD) has a prevalence of 5% in adolescents. Several studies have described the association between the inflammatory response and MDD, but little is known about the relationship between MDD and growth factors, such as IL-7, IL-9, IL-17A, VEGF, basic FGF, G-CSF, and GM-CSF. It must be appointed that there are scarce reports on growth factors in adolescents with MDD and even fewer with a clinical follow-up. In this work, we evaluated the levels of growth factors (IL-7, IL-9, IL-17A, VEGF, basic FGF, G-CSF, and GM-CSF) in MDD adolescents and the clinical follow-up during eight weeks of treatment with fluoxetine. Methods. All patients were diagnosed according to the DSM-IV-TR, and the severity of the symptoms was evaluated using the Hamilton Depression Rating Scale (HDRS). Growth factors IL-7, IL-9, IL-17A, VEGF, basic FGF, G-CSF, and GM-CSF were quantified by cytometric bead array using serum samples from 22 adolescents with MDD and 18 healthy volunteers. Results. All patients showed clinical improvement since the fourth week of pharmacological treatment according to the HDRS. Considerably higher levels of IL-7, IL-9, IL-17A, VEGF, basic FGF, G-CSF, and GM-CSF were detected in MDD adolescents as compared to healthy volunteers. A significant but temporal decrease was detected in basic FGF, G-CSF, and GM-CSF at week four of fluoxetine administration. Conclusions. To the best of our knowledge, this is the first report to show alterations in the levels of growth factors, such as IL-7, IL-9, IL-17A, VEGF, basic FGF, G-CSF, and GM-CSF in MDD adolescents during eight weeks of clinical follow-up. These disturbances might be involved in the physiopathology of MDD since such growth factors have been proven to participate in the neural development and correct functioning of the CNS; therefore, subtle alterations in it may contribute to MDD.