Oxytocin signaling as a target to block social defeat-induced increases in drug abuse reward

There is huge scientific interest in the neuropeptide oxytocin (OXT) due to its putative capacity to modulate a wide spectrum of physiological and cognitive processes including motivation, learning, emotion, and the stress response. The present review seeks to increase the understanding of the role of OXT in an individual’s vulnerability or resilience with regard to developing a substance use disorder. It places specific attention on the role of social stress as a risk factor of addiction, and explores the hypothesis that OXT constitutes a homeostatic response to stress that buffers against its negative impact. For this purpose, the review summarizes preclinical and clinical literature regarding the effects of OXT in different stages of the addiction cycle. The current literature affirms that a well-functioning oxytocinergic system has protective effects such as the modulation of the initial response to drugs of abuse, the attenuation of the development of dependence, the blunting of drug reinstatement and a general anti-stress effect. However, this system is dysregulated if there is continuous drug use or chronic exposure to stress. In this context, OXT is emerging as a promising pharmacotherapy to restore its natural beneficial effects in the organism and to help rebalance the functions of the addicted brain

The Transcription Factor NURR1 Exerts Concentration-Dependent Effects on Target Genes Mediating Distinct Biological Processes

The transcription factor NURR1 plays a pivotal role in the development and maintenance of neurotransmitter phenotype in midbrain dopamine neurons. Conversely, decreased NURR1 expression is associated with a number of dopamine-related CNS disorders, including Parkinson’s disease and drug addiction. In order to better understand the nature of NURR1-responsive genes and their potential roles in dopamine neuron differentiation and survival, we used a human neural cellular background (SK-N-AS cells) in which to generate a number of stable clonal lines with graded NURR1 gene expression that approximated that seen in DA cell-rich human substantia nigra. Gene expression profiling data from these NURR1-expressing clonal lines were validated by quantitative RT-PCR and subjected to bioinformatic analyses. The present study identified a large number of NURR1-responsive genes and demonstrated the potential importance of concentration-dependent NURR1 effects in the differential regulation of distinct NURR1 target genes and biological pathways. These data support the promise of NURR1-based CNS therapeutics for the neuroprotection and/or functional restoration of DA neurons

Brain-Targeted Drug Delivery

Brain diseases currently affect one in six people worldwide; they include a wide range of neurological diseases, from Alzheimer’s and Parkinson’s diseases to epilepsy, brain injuries, brain cancer, neuroinfections, and strokes. The treatment of these diseases is complex and limited due to the presence of the blood–brain barrier (BBB), which covers the entirety of the brain. The BBB not only has the function of protecting the brain from harmful substances; it is also a metabolic barrier and a transport regulator of nutrients/serum factors/neurotoxins. Knowing these characteristics when it comes to the treatment of brain diseases makes it easier to understand the lack of efficacy of therapeutic drugs, resulting from the innate resistance of the BBB to permeation. To overcome this limitation, drug delivery systems based on nanotechnology/microtechnology have been developed. Brain-targeted drug delivery enables targeted therapy with a higher therapeutic efficacy and fewer side effects because it targets moieties present in the drug delivery systems

Marcadores biológicos en trastornos por uso de alcohol y comorbilidad psiquiátrica asociada

Este trabajo tiene como objetivo el estudio de los efectos del uso patológico de alcohol sobre la expresión en plasma de moléculas bioactivas de las familias de los acilgliceroles, aciletanolamidas y quimioquinas, y su asociación con la presencia de comorbilidad psiquiátrica. Para ello se realizó una evaluación clínica de sintomatología psiquiátrica en una muestra de pacientes con trastornos por uso de alcohol procedentes de un centro hospitalario y de un grupo control de voluntarios sanos del entorno sanitario pareado por edad, sexo e índice de masa corporal. Se recogieron muestras de sangre que se procesaron para la medición de potenciales marcadores biológicos de adicción en plasma. Además, se realizó una validación en modelo animal de algunos hallazgos realizados en el estudio clínico en quimioquinas. En el primer estudio se estiman las prevalencias de comorbilidad psiquiátrica y de trastornos por uso de otras sustancias evaluando las diferencias entre hombres y mujeres en patrones de uso de alcohol. La psicopatología estaba asociada a un mayor número de criterios de abuso y dependencia de alcohol. Se obtuvo una prevalencia elevada en comorbilidad psiquiátrica destacando los trastornos del estado de ánimo, los trastornos de personalidad y los trastornos de ansiedad. Las mujeres muestran mayores prevalencias en diagnósticos del estado de ánimo. Las concentraciones de monoacilgliceroles 2-araquidonilglicerol y 2-oleoilglicerol se encontraron disminuidas significativamente en pacientes con trastornos de ansiedad diagnosticados en el último año. En el segundo estudio se caracterizaron los niveles de determinadas aciletanolamidas en pacientes con trastornos por uso de alcohol en abstinencia y el grupo control. Los niveles de aciletanolamidas están significativamente aumentados debido al consumo y se desarrolló un modelo logístico con un alto poder discriminativo en el consumo de alcohol utilizando como variables predictoras las concentraciones plasmáticas de Oleiletanolamida, Anandamida y Docosatetraenoiletanolamida. Además, mediante un modelo de regresión se encontró un efecto significativo del tiempo de abstinencia en las concentraciones de estas aciletanolamidas que pueden convertirse en biomarcadores de la duración de la abstinencia. Estos resultados apoyan a los estudios preclínicos que sugerían que determinadas aciletanolamidas estaban alteradas durante la abstinencia actuando como potenciales biomarcadores de consumo de alcohol. En el tercer estudio se caracterizaron los niveles plasmáticos de determinadas quimioquinas en los trastornos por uso de alcohol. Las concentraciones de determinadas quimioquinas se ven afectadas por dimorfismo sexual, especialmente en Eoaxina-1. Las concentraciones de las quimioquinas SDF-1 y Fractalquina están disminuidas en el grupo alcohol en comparación con los controles, mientras que las concentraciones de Eotaxina-1 son menores en pacientes mujeres. Los pacientes con trastornos afectivos y con trastornos de ansiedad tenían menores concentraciones de Eotaxina-1 que los pacientes sin comorbilidad psiquiátrica. El estudio con ratas expuestas a etanol durante 4 semanas revelan cambios significativos en las concentraciones plasmáticas de SDF-1, pero no en Fractalquina durante la abstinencia. Las ratas expuestas a etanol y a estrés temprano muestran cambios en las concentraciones de Eotaxina-1. La medición objetiva de moléculas circulantes en pacientes con adicción ayuda a la comprensión de los procesos de regulación homeostática interna, incluyendo los procesos de neuroinflamación que empiezan a describirse como subyacentes a la enfermedad mental. Estudios exploratorios como la presente investigación, basada en estudios experimentales previos, aportan un nivel traslacional a la investigación basada en modelos clínicos y son de gran ayuda en la búsqueda de mejoras terapéuticas

Neuroendocrinology and Behavior

Understanding of the neuroendocrine system provides an insight into a wide range of bodily and mental processes. Neuroendocrinology and Behavior brings its readers a concise guide to up-to-date knowledge on the function of the endocrine glands and organs in association with neurotransmitters, neuropeptides, and behavioral manifestations. Various forms of stress response, e.g. anxiety and cognitive changes, have been intrinsic to both ourselves and other species. Specifically, these mechanisms involve complex interplays among physical, emotional, and behavioral processes in humans. This volume provides information on peptide hormones, i.e. oxytocin and vasopressin, and how studies of these neuropeptides enrich our understanding of social and other behaviors. These neuromodulators also affect sexual behavior and water balance in the body, an issue also addressed in this Book

Hippocampal gabaergic inhibitory interneurons

This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this record In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10–15% of the total neuronal population; however, their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and circuit function. Here we provide an overview of the current state of the field of interneuron research, focusing largely on the hippocampus. We discuss recent advances related to the various cell types, including their development and maturation, expression of subtype-specific voltage-and ligand-gated channels, and their roles in network oscillations. We also discuss recent technological advances and approaches that have permitted high-resolution, subtype-specific examination of their roles in numerous neural circuit disorders and the emerging therapeutic strategies to ameliorate such pathophysiological conditions. The ultimate goal of this review is not only to provide a touchstone for the current state of the field, but to help pave the way for future research by highlighting where gaps in our knowledge exist and how a complete appreciation of their roles will aid in future therapeutic strategies.National Institute of Child Health and Human Developmen

Hippocampal GABAergic inhibitory interneurons

In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10–15% of the total neuronal population; however, their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and circuit function. Here we provide an overview of the current state of the field of interneuron research, focusing largely on the hippocampus. We discuss recent advances related to the various cell types, including their development and maturation, expression of subtype-specific voltage- and ligand-gated channels, and their roles in network oscillations. We also discuss recent technological advances and approaches that have permitted high-resolution, subtype-specific examination of their roles in numerous neural circuit disorders and the emerging therapeutic strategies to ameliorate such pathophysiological conditions. The ultimate goal of this review is not only to provide a touchstone for the current state of the field, but to help pave the way for future research by highlighting where gaps in our knowledge exist and how a complete appreciation of their roles will aid in future therapeutic strategies

Effect of pyrethroid insecticides on gene expression in the mammalian central nervous system

Pyrethroids interfere with nervous system function by increasing neuronal excitability. Increased excitability underlies the toxicity observed at the whole organism level following an acute pyrethroid exposure. However, changes in neuronal excitability also trigger de novo gene expression which may impact neuronal function. This aspect of pyrethroid toxicity has not been extensively examined. The present studies test the hypothesis that in vivo pyrethroid exposures, at doses surrounding the threshold for neurobehavioral effects, result in changes in gene expression in the rat cortex. In the first aim, adult rats were orally dosed with deltamethrin (DLT: 0.3, 1, 3 mg/kg), permethrin (PERM: 1, 10, 100 mg/kg) or vehicle. Frontal cortex was collected at 6 hr and global transcriptional profiles were generated. Dose-dependent changes in gene expression were identified using penalized linear and isotonic regressions. A set of altered transcripts were then confirmed by qRT-PCR. In addition, rats were dosed with either DLT (3 mg/kg), PERM (100 mg/kg) or vehicle and cortical tissue collected at 1,3,6 and 9 hr. Expression of transcripts examined by qRT-PCR in the dose-response studies were investigated in this time course cohort. Functional category analysis identified 'branching morphogenesis' as a biological process potentially sensitive to pyrethroids. This prediction was confirmed in an in vitro model of neuronal morphogenesis. The time course of expression for Camk1g was further examined by qRT-PCR and Western blot. Expression of the Camk1g1 mRNA splice variant changed in response to pyrethroids with no detectable change in Camk1g1 protein. The second aim determined if Type I and Type II pyrethroids produce similar effects on gene transcription in the cortex. Rats were dosed with vehicle or either a Type I or Type II pyrethroid at doses that produce the same effect on an apical behavior. Cortex was sampled at 3 and 6 hr and global transcriptional profiles were generated. Qualitatively similar but quantitatively different patterns of expression between Type I and Type II pyrethroids were observed that is consistent with increases in neuronal excitability. These data contribute to a comprehensive mode-of-action model for pyrethroids

Transcriptional changes in the rat brain induced by repetitive transcranial magnetic stimulation

IntroductionTranscranial Magnetic Stimulation (TMS) is a noninvasive technique that uses pulsed magnetic fields to affect the physiology of the brain and central nervous system. Repetitive TMS (rTMS) has been used to study and treat several neurological conditions, but its complex molecular basis is largely unexplored.MethodsUtilizing three experimental rat models (in vitro, ex vivo, and in vivo) and employing genome-wide microarray analysis, our study reveals the extensive impact of rTMS treatment on gene expression patterns.ResultsThese effects are observed across various stimulation protocols, in diverse tissues, and are influenced by time and age. Notably, rTMS-induced alterations in gene expression span a wide range of biological pathways, such as glutamatergic, GABAergic, and anti-inflammatory pathways, ion channels, myelination, mitochondrial energetics, multiple neuron-and synapse-specific genes.DiscussionThis comprehensive transcriptional analysis induced by rTMS stimulation serves as a foundational characterization for subsequent experimental investigations and the exploration of potential clinical applications