Behavioural traits related with resilience or vulnerability to the development of cocaine-induced conditioned place preference after exposure of female mice to vicarious social defeat.

Exposure to stress induced by intermittent repeated social defeat (IRSD) increases vulnerability to the development of cocaine-induced conditioned place preference (CPP) among male mice; however, some defeated mice are resilient to these effects of stress. In the present study we evaluated the effects of vicarious IRSD (VIRSD) in female mice and explored behavioural traits that are potentially predictive of resilience. C57BL/6 female mice (n = 28) were exposed to VIRSD, which consisted of the animals witnessing a short experience of social defeat by a male mouse on postnatal day (PND) 47, 50, 53 and 56. The control group (n = 10) was not exposed to stress. Blood samples were collected on PND 47 and 56 for corticosterone and interleukin-6 determinations. On PND 57-58, female mice performed several behavioural tests (elevated plus maze, hole-board, object recognition, social interaction, TST and splash tests). Three weeks later, the effects of cocaine (1.5 mg/kg) on the CPP paradigm were assessed. VIRSD decreased corticosterone levels (on PND 56), increased interleukin-6 levels, enhanced novelty-seeking, improved recognition memory and induced anxiety- and depression-like symptoms. Control and VIRSD female mice did not acquire CPP, although some stressed individuals with certain behavioural traits - including a high novelty-seeking profile or the development of depression-like behaviour in the splash test shortly after VIRSD - acquired cocaine CPP. Our results confirm that some behavioural traits of female mice are associated with vulnerability or resilience to the long-term effects of social stress on cocaine reward, as previously observed in males.

Exploring the impact of ketogenic diet on multiple sclerosis: obesity, anxiety, depression, and the glutamate system.

Background: Multiple sclerosis (MS) is a neurodegenerative disorder. Individuals with MS frequently present symptoms such as functional disability, obesity, and anxiety and depression. Axonal demyelination can be observed and implies alterations in mitochondrial activity and increased inflammation associated with disruptions in glutamate neurotransmitter activity. In this context, the ketogenic diet (KD), which promotes the production of ketone bodies in the blood [mainly ß-hydroxybutyrate (ßHB)], is a non-pharmacological therapeutic alternative that has shown promising results in peripheral obesity reduction and central inflammation reduction. However, the association of this type of diet with emotional symptoms through the modulation of glutamate activity in MS individuals remains unknown. Aim: To provide an update on the topic and discuss the potential impact of KD on anxiety and depression through the modulation of glutamate activity in subjects with MS. Discussion: The main findings suggest that the KD, as a source of ketone bodies in the blood, improves glutamate activity by reducing obesity, which is associated with insulin resistance and dyslipidemia, promoting central inflammation (particularly through an increase in interleukins IL-1ß, IL-6, and IL-17). This improvement would imply a decrease in extrasynaptic glutamate activity, which has been linked to functional disability and the presence of emotional disorders such as anxiety and depression.

Resilience to the short- and long-term behavioral effects of intermittent repeated social defeat in adolescent male mice.

BACKGROUND: Exposure to intermittent repeated social defeat (IRSD) increases the sensitivity of mice to the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. Some animals are resilient to this effect of IRSD, though research exploring this inconsistency in adolescent mice is scarce. Thus, our aim was to characterize the behavioral profile of mice exposed to IRSD during early adolescence and to explore a potential association with resilience to the short- and long-term effects of IRSD. METHODS: Thirty-six male C57BL/6 mice were exposed to IRSD during early adolescence (PND 27, 30, 33 and 36), while another 10 male mice did not undergo stress (controls). Defeated mice and controls then carried out the following battery of behavioral tests; the Elevated Plus Maze, Hole-Board and Social Interaction Test on PND 37, and the Tail Suspension and Splash tests on PND 38. Three weeks later, all the mice were submitted to the CPP paradigm with a low dose of cocaine (1.5 mg/kg). RESULTS: IRSD during early adolescence induced depressive-like behavior in the Social Interaction and Splash tests and increased the rewarding effects of cocaine. Mice with low levels of submissive behavior during episodes of defeat were resilient to the short- and long-term effects of IRSD. In addition, resilience to the short-term effects of IRSD on social interaction and grooming behavior predicted resilience to the long-term effects of IRSD on cocaine reward. CONCLUSION: Our findings help to characterize the nature of resilience to the effects of social stress during adolescence.

Relationship of Motor Impairment with Cognitive and Emotional Alterations in Patients with Multiple Sclerosis.

Introduction. Multiple sclerosis (MS) is a neurodegenerative disease that, despite mainly affecting women, is more severe in men and causes motor, cognitive and emotional alterations. The objective of this study was to determine the possible relationship between motor, cognitive and emotional alterations. Materials and Methods. This is a descriptive, observational and cross-sectional study, with 67 patients with MS (20 men and 47 women), who were given the following questionnaires: Expanded Disability Status Scale (EDSS), Two-Minute Walk Test (2MWT), Berg Balance Scale, Beck's Depression Inventory (BDI-II), State-Trait Anxiety Inventory (STAI) and Prefrontal Symptoms Inventory (PSI) to analyze their cognitive level, body mass index (BMI) and percentage of muscle mass. In addition, regression analysis was conducted to study the relationship among variables. Results. No significant differences were found between men and women in any of the variables. Regarding the relationship between parameters, the regression analysis was statistically significant, showing an effect of age on the walking and balance performance (ß â‰… −0.4, p < 0.05); in addition, there was a relationship between 2MWT and STAI A/S, indicating that both older age and a high anxiety state could impact walking performance. On the other hand, prefrontal symptoms showed moderate relationships with both anxiety and depression (ß â‰… 0.6, p < 0.05); thus, high levels of anxiety and depression could increase prefrontal alterations. Conclusions. There is a relationship between motor and emotional variables. Specifically, state anxiety is related to walking resistance. No relationship was found between depression and cognitive alteration and balance or walking ability. Only age has an effect in these relationships.

Can Ketogenic Diet Improve Alzheimer's Disease? Association With Anxiety, Depression, and Glutamate System.

Background: Alzheimer's disease is the most common neurodegenerative disorder in our society, mainly characterized by loss of cognitive function. However, other symptoms such as anxiety and depression have been described in patients. The process is mediated by alterations in the synaptic and extrasynaptic activity of the neurotransmitter glutamate, which are linked to a hypometabolism of glucose as the main source of brain energy. In that respect, Ketogenic diet (KD) has been proposed as a non-pharmacological treatment serving as an alternative energy source to the neurons increasing the fat percentage and reducing the carbohydrates percentage, showing promising results to improve the cognitive symptoms associated with different neurodegenerative disorders, including AD. However, the association of this type of diet with emotional symptoms and the modulation of glutamate neurotransmission systems after this dietary reduction of carbohydrates are unknown. Objective: The aim of this short review is to provide update studies and discuss about the relationship between KD, anxiety, depression, and glutamate activity in AD patients. Discussion: The main results suggest that the KD is an alternative energy source for neurons in AD with positive consequences for the brain at different levels such as epigenetic, metabolic and signaling, and that the substitution of carbohydrates for fats is also associated with emotional symptoms and glutamate activity in AD.

The Impact of Epigallocatechin Gallate and Coconut Oil Treatment on Cortisol Activity and Depression in Multiple Sclerosis Patients.

(1) Background: Multiple sclerosis (MS) is pathogenically characterized by high oxidative stress and symptomatically by progressive muscle loss and increased body fat associated with the presence of depression. Epigallocatechin gallate (EGCG) (particularly present in green tea) and ketone bodies (in particular beta-hydroxybutyrate (BHB)), whose main source is coconut oil, have shown emotional benefits and body fat loss. The aim of this study was to assess the impact of EGCG and coconut oil on cortisol activity related to fat loss and depression in MS patients. (2) Methods: The study involved 51 MS patients who were randomly divided into an intervention group or a control group. The intervention group received 800 mg of EGCG and 60 mL of coconut oil, which were included in their daily diet for four months. The control group received placebo and all patients followed an isocaloric diet. A blood sample was collected before and after the four-month period, and levels of cortisol, albumin and BHB were measured in serum. In addition, immediately before and after the intervention, anthropometric variables were measured: waist-to-hip ratio (WHR), body fat mass percentage, fat weight, total weight, and muscle mass percentage. Depression was assessed with the Beck Depression Inventory II (BDI-II). (3) Results: No significant changes were obtained in cortisol levels in any of the groups, and there was a significant increase in albumin in the blood of the intervention group only that could lead to a decrease in serum free cortisol. In addition, it was observed a significant decrease in levels of depression and abdominal fat. (4) Conclusions: EGCG combined with coconut oil increase the concentration of albumin in blood and produce less depression in MS patients.

Cortisol and IgA are Involved in the Progression of Alzheimer's Disease. A Pilot Study.

It is known that stress and immune systems are related with Alzheimer's disease (AD). However, the relationship of both systems in the progression of disease is not clearly demonstrated. Hair cortisol and salivary immunoglobulin A (IgA) were quantified in 49 patients with mild, moderate, and severe AD. A significant change was seen in both molecules as AD progressed from mild to moderate and severe. Low levels of cortisol were observed in mild AD patients compared with moderate and severe. However, IgA showed a contrary pattern. High levels were observed in mild AD patientes but low in moderate and severe AD subjects. The secretion of cortisol and IgA seems to be very different at the start compared with posterior development of AD suggesting that neuroinflammation can be involved. Both molecules could be used as possible therapeutical tools.

Valor de la testosterona en saliva en el diagnóstico de la enfermedad de Alzheimer / Value of testosterone in saliva in the diagnosis of Alzheimer's disease

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Behavioral Traits Associated With Resilience to the Effects of Repeated Social Defeat on Cocaine-Induced Conditioned Place Preference in Mice.

The relationship between stress and drug use is well demonstrated. Stress-induced by repeated social defeat (RSD) enhances the conditioned place preference (CPP) induced by cocaine in mice. The phenomenon of resilience understood as the ability of subjects to overcome the negative effects of stress is the focus of increasing interest. Our aim is to characterize the behavior of resilient animals with respect to the effects of RSD on the CPP induced by cocaine. To this end, 25 male C57BL/6 mice were exposed to stress by RSD during late adolescence, while other 15 male mice did not undergo stress (controls). On the 2 days following the last defeat, all the animals carried out the elevated plus maze (EPM) and Hole Board, Social Interaction, Tail Suspension and Splash tests. Three weeks later, all the animals performed the CPP paradigm with a low dose of cocaine (1 mg/kg). Exposure to RSD decreased all measurements related to the open arms of the EPM. It also reduced social interaction, immobility in the tail suspension test (TST) and grooming in the splash test. RSD exposure also increased the sensitivity of the mice to the rewarding effects of cocaine, since only defeated animals acquired CPP. Several behavioral traits were related to resilience to the potentiating effect of RSD on cocaine CPP. Mice that showed less submission during defeat episodes, a lower percentage of time in the open arms of the EPM, low novelty-seeking, high social interaction, greater immobility in the TST and a higher frequency of grooming were those that were resilient to the long-term effects of social defeat on cocaine reward since they behaved like controls and did not develop CPP. These results suggest that the behavioral profile of resilient defeated mice is characterized by an active coping response during episodes of defeat, a greater concern for potential dangers, less reactivity in a situation of inevitable moderate stress and fewer depressive-like symptoms after stress. Determining the neurobehavioral substrates of resilience is the first step towards developing behavioral or pharmacological interventions that increase resilience in individuals at a high risk of suffering from stress.

Improvement of Main Cognitive Functions in Patients with Alzheimer's Disease after Treatment with Coconut Oil Enriched Mediterranean Diet: A Pilot Study.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder (mainly in women), and new therapies are needed. In this way, ketone bodies are a direct source of cellular energy and can be obtained from coconut oil, postulating that coconut oil could be a new non-pharmacological alternative in AD patients. OBJECTIVE: The aim of this study is to detect changes in the main cognitive functions of patients with AD after following a coconut oil enriched Mediterranean diet, and to determine whether there are differences in function of stage or sex. METHODS: A prospective, longitudinal, qualitative, analytic, experimental study was carried out in 44 patients with AD, who were randomly divided into two homogenous groups of 22 patients each: an experimental group of patients who followed a coconut oil enriched Mediterranean diet for 21 days and a control group. In order to determine the cognitive changes after the intervention, we carried out the 7 Minute Screen, which analyses temporal orientation, visuospatial and visuoconstructive abilities, and semantic and episodic memory. RESULTS: After intervention with coconut oil, improvements in episodic, temporal orientation, and semantic memory were observed, and it seems that the positive effect is more evident in women with mild-moderate state, although other improvements in males and severe state were also shown. CONCLUSIONS: The isocaloric coconut oil enriched Mediterranean diet seems to improve cognitive functions in patients with AD, with differences according to patient sex and degree of severity of the disease, although more studies in this line are needed.

Drogas alarmantes en la última década, ¿qué sabemos sobre ellas? / Alarming drugs in the last decade, what do we know about them?

La drogadicción se define como una enfermedad mental crónica en la que se presentan modificaciones del comportamiento en los consumidores como búsqueda compulsiva de la sustancia y aparición de un estado emocional negativo cuando esta no se encuentra presente. Actualmente es una gran problemática social y de salud en nuestro país. Frente a las conocidas drogas históricas, en las últimas décadas están emergiendo nuevas sustancias, sintetizadas principalmente en laboratorios clandestinos, que buscan provocar un efecto similar o mucho mayor al de la droga original o a las mencionadas anteriormente como "históricas". El objetivo de este trabajo se centra en avanzar en el conocimiento de estas nuevas drogas emergentes para conocer sus efectos y consecuencias tras el consumo con la finalidad de poder servir a nuevas futuras vías terapéuticas. Especialmente se han recogido trabajos publicados en los últimos diez años, con el objetivo de obtener resultados recientes en el área. Los datos apuntan a que la aparición de relevantes drogas clandestinas (entre las que destacan Ketamina, GHB, droga caníbal (metilendio-xipirovalerona) o sales de baño y cannabinoides sintéticos) en los últimos años es un factor que se suma al grave problema de la drogadicción en la sociedad y que más estudios son necesarios ya que el conocimiento hasta la fecha sobre las mismas es escaso

Drug addiction is defined as a chronic mental illness in which behavioural changes occur as a compulsive search for the substance and appearance of a negative emotional state when it is not present. At present, it is a great social and health problem in this country. In contrast to the well-known historical drugs, new substances have been emerging over the last decades, mainly synthesized and made in clandestine laboratories, which seek to produce a similar or much greater effect than the original drug. The objective of this work is to further the knowledge of these new emerging drugs in order to learn their effects and consequences after consumption in order to be able to serve new therapeutic pathways. In this manuscript, we have been compiling work over the last ten years, with the aim of obtaining recent results in this area. The data suggests that the appearance of new clandestine drugs (among which Ketamine, GHB, cannibal drug and synthetic cannabinoids stand out) in recent years constitutes a factor that adds to the serious problem of drug addiction in society and that more studies are necessary since the knowledge to date on these is scarce

Does Music Therapy Improve Anxiety and Depression in Alzheimer's Patients?

OBJECTIVE: To evaluate the effectiveness of the implementation of a short protocol of music therapy as a tool to reduce stress and improve the emotional state in patients with mild Alzheimer's disease. METHODS: A sample of 25 patients with mild Alzheimer's received therapy based on the application of a music therapy session lasting 60 min. Before and after the therapy, patient saliva was collected to quantify the level of salivary cortisol using the Enzyme-Linked ImmunoSorbent Assay (ELISA) immunoassay technique and a questionnaire was completed to measure anxiety and depression (Hospital Anxiety and Depression Scale). RESULTS: The results show that the application of this therapy lowers the level of stress and decreases significantly depression and anxiety, establishing a linear correlation between the variation of these variables and the variation of cortisol. CONCLUSIONS: A short protocol of music therapy can be an alternative medicine to improve emotional variables in Alzheimer patients.

Differential effects of MDMA and cocaine on inhibitory avoidance and object recognition tests in rodents.

INTRODUCTION: Drug addiction continues being a major public problem faced by modern societies with different social, health and legal consequences for the consumers. Consumption of psychostimulants, like cocaine or MDMA (known as ecstasy) are highly prevalent and cognitive and memory impairments have been related with the abuse of these drugs. AIM: The aim of this work was to review the most important data of the literature in the last 10 years about the effects of cocaine and MDMA on inhibitory avoidance and object recognition tests in rodents. DEVELOPMENT: The object recognition and the inhibitory avoidance tests are popular procedures used to assess different types of memory. We compare the effects of cocaine and MDMA administration in these tests, taking in consideration different factors such as the period of life development of the animals (prenatal, adolescence and adult age), the presence of polydrug consumption or the role of environmental variables. Brain structures involved in the effects of cocaine and MDMA on memory are also described. CONCLUSIONS: Cocaine and MDMA induced similar impairing effects on the object recognition test during critical periods of lifetime or after abstinence of prolonged consumption in adulthood. Deficits of inhibitory avoidance memory are observed only in adult rodents exposed to MDMA. Psychostimulant abuse is a potential factor to induce memory impairments and could facilitate the development of future neurodegenerative disorders.

Animal models of drug addiction. / Modelos animales de adicción a las drogas.

The development of animal models of drug reward and addiction is an essential factor for progress in understanding the biological basis of this disorder and for the identification of new therapeutic targets. Depending on the component of reward to be studied, one type of animal model or another may be used. There are models of reinforcement based on the primary hedonic effect produced by the consumption of the addictive substance, such as the self-administration (SA) and intracranial self-stimulation (ICSS) paradigms, and there are models based on the component of reward related to associative learning and cognitive ability to make predictions about obtaining reward in the future, such as the conditioned place preference (CPP) paradigm. In recent years these models have incorporated methodological modifications to study extinction, reinstatement and reconsolidation processes, or to model specific aspects of addictive behavior such as motivation to consume drugs, compulsive consumption or drug seeking under punishment situations. There are also models that link different reinforcement components or model voluntary motivation to consume (two-bottle choice, or drinking in the dark tests). In short, innovations in these models allow progress in scientific knowledge regarding the different aspects that lead individuals to consume a drug and develop compulsive consumption, providing a target for future treatments of addiction.

El desarrollo de modelos animales de refuerzo y adicción a las drogas es imprescindible para el avance en el conocimiento de las bases biológicas de este trastorno y la identificación de nuevas dianas terapéuticas. En función del componente del refuerzo que deseemos estudiar podemos servirnos de un tipo de modelos animales u otros. Podemos utilizar modelos de refuerzo basados en el efecto hedónico primario que produce el consumo de la sustancia adictiva, como los modelos de autoadministración (AA) y autoestimulación eléctrica intracraneal (AEIC), o modelos basados en el componente relacionado con el aprendizaje asociativo y la capacidad cognitiva de realizar predicciones sobre la obtención del refuerzo en el futuro, como el modelo de condicionamiento de preferencia de lugar (CPL). En los últimos años los modelos han incorporado modificaciones metodológicas para incluir el estudio de los procesos de extinción, reinstauración y reconsolidación o para modelar aspectos concretos de la conducta adictiva como puede ser la motivación para consumir la droga, el consumo compulsivo o la búsqueda de la droga bajo situaciones de castigo. Otros modelos interrelacionan diferentes componentes del refuerzo o modelan la motivación voluntaria por consumir (modelos de "two-bottle choice" o "drinking in the dark"). En definitiva, las innovaciones en estos modelos contribuyen al avance en el conocimiento científico de los diferentes factores que llevan a tomar una droga y a desarrollar un consumo compulsivo, ofreciendo una vía para identificar futuros tratamientos para la adicción.

Impact of the Relationship of Stress and the Immune System in the Appearance of Alzheimer's Disease.

The understanding of how the immune system works, as well as its relationship with the stress level, seems to be important at the start of the Alzheimer's disease (AD). To analyze this, immunoglobulin A (IgA) and cortisol in saliva were measured using ELISA in patients with mild AD and healthy volunteers, and the production of both biomarkers was compared and correlated. In participants without AD, IgA was higher when cortisol was lower, and the opposite happened in participants with AD, with the quantification in saliva being a suitable method to determine it.

Modelos animales de adicción a las drogas / Animal Models of Drug Addiction

El desarrollo de modelos animales de refuerzo y adicción a las drogas es imprescindible para el avance en el conocimiento de las bases biológicas de este trastorno y la identificación de nuevas dianas terapéuticas. En función del componente del refuerzo que deseemos estudiar podemos servirnos de un tipo de modelos animales u otros. Podemos utilizar modelos de refuerzo basados en el efecto hedónico primario que produce el consumo de la sustancia adictiva, como los modelos de autoadministración (AA) y autoestimulación eléctrica intracraneal (AEIC), o modelos basados en el componente relacionado con el aprendizaje asociativo y la capacidad cognitiva de realizar predicciones sobre la obtención del refuerzo en el futuro, como el modelo de condicionamiento de preferencia de lugar (CPL). En los últimos años los modelos han incorporado modificaciones metodológicas para incluir el estudio de los procesos de extinción, reinstauración y reconsolidación o para modelar aspectos concretos de la conducta adictiva como puede ser la motivación para consumir la droga, el consumo compulsivo o la búsqueda de la droga bajo situaciones de castigo. Otros modelos interrelacionan diferentes componentes del refuerzo o modelan la motivación voluntaria por consumir (modelos de "two-bottle choice" o "drinking in the dark"). En definitiva, las innovaciones en estos modelos contribuyen al avance en el conocimiento científico de los diferentes factores que llevan a tomar una droga y a desarrollar un consumo compulsivo, ofreciendo una vía para identificar futuros tratamientos para la adicción

The development of animal models of drug reward and addiction is an essential factor for progress in understanding the biological basis of this disorder and for the identification of new therapeutic targets. Depending on the component of reward to be studied, one type of animal model or another may be used. There are models of reinforcement based on the primary hedonic effect produced by the consumption of the addictive substance, such as the self-administration (SA) and intracranial self-stimulation (ICSS) paradigms, and there are models based on the component of reward related to associative learning and cognitive ability to make predictions about obtaining reward in the future, such as the conditioned place preference (CPP) paradigm. In recent years these models have incorporated methodological modifications to study extinction, reinstatement and reconsolidation processes, or to model specific aspects of addictive behavior such as motivation to consume drugs, compulsive consumption or drug seeking under punishment situations. There are also models that link different reinforcement components or model voluntary motivation to consume (two-bottle choice, or drinking in the dark tests). In short, innovations in these models allow progress in scientific knowledge regarding the different aspects that lead individuals to consume a drug and develop compulsive consumption, providing a target for future treatments of addiction

Pharmacological modulation of protein kinases as a new approach to treat addiction to cocaine and opiates.

Drug addiction shares brain mechanisms and molecular substrates with learning and memory processes, such as the stimulation of glutamate receptors and their downstream signalling pathways. In the present work we provide an up-to-date review of studies that have demonstrated the implication of the main memory-related calcium-dependent protein kinases in opiate and cocaine addiction. The effects of these drugs of abuse in different animal models of drug reward, dependence and addiction are altered by manipulation of the mitogen-activated protein kinase (MAPK) family, particularly extracellular signal regulated kinase (ERK), calcium/calmodulin-dependent kinase II (CaMKII), the protein kinase C (PKC) family (including PKMζ), cAMP-dependent protein kinase A (PKA), cGMP-dependent protein kinase G (PKG), the phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target mammalian target of Rapamycin (mTOR), cyclin-dependent kinase 5 (Cdk5), heat-shock proteins (Hsp) and other enzymes and proteins. Research suggests that drugs of abuse induce dependence and addiction by modifying the signalling pathways that involve these memory-related protein kinases, and supports the idea that drug addiction is an excessive aberrant learning disorder in which the maladaptive memory of drug-associated cues maintains compulsive drug use and contributes to relapse. Moreover, the studies we review offer new pharmacological strategies to treat opiate and cocaine dependence based on the manipulation of these protein kinases. In particular, disruption of reconsolidation of drug-related memories may have a high therapeutic value in the treatment of drug addiction.