Sleep debt-induced anxiety and addiction to substances of abuse: A narrative review.

Substance Use Disorder (SUD) has been conceptualized as an outcome of a dysregulated reward system. However, individuals with SUD suffer from anxiety with an intensity depending on the abstinence period length. This review discusses the role of anxiety as a major contributor to the initiation and perpetuation of SUD, and its dependence on an up-regulated defense-antireward system. In addition, it is discussed that sleep debt, and its psychosocial consequences, promote anxiety, contributing to SUD generation and maintenance. Healthy sleep patterns can be disrupted by diverse medical conditions and negative psychosocial interactions, resulting in accumulated sleep debt and anxiety. Within this narrative review, we discuss the interplay between the motivation-reward and defense-antireward systems, framing the progression from recreational drug use to addiction. This interplay is nuanced by sleep debt-induced anxiety and its psychosocial consequences as contributory vulnerability factors in the genesis of addiction.

Advancements in addressing drug dependence: A review of promising therapeutic strategies and interventions.

Substance dependence represents a pervasive global concern within the realm of public health. Presently, it is delineated as a persistent and recurrent neurological disorder stemming from drug-triggered neuroadaptations in the brain's reward circuitry. Despite the availability of various therapeutic modalities, there has been a steady escalation in the mortality rate attributed to drug overdoses. Substantial endeavors have been directed towards the exploration of innovative interventions aimed at mitigating cravings and drug-induced repetitive behaviors. Within this review, we encapsulate the most auspicious contemporary treatment methodologies, accentuating meta-analyses of efficacious pharmacological and non-pharmacological approaches: including gabapentin, topiramate, prazosin, physical exercise regimens, and cerebral stimulation techniques.

Changes in ethanol effects in knock-in mice expressing ethanol insensitive alpha1 and alpha2 glycine receptor subunits.

AIMS: Glycine receptors (GlyRs) are potentiated by physiologically relevant concentrations of ethanol, and mutations in the intracellular loop of α1 and α2 subunits reduced the effect of the drug. Knock-in (KI) mice having these individual mutations revealed that α1 and α2 subunits played a role in ethanol-induced sedation and ethanol intake. In this study, we wanted to examine if the effects of stacking both mutations in a 2xKI mouse model (α1/α2) generated by a selective breeding strategy further impacted cellular and behavioral responses to ethanol. MAIN METHODS: We used electrophysiological recordings to examine ethanol's effect on GlyRs and evaluated ethanol-induced neuronal activation using c-Fos immunoreactivity and the genetically encoded calcium indicator GCaMP6s in the nucleus accumbens (nAc). We also examined ethanol-induced behavior using open field, loss of the righting response, and drinking in the dark (DID) paradigm. KEY FINDINGS: Ethanol did not potentiate GlyRs nor affect neuronal excitability in the nAc from 2xKI. Moreover, ethanol decreased the Ca2+ signal in WT mice, whereas there were no changes in the signal in 2xKI mice. Interestingly, there was an increase in c-Fos baseline in the 2xKI mice in the absence of ethanol. Behavioral assays showed that 2xKI mice recovered faster from a sedative dose of ethanol and had higher ethanol intake on the first test day of the DID test than WT mice. Interestingly, an open-field assay showed that 2xKI mice displayed less anxiety-like behavior than WT mice. SIGNIFICANCE: The results indicate that α1 and α2 subunits are biologically relevant targets for regulating sedative effects and ethanol consumption.

Therapeutic potential of psychedelics: History, advancements, and unexplored frontiers.

Psychedelics (serotonergic hallucinogens) are psychoactive substances that can alter perception and mood, and affect cognitive functions. These substances activate 5-HT2A receptors and may exert therapeutic effects. Some of the disorders for which psychedelic-assisted therapy have been studied include depression, addiction, anxiety and post-traumatic stress disorder. Despite the increasing number of studies reporting clinical effectiveness, with fewer negative symptoms and, additionally, minimal side effects, questions remain to be explored in the field of psychedelic medicine. Although progress has been achieved, there is still little understanding of the relationship among human brain and the modulation induced by these drugs. The present article aimed to describe, review and highlight the most promising findings in the literature regarding the (putative) therapeutic effects of psychedelics.

Animal model for high consumption and preference of ethanol and its interplay with high sugar and butter diet, behavior, and neuroimmune system.

Introduction: Mechanisms that dictate the preference for ethanol and its addiction are not only restricted to the central nervous system (CNS). An increasing body of evidence has suggested that abusive ethanol consumption directly affects the immune system, which in turn interacts with the CNS, triggering neuronal responses and changes, resulting in dependence on the drug. It is known that neuroinflammation and greater immune system reactivity are observed in behavioral disorders and that these can regulate gene transcription. However, there is little information about these findings of the transcriptional profile of reward system genes in high consumption and alcohol preference. In this regard, there is a belief that, in the striatum, an integrating region of the brain reward system, the interaction of the immune response and the transcriptional profile of the Lrrk2 gene that is associated with loss of control and addiction to ethanol may influence the alcohol consumption and preference. Given this information, this study aimed to assess whether problematic alcohol consumption affects the transcriptional profile of the Lrrk2 gene, neuroinflammation, and behavior and whether these changes are interconnected. Methods: An animal model developed by our research group has been used in which male C57BL/6 mice and knockouts for the Il6 and Nfat genes were subjected to a protocol of high fat and sugar diet intake and free choice of ethanol in the following stages: Stage 1 (T1)-Dietary treatment, for 8 weeks, in which the animals receive high-calorie diet, High Sugar and Butter (HSB group), or standard diet, American Institute of Nutrition 93-Growth (AIN93G group); and Stage 2 (T2)-Ethanol consumption, in which the animals are submitted, for 4 weeks, to alcohol within the free choice paradigm, being each of them divided into 10 groups, four groups continued with the same diet and in the other six the HSB diet is substituted by the AIN93G diet. Five groups had access to only water, while the five others had a free choice between water and a 10% ethanol solution. The weight of the animals was evaluated weekly and the consumption of water and ethanol daily. At the end of the 12-week experiment, anxiety-like behavior was evaluated by the light/dark box test; compulsive-like behavior by Marble burying, transcriptional regulation of genes Lrrk2, Tlr4, Nfat, Drd1, Drd2, Il6, Il1ß, Il10, and iNOS by RT-qPCR; and inflammatory markers by flow cytometry. Animals that the diet was replaced had an ethanol high preference and consumption. Results and discussion: We observed that high consumption and preference for ethanol resulted in (1) elevation of inflammatory cells in the brain, (2) upregulation of genes associated with cytokines (Il6 and Il1ß) and pro-inflammatory signals (iNOS and Nfat), downregulation of anti-inflammatory cytokine (Il10), dopamine receptor (Drd2), and the Lrrk2 gene in the striatum, and (3) behavioral changes such as decreased anxiety-like behavior, and increased compulsive-like behavior. Our findings suggest that interactions between the immune system, behavior, and transcriptional profile of the Lrrk2 gene influence the ethanol preferential and abusive consumption.

Consumo de alimentos altamente procesados y de alta palatabilidad y su relación con el sobrepeso y la obesidad / Ultra-processed and highly palatable foods on the development of obesity

Resumen Introducción: la obesidad es un rasgo multifactorial determinado por la interacción de factores biológicos, ambientales, psicosociales y político-socioeconómicos. Propósito: el objetivo de esta revisión descriptiva-exploratoria es discutir el papel del consumo de alimentos altamente procesados y de alta palatabilidad (APAP) en la epidemia de la obesidad, así como presentar algunas propuestas para disminuir su ingesta. Argumentos para la discusión: los APAP se caracterizan por ser energéticamente densos, ricos en grasas y azúcares. En su formulación se utiliza una gran cantidad de aditivos industriales para potenciar su sabor, vida útil y la estabilidad de sus componentes. Suelen contener sustancias químicas conocidas como disruptores endocrinos (EDC) que se transfieren de los empaques al alimento, como el bisfenol A y los ftalatos, y afectan distintas vías de señalización hormonal, promoviendo alteraciones en el metabolismo del tejido adiposo y otros sistemas endocrinos. El sobreconsumo de APAP induce a cambios neuroplásticos en el sistema de recompensa y esto aumenta, a la vez, el número de porciones, con la subsecuente acumulación de grasa corporal; además, dicho abuso causa desbalances en la composición del microbioma intestinal (disbiosis) asociados al desarrollo de obesidad. Conclusiones: el sobreconsumo de APAP incrementa el riesgo de obesidad y enfermedades crónicas no transmisibles, máxime si se inicia a edades tempranas. Para contrarrestar esta problemática, se plantea cambiar la estructura de la canasta básica, regular la venta dentro y alrededor de centros educativos, crear mayores impuestos y fortalecer la investigación en obesidad, APAP y EDC.

Abstract Introduction. Obesity is a multifactorial trait provoked by the interaction of biological, environmental, psychosocial, and socioeconomic factors. Proposal: The goal of the present review is to discuss the role of ultra-processed and highly palatable foods (UPHP) in the development of the obesity epidemic through an exploratory-descriptive review and to present some suggestions for controlling its consumption. Arguments for discussion: UPHP are energy dense foods with high contents of fat and sugar. UPHP are formulated with many industrial additives used for enhancing flavor, shelf life, and the stability of their components. UPHP used to contain diverse chemicals known as endocrine disruptors (EDC), which are transferred from packaging to foods, with bisphenol A and phthalates as the most common EDC. The EDC disrupt different hormonal signaling pathways affecting the metabolism of the adipose tissue and other endocrine systems. The overconsumption of UPHP induces neuroplastic changes in the brain reward system that increases their consumption, leading to body fat accumulation. In addition, the overconsumption of UPHP alters the composition of the intestinal microbiome (dysbiosis), which is associated with the development of obesity. Conclusions: The overconsumption of UPHP increases the risk of obesity and its related chronic, non-communicable diseases, especially when consumption initiates during early life. To counteract this problem, we proposed the following actions: changing the structure of the market-food basket, incorporating regulations to reduce the UPHP supply in and around educational centers, creating new taxes upon UPHP, and strengthening the research regarding obesity, and the effects of UPHP and EDC.

Fat Intake and Obesity-related Parameters Predict Striatal BDNF Gene Expression and Dopamine Metabolite Levels in Cafeteria Diet-fed Rats.

Modern westernized diet is a major risk factor associated with the current obesity epidemic. To study the effects of dietary choices of Western societies, the cafeteria diet has been validated as a preclinical model of obesity. We aimed to investigate the behavioral and metabolic alterations induced by a cafeteria diet on gene expression and neurotransmitter contents involved in neural plasticity and reward processing. Male Wistar rats were exposed to either standard or cafeteria diet for 9 weeks. Food intake and body weight were scored daily. Behavioral effects were assessed in the elevated plus-maze (EPM) and open field (OFT) tests. Serum biochemical parameters, brain monoamines, and BDNF, TrkB, CRF, CREB, and Dnmt3A mRNA levels were analyzed in reward-related brain regions. We found that cafeteria-diet rats consumed more energy and food than the control group, leading to increased body weight gain and adiposity. The cafeteria-diet rats showed an anxiolytic-like effect in the OFT, but not in the EPM. The cafeteria diet increased BDNF expression in the dorsal striatum (DS), and norepinephrine, 5-HT, TrkB, CREB, and Dnmt3A levels in the hippocampus. Additionally, multiple regression analysis showed that accumbal DOPAC and BDNF mRNA levels were robustly predicted by hyperphagia, fat mass accumulation, and body weight gain only in the cafeteria group. Overall, cafeteria diet-induced hyperphagia could lead to alterations in hedonic and motivational control of food intake through changes in dopamine metabolism and BDNF signaling in the nucleus accumbens and the DS.

The Role of Glia in Addiction: Dopamine as a Modulator of Glial Responses in Addiction.

Addiction is a chronic and potentially deadly disease considered a global health problem. Nevertheless, there is still no ideal treatment for its management. The alterations in the reward system are the most known pathophysiological mechanisms. Dopamine is the pivotal neurotransmitter involved in neuronal drug reward mechanisms and its neuronal mechanisms have been intensely investigated in recent years. However, neuroglial interactions and their relation to drug addiction development and maintenance of drug addiction have been understudied. Many reports have found that most neuroglial cells express dopamine receptors and that dopamine activity may induce neuroimmunomodulatory effects. Furthermore, current research has also shown that pro- and anti-inflammatory molecules modulate dopaminergic neuron activity. Thus, studying the immune mechanisms of dopamine associated with drug abuse is vital in researching new pathophysiological mechanisms and new therapeutic targets for addiction management.

Contribution of GlyR α3 Subunits to the Sensitivity and Effect of Ethanol in the Nucleus Accumbens.

The glycine receptor (GlyR), a ligand-gated ion channel, is critical for inhibitory neurotransmission in brainstem, spinal cord, and in supraspinal regions. Recent data from several laboratories have shown that GlyRs are expressed in the brain reward circuitry and that α1 and α2 are the principal subunits expressed in the nucleus accumbens (nAc). In the present study, we studied the sensitivity to ethanol of homomeric and heteromeric α3 GlyR subunits in HEK293 cells and dissociated neurons from the nAc. Finally, we explored ethanol-related behaviors in a Glra3 knockout mouse (Glra3 -/-). Studies in HEK293 cells showed that while homomeric α3 GlyR subunits were insensitive to ethanol, heteromeric α3ß GlyR subunits showed higher sensitivity to ethanol. Additionally, using electrophysiological recordings in dissociated accumbal neurons, we found that the glycine current density increased in Glra3 -/- mice and the GlyRs were less affected by ethanol and picrotoxin. We also examined the effect of ethanol on sedation and drinking behavior in Glra3 -/- mice and found that the duration in the loss of righting reflex (LORR) was unchanged compared to wild-type (WT) mice. On the other hand, using the drinking in the dark (DID) paradigm, we found that Glra3 -/- mice have a larger ethanol consumption compared to WT mice, and that this was already high during the first days of exposure to ethanol. Our results support the conclusion that heteromeric α3ß, but not homomeric α3, GlyRs are potentiated by ethanol. Also, the increase in GlyR and GABA A R mediated current densities in accumbal neurons in the KO mice support the presence of compensatory changes to α3 knock out. The increase in ethanol drinking in the Glra3 -/- mice might be associated to the reduction in ß and compensatory changes in other subunits in the receptor arrangement.

Presence of ethanol-sensitive and ethanol-insensitive glycine receptors in the ventral tegmental area and prefrontal cortex in mice.

BACKGROUND AND PURPOSE: Glycine receptors composed of α1 and ß subunits are primarily found in the spinal cord and brainstem and are potentiated by ethanol (10-100 mM). However, much less is known about the presence, composition and ethanol sensitivity of these receptors in higher CNS regions. Here, we examined two regions of the brain reward system, the ventral tegmental area (VTA) and the prefrontal cortex (PFC), to determine their glycine receptor subunit composition and sensitivity to ethanol. EXPERIMENTAL APPROACH: We used Western blot, immunohistochemistry and electrophysiological techniques in three different models: wild-type C57BL/6, glycine receptor subunit α1 knock-in and glycine receptor subunit α2 knockout mice. KEY RESULTS: Similar levels of α and ß receptor subunits were detected in both brain regions, and electrophysiological recordings demonstrated the presence of glycine-activated currents in both areas. Sensitivity of glycine receptors to glycine was lower in the PFC compared with VTA. Picrotoxin only partly blocked the glycine-activated current in the PFC and VTA, indicating that both regions express heteromeric αß receptors. Glycine receptors in VTA neurons, but not in PFC neurons, were potentiated by ethanol. CONCLUSION AND IMPLICATIONS: Glycine receptors in VTA neurons from WT and α2 KO mice were potentiated by ethanol, but not in neurons from the α1 KI mice, supporting the conclusion that α1 glycine receptors are predominantly expressed in the VTA. By contrast, glycine receptors in PFC neurons were not potentiated in any of the mouse models studied, suggesting the presence of α2/α3/α4, rather than α1 glycine receptor subunits.

Withdrawing from obesogenic diets: benefits and barriers in the short- and long-term in rodent models.

There is accumulating evidence of dietary impact on several metabolic parameters. Unhealthy diets are estimated to be responsible for about 20% of the deaths worldwide. The recommendation is to improve the dietary pattern, aiming to prevent further harm. In this context, we reviewed the benefits and barriers of withdrawing from continuous obesogenic diet intake in the short- and long-term, which were found in rodent models. Although dietary modifications demand a re-establishment of the equilibrium, withdrawing was seen as a homeostatic insult and thus elicited several responses to protect the organism. In the short-term, withdrawal presented stressful and reward destimulating responses. The intake of obesogenic diets presented rewarding and stress destimulating responses. Whereas withdrawing in the long term ameliorated several biological functions and histopathologic features, it was not effective at reestablishing food intake and normalizing feeding behaviors or reward pathways. Altogether, terminating obesogenic diet intake does not immediately extinguish all negative consequences, and it even elicits brain behavioral and metabolic modifications. These modifications can hinder the maintenance of habits' change and prevent reaching the long-term benefits of diet improvement.

Estrés y cortisol: implicaciones en la ingesta de alimento / Stress and cortisol: implications on food intake

La búsqueda de alimento y su consumo son conductas dirigidas a satisfacer la obtención de los sustratos energéticos necesarios para sostener las diferentes funciones orgánicas que un individuo requiere para garantizar su supervivencia. La conducta alimentaria cuenta con dos sistemas reguladores, uno homeostático ubicado en hipotálamo y otro de tipo hedónico, representado por el sistema de recompensa cerebral. Dichos sistemas están modulados por señales estimuladoras (orexigénicas) e inhibidoras (anorexigénicas) del apetito. En condiciones de estrés crónico, la actividad del eje hipotálamo-hipófisis-adrenal, que regula la concentración de cortisol plasmático, dará lugar al establecimiento de diferentes mecanismos que promuevan la ingesta de alimento de elevada densidad energética, los cuales son considerados como poderosos disruptores de los procesos de regulación del apetito, condición potencialmente capaz de favorecer el desarrollo de una conducta compulsiva en la búsqueda de alimento, una disrupción en el balance energético y obesidad. El consumo repetido de alimentos apetitosos representa para los individuos vulnerados una oportunidad de automedicación dirigida al alivio del estrés, brindando una condición u oportunidad de confort. Los datos epidemiológicos sustentan la idea de un fuerte vínculo entre glucocorticoides y síndrome metabólico. La relación entre estrés crónico, cortisol e ingesta elevada de alimento tienen a la adiposidad visceral y a la resistencia a la insulina como factores predisponentes de una disrupción metabólica con consecuencias importantes al estado de salud de los seres humanos. El presente artículo tiene como objetivo valorar las implicaciones del estrés y cortisol sobre la ingesta de alimento.

Behaviors such as the search and consumption of food are aimed to obtain the energy substrates needed to sustain diverse organic functions required to guarantee the survival of an individual. The alimentary behavior has two regulatory systems: the homeostatic system, located in the hypothalamus and the hedonic system, represented by the cerebral reward system. These systems are modulated by both stimulatory (orexigenic) and inhibitory (anorexigenic) signals of appetite. Under chronic stress conditions, the activity of the hypothalamic-pituitary-adrenal axis, which regulates the plasma cortisol concentration, will lead to the establishment of different mechanisms that promote the ingestion of food with high energy density, which are considered as powerful disruptors of appetite regulation processes, a condition potentially capable of promoting the development of compulsive food search behavior, a disruption in the energy balance and obesity. Repeated consumption of appetizing foods represents an opportunity for self-medication aimed at stress relief, providing a condition or opportunity for comfort. Epidemiological data suggests a strong link between glucocorticoids and metabolic syndrome. The relationship between chronic stress, cortisol and high food intake has visceral adiposity and insulin resistance as predisposing factors of metabolic disruption with important consequences to the health status of humans. The purpose of this article is to evaluate the implications of stress and cortisol on food intake.

Forced ethanol ingestion by Wistar rats from a juvenile age increased voluntary alcohol consumption in adulthood, with the involvement of orexin-A.

Human adolescents who drink alcohol are more likely to become alcoholics in adulthood. Alcohol administration (intraperitoneally) or drinking (in a 2-bottle free choice paradigm) during the juvenile/adolescent age of rats promotes voluntary alcohol consumption in adulthood. On the other hand, there is growing evidence that the orexinergic system plays a role in several rewarded behaviors, including alcohol ingestion. Since it is unknown what effect is exerted in adulthood by forced oral ethanol intake and/or administration of orexin-A (OX-A) in juvenile rats, the present study aimed to evaluate this question. A group of male Wistar rats was forced to drink ethanol (10% v/v) as the only liquid in the diet from weaning (postnatal day 21) to postnatal day 67 (46 days), followed by a forced withdrawal period. An age-matched group was raised drinking tap water (control). OX-A or its vehicle was microinjected intracerebroventricularly (i.c.v.) (1 nmol/0.6 µL) to explore its effect as well. Locomotor activity and voluntary ethanol consumption were later assessed in all groups. The rats forced to consume ethanol early in life showed an elevated level of ambulation and alcohol ingestion in adulthood. A single injection of OX-A increased locomotor activity and acute ethanol intake in rats with or without prior exposure to alcohol at the juvenile stage. In conclusion, forced ethanol consumption in juvenile rats led to increased voluntary alcohol drinking behavior during adulthood, an effect likely facilitated by OX-A.

Leptin levels and its correlation with crack-cocaine use severity: A preliminary study.

BACKGROUND: Crack-cocaine is an important public health problem in Brazil and worldwide. It is a potent form of cocaine which results in rapid and damaging stimulating effects on the central nervous system through inhibition of the dopamine transporter. Some studies have suggested that both food and drugs - including crack, can act on the same brain reward mechanisms, altering the dopamine pathways that modulate behavioral responses. Our hypothesis was that leptin, a well-known peptide that modulates energy metabolism and appetite, can be used as a biomarker for drug use. METHODS: Anthropometric data, drug use profiles, and leptin serum levels were evaluated in a cross-sectional study of 40 crack-cocaine users. RESULTS: Leptin showed an inverse correlation with the severity of crack use, and this correlation remained when corrected by body mass index (BMI) and body composition by bioimpedance (BIA). The majority of subjects were eutrophic or overweight/obese considering BMI and BIA, and these variables were not significantly associated with the severity of crack use, but positively correlated with leptin levels. CONCLUSIONS: Our preliminary findings suggest that leptin could be involved in drug use severity, perhaps through pathways similar to those whereby it modulates food intake. Considering the anthropometric parameters, these findings provide additional evidence that low weight is not predominant in crack users.

Undernutrition during pregnancy and lactation increases the number of fos-cells in the reward system in response to a 5-HT6 receptor agonist in male adolescent rats.

Undernutrition promotes morphofunctional adaptations in neuroanatomical circuits, leading to behavioural changes. Adolescence is a period of vulnerability for these adaptations, such as the control of food intake and the serotonergic system. The serotonergic system is capable of promoting satiety. However, its role in hedonic control has not been fully elucidated. The involvement of the 5-HT6 receptor in motivational feeding behaviours was recently observed. Therefore, we aimed to evaluate the effect of a 5-HT6 receptor agonist on food intake and neuronal activation in areas of the reward system in adolescent rats subjected to perinatal protein undernutrition. Wistar rats were divided into two groups according to nutritional manipulation during gestation and lactation. It has been observed that undernourished animals present greater neuronal activation in response to the 5HT-6 receptor agonist in areas of the food reward system.

Genes, emotions and gut microbiota: The next frontier for the gastroenterologist.

Most medical specialties including the field of gastroenterology are mainly aimed at treating diseases rather than preventing them. Genomic medicine studies the health/disease process based on the interaction of the human genes with the environment. The gastrointestinal (GI) system is an ideal model to analyze the interaction between our genes, emotions and the gut microbiota. Based on the current knowledge, this mini-review aims to provide an integrated synopsis of this interaction to achieve a better understanding of the GI disorders related to bad eating habits and stress-related disease. Since human beings are the result of an evolutionary process, many biological processes such as instincts, emotions and behavior are interconnected to guarantee survival. Nourishment is a physiological need triggered by the instinct of survival to satisfy the body's energy demands. The brain-gut axis comprises a tightly connected neural-neuroendocrine circuitry between the hunger-satiety center, the dopaminergic reward system involved in the pleasure of eating and the gut microbiota that regulates which food we eat and emotions. However, genetic variations and the consumption of high-sugar and high-fat diets have overridden this energy/pleasure neurocircuitry to the point of addiction of several foodstuffs. Consequently, a gut dysbiosis generates inflammation and a negative emotional state may lead to chronic diseases. Balancing this altered processes to regain health may involve personalized-medicine and genome-based strategies. Thus, an integrated approach based on the understanding of the gene-emotions-gut microbiota interaction is the next frontier that awaits the gastroenterologist to prevent and treat GI disorders associated with obesity and negative emotions.

Different levels of brain-derived neurotrophic factor and cortisol in healthy heavy smokers

Studies suggest that brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis modulate dopaminergic activity in response to nicotine and that the concentrations of BDNF and cortisol seem to be dependent on the amount and duration of smoking. Therefore, we investigated BDNF and cortisol levels in smokers ranked by daily cigarette consumption. Twenty-seven adult males (13 non-smokers and 14 smokers) participated in the study. The smokers were divided in two groups: light (n=7) and heavy smokers (n=7). Anthropometric parameters and age were paired between the groups, and plasma BDNF and salivary cortisol levels were measured. Saliva samples were collected on awakening, 30 min after awakening, at 10:00 and 12:00 am, 5:00 and 10:00 pm. Additionally, cotinine serum levels were measured in smokers. Heavy smokers had higher mean values of BDNF compared to the control group (P=0.01), whereas no difference was observed in light smokers. Moreover, heavy smokers presented lower cortisol levels in the last collection (10:00 pm) than the control group (P=0.02) and presented statically higher values of cotinine than the light smokers (P=0.002). In conclusion, changes in BDNF and cortisol levels (10:00 pm) appear to be dependent on heavy cigarette smoking and can be involved in activation and in the relationship between the mesolimbic system and the HPA axis.

Reward and aversion systems of the brain as a functional unit. Basic mechanisms and functions / Sistemas de recompensa y aversión del cerebro como una unidad funcional. Mecanismos básicos y funciones

INTRODUCTION: It is increasingly important to recognize the reward and aversion systems of the brain as a functional unit. A fundamental task of the mammalian brain is to assign an emotional/motivational valence to any stimuli by determining whether they are rewarding and should be approached or are aversive and should be avoided. Internal stimuli are also assigned an emotional/motivational valence in a similar fashion.OBJECTIVE: To understand the basic mechanisms and functions of the reward and aversion system of the brain.METHOD: A bibliographical search was conducted in the Pubmed database using different key words. Documents on relevant aspects of the topic were selected.RESULTS: In the ventral tegmental area, dopaminergic (VTA-DA) neurons play a role in reward-dependent behaviors. It is also known that the inhibition of the VTA-DA neurons by GABAergic neurons contributes to a reward prediction error calculation that promotes behaviors associated with aversion. The ventral dopaminergic mesolimbic system and the nucleus accumbens are activated during reward and inhibited during aversions. The amygdala is activated during aversive behavior.DISCUSSION AND CONCLUSION: The reward/aversion system is highly relevant for survival, which is most likely its primary function. It is involved in important pathologies such as addiction, depression and autonomic and endocrine disturbances. Therefore, its knowledge has become of clinical importance.Although great advances have been made in the knowledge of the basic mechanisms of the reward/aversion system, the detailed circuits within the VTA that mediate reward and aversion and the anatomical substrates are not completely clear.

INTRODUCCIÓN: Es muy importante reconocer el sistema de recompensa y aversión del cerebro como una unidad funcional. Una de las funciones fundamentales del cerebro de los mamíferos es la capacidad para designar un valor emocional/motivacional a cualquier estímulo. Esta capacidad permite identificar un estímulo como gratificante y aproximarnos a él, o reconocerlo como aversivo y evitarlo.OBJETIVO: Comprender los mecanismos fisiológicos del sistema de recompensa-aversión.MÉTODO: Se realizó una búsqueda bibliográfica en la base de datos Pubmed con las diferentes palabras clave. Se seleccionaron los documentos sobre los aspectos relevantes.RESULTADOS: Las neuronas dopaminérgicas del área tegmental ventral (ATV) cumplen un papel importante en los comportamientos dependientes de la recompensa. Asimismo, la inhibición de las neuronas dopaminérgicas ATV por parte de las neuronas GABAérgicas contribuye a predecir la recompensa y promueve comportamientos aversivos. Este sistema se activa durante actividades de recompensa y se inhibe durante la aversión. La amígdala es la principal estructura relacionada con la aversión.DISCUSIÓN Y CONCLUSIÓN: Este sistema se considera de gran importancia para la supervivencia de las especies, la que parece ser su función primordial. Interviene en distintas patologías como adicciones, depresión, trastorno por estrés postraumático, fobias y trastornos endocrinos y autonómicos, por lo que el conocimiento de este sistema es de gran importancia clínica.Aunque se ha avanzado mucho en el estudio y entendimiento de este sistema y de sus circuitos anatómicos ubicados en el ATV mesencefálica y sus conexiones con áreas subcorticales, el conocimiento de este sistema funcional sigue siendo un desafío científico.

Exposure to nicotine increases dopamine receptor content in the mesocorticolimbic pathway of rat dams and offspring during lactation.

Nicotine exposure causes the release of dopamine from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). We have previously shown that maternal exposure to nicotine during lactation causes hyperleptinemia in dams and pups, and leptin is known to decrease dopamine release from the VTA. Here we evaluated whether maternal exposure to nicotine during lactation causes changes in dopamine and leptin signaling pathways at the end of exposure and after 5days of withdrawal in the: VTA, NAc, arcuate nucleus (ARC) and dorsal striatum (DS). On postnatal day (PN) 2, lactating Wistar rats were implanted with minipumps releasing nicotine (NIC; 6mg/kg/day, s.c.) or saline (C) for 14days. Offspring were tested in the elevated plus maze (EPM) and open field on PN14 or PN20, and euthanized on PN15 or PN21. Entries into the open arms and head dips in the EPM were reduced in NIC pups at P20. At weaning (PN21), NIC dams had: lower tyrosine hydroxylase (TH), higher OBRb and SOCS3 contents in VTA; lower TH, higher D1R, D2R and DAT contents in NAc; higher TH content in DS; and higher D2R and SOCS3 contents in ARC. On PN15, NIC offspring had higher D1R, D2R and lower DAT contents in NAc, while on PN21, they had lower DAT in DS, and lower pSTAT3 content in ARC. We evidenced that postnatal nicotine exposure induces relevant changes in the brain reward system of dams and pups, possibly associated with changes in leptinemia and increased offspring anxiety-like behavior.

Maternal nicotine exposure during lactation alters food preference, anxiety-like behavior and the brain dopaminergic reward system in the adult rat offspring.

The mesolimbic reward pathway is activated by drugs of abuse and palatable food, causing a sense of pleasure, which promotes further consumption of these substances. Children whose parents smoke are more vulnerable to present addictive-like behavior to drugs and food.We evaluated the association between maternal nicotine exposure during lactation with changes in feeding, behavior and in the dopaminergic reward system. On postnatal day (PN) 2,Wistar rat dams were implanted with minipumps releasing nicotine (N; 6 mg/kg/day, s.c.) or saline (C) for 14 days. On PN150 and PN160, offspring were divided into 4 groups for a food challenge: N and C that received standard chow(SC); and N and C that could freely self-select (SSD) between high-fat and high-sugar diets (HFD and HSD, respectively). Offspring were tested in the elevated plus maze (EPM) and open field (OF) arena on PN152­153. On PN170, offspring were euthanized for central dopaminergic analysis. SSD animals showed an increased food intake compared to SC ones and a preference for HFD. However, N-SSD animals consumed relatively more HSD than C-SSD ones. Regarding behavior, N animals showed an increase in the time spent in the EPM center and a reduction in relative activity in the OF center. N offspring presented lower dopamine receptor (D2R) and transporter (DAT) contents in the nucleus accumbens, and lower D2R in the arcuate nucleus. Postnatal exposure to nicotine increases preference for sugar and anxiety levels in the adult progeny possibly due to a decrease in dopaminergic action in the nucleus accumbens and arcuate nucleus.