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1.
Nutr Neurosci ; 23(4): 251-280, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29985117

RESUMO

Background: The clinical and preclinical exploration of the therapeutic properties of vitamin D have significantly increased in the past decade, owing to the growing associative evidence suggesting vitamin D is neuroprotective. However, whether depletion of vitamin D contributes to the onset of neurological disorders or is a symptom of neurological disease has yet to be defined. Much remains unclear about the causal role of vitamin D and the method of use and forms of vitamin D.Objectives: We sought to quantitatively assess if neuroprotective benefits from vitamin D in neurodegenerative diseases are dependent on route of administration: comparing the effect of endogenously sourced vitamin D from UV exposure to exogenously derived vitamin D through synthetic supplementation.Design: We systematically searched PubMed, Embase and PsycInfo databases which included both pre-clinical and clinical studies investigating vitamin D in neurodegenerative diseases. Articles were subject to strict inclusion criteria and objectively assessed for quality. Additionally, Medline data was analysed to identify trends in topic publications and linguistic characteristics of papers.Results: From a total of 231 screened articles, we identified 73 appropriate for review based on inclusion criteria: original studies that investigated vitamin D levels or levels of vitamin D supplementation in neurodegenerative diseases or investigated past/present sun exposure in disease cohorts. Results indicate there is insufficient evidence to comprehensively reflect on a potential neuroprotective role for vitamin D and if this was dependent on route of administration. The majority of current data supporting neuroprotective benefits from vitamin D are based on pre-clinical and observational studies. Solid evidence is lacking to support the current hypothesis that the beneficial effect of UV exposure results from the synthesis of vitamin D. Sun exposure, independent of vitamin D production, may be protective against multiple Sclerosis, Parkinson's disease and Alzheimer's disease. Yet, further research is required to elucidate the beneficial mechanism of actions of UV exposure. The literature of vitamin D and amyotrophic lateral sclerosis was limited, and no conclusions were drawn. Therefore, in cases where UV-derived vitamin D was hypothesized to be the beneficial mediator in the neuroprotective effects of sun exposure, we propose results are based only on associative evidence.Conclusion: On the basis of this systematic review, strong recommendations regarding therapeutic benefits of vitamin D in neurodegenerative disease cannot be made. It is unclear if vitamin D mediates a protective benefit in neurodegenerative disease or whether it is an associative marker of UV exposure, which may contribute to as of yet unidentified neuroprotective factors.


Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Vitamina D/administração & dosagem , Animais , Suplementos Nutricionais , Humanos , Luz Solar , Resultado do Tratamento
2.
J Opioid Manag ; 15(4): 285-293, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31637681

RESUMO

OBJECTIVE: To compare dependence characteristics between patients with chronic pain treated within an addiction medicine setting with those attending specialist pain clinics. SETTING AND PATIENTS: Forty patients with chronic non-cancer pain taking opioid analgesics for >1 year were recruited from university-affiliated, tertiary teaching hospital clinics; 20 from an addiction medicine clinic (addiction clinic group) and 20 from specialist pain clinics (pain clinic group). DESIGN AND MAIN OUTCOME MEASURES: Data regarding demographics, past and current substance use, pain history and current daily opioid intake were collected. Patients completed three questionnaires: the Severity of Opioid Dependence Questionnaire, Leeds Dependence Questionnaire, and Pain Disability Index. A novel "Opioid Problem Checklist score" assessing drug-related problems was also determined for each patient. RESULTS: The addiction clinic group were younger, more likely to have experienced drug overdose and had a shorter duration of chronic pain. No significant differences in dependence questionnaire scores were found between groups. However, higher Pain Disability Index scores and higher Opioid Problem Checklist scores (indicating more drug-related problems) were found for the addiction clinic group. CONCLUSIONS: Some degree of dependence was present across both addiction and pain clinic groups, supporting the notion a state of dependence can be identified among chronic pain patients taking opioids long term. Aberrant behaviors were not common in the pain clinic sample, suggesting these patients are unlikely to meet Diagnostic and Statistical Manual of Mental Disorders-V criteria for Substance Use Disorder. However, opioid dependence carries significant risks for relapse, chronicity, morbidity and mortality, warranting specific medical management. Management of such risks should be considered routine care in chronic pain patients taking opioids long term.


Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Comportamento Aditivo , Dor Crônica , Transtornos Relacionados ao Uso de Opioides , Dor Crônica/tratamento farmacológico , Humanos , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Clínicas de Dor , Avaliação de Sintomas
3.
Neurogastroenterol Motil ; 31(12): e13669, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31241809

RESUMO

BACKGROUND: Stress exposure is known to trigger and exacerbate functional dyspepsia (FD) symptoms. Increased gastric sensitivity to food-related stimuli is widely observed in FD patients and is associated with stress and psychological disorders. The mechanisms underlying the hypersensitivity are not clear. Gastric vagal afferents (GVAs) play an important role in sensing meal-related mechanical stimulation to modulate gastrointestinal function and food intake. This study aimed to determine whether GVAs display hypersensitivity after chronic stress, and whether its interaction with leptin was altered by stress. METHODS: Eight-week-old male C57BL/6 mice were exposed to unpredictable chronic mild stress or no stress (control) for 8 weeks. The metabolic rate, gastric emptying rate, and anxiety- and depression-like behaviors were determined. GVA mechanosensitivity, and its modulation by leptin, was determined using an in vitro single fiber recording technique. QRT-PCR was used to establish the levels of leptin and leptin receptor mRNA in the stomach and nodose ganglion, respectively. KEY RESULTS: The stressed mice had lower body weight and food intake, and increased anxiety-like behavior compared to the control mice. The mechanosensitivity of mucosal and tension-sensitive GVAs was higher in the stressed mice. Leptin potentiated mucosal GVA mechanosensitivity in control but not stressed mice. The expression of leptin mRNA in the gastric mucosa was lower in the stressed mice. CONCLUSIONS AND INFERENCES: In conclusion, chronic stress enhances GVA mechanosensitivity, which may contribute to the gastric hypersensitivity in FD. In addition, the modulatory effect of leptin on GVA signaling is lost after chronic stress exposure.


Assuntos
Estresse Psicológico/fisiopatologia , Nervo Vago/fisiopatologia , Vias Aferentes/fisiologia , Animais , Ansiedade/etiologia , Glicemia/análise , Doença Crônica , Corticosterona/sangue , Depressão/etiologia , Comportamento Exploratório , Comportamento Alimentar , Esvaziamento Gástrico , Humanos , Leptina/metabolismo , Masculino , Aprendizagem em Labirinto , Mecanorreceptores/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Noxas , Sacarose , Natação
5.
J Neuroendocrinol ; 30(11): e12645, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30216577

RESUMO

Exogenously administered oxytocin interacts with the hypothalamic-pituitary-adrenal (HPA) axis to modulate endogenous cortisol levels, suggesting a synergistic role for these two hormones in the response to stress, cognitive performance and the development of psycho-behavioural disorders. The cortisol awakening response (CAR) is considered a reliable measure of HPA axis function in humans. However, the CAR appears to vary considerably from day to day and may be strongly influenced by the anticipated demands of the day ahead. The level of variation intrinsic to the CAR is unclear because few studies have examined the CAR in the absence of daily environmental variation. It is not known whether oxytocin has a similar or complementary awakening response. Therefore, over three consecutive days, we examined 12 adolescents (aged 15-17 years) in a highly-controlled sleep laboratory. Saliva was collected on days 4-6 of a 9-day laboratory visit. Cortisol and oxytocin levels were determined by an enzyme-linked immunosorbent assay from saliva sampled at 0, 15, 30 and 45 minutes, and 8 and 12 hours post-awakening. CAR magnitude varied between days and was associated with sleep duration and pre-awakening sleep stage. Conversely, oxytocin levels dropped dramatically in the first 15 minutes post-awakening and were highly consistent across participants and days. Older participants had higher awakening oxytocin concentrations. Although cortisol increases and oxytocin rapidly declines upon awakening, their diurnal variation does not appear to be related at basal, peripheral levels, consistent with a previous finding that exogenously administered oxytocin only modulates cortisol under conditions of stress.


Assuntos
Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Ocitocina/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Vigília/fisiologia , Adolescente , Ritmo Circadiano , Feminino , Humanos , Masculino , Saliva/metabolismo , Sono
6.
Brain Behav Immun ; 73: 125-132, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30009997

RESUMO

High ultraviolet (UV) light exposure on the skin acts as a reinforcing stimulus, increasing sun-seeking behavior and even addiction-like sun seeking behavior. However, the physiological mechanisms that underlie this process remain to be defined. Here, we propose a novel hypothesis that neuroimmune signaling, arising from inflammatory responses in UV-damaged skin cells, causes potentiated signaling within the cortico-mesolimbic pathway, leading to increased sun-seeking behaviors. This hypothesized UV-induced, skin-to-brain signaling depends upon cell stress signals, termed alarmins, reaching the circulation, thereby triggering the activation of innate immune receptors, such as toll-like receptors (TLRs). This innate immune response is hypothesized to occur both peripherally and centrally, with the downstream signaling from TLR activation affecting both the endogenous opioid system and the mesolimbic dopamine pathway. As both neurotransmitter systems play a key role in the development of addiction behaviors through their actions at key brain regions, such as the nucleus accumbens (NAc), we hypothesize a novel connection between UV-induced inflammation and the activation of pathways that contribute to the development of addiction. This paper is a review of the existing literature to examine the evidence which suggests that chronic sun tanning resembles a behavioral addiction and proposes a novel pathway by which persistent sun-seeking behavior could affect brain neurochemistry in a manner similar to that of repeated drug use.


Assuntos
Comportamento Aditivo/metabolismo , Neuroimunomodulação/fisiologia , Raios Ultravioleta/efeitos adversos , Alarminas/metabolismo , Alarminas/fisiologia , Encéfalo/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Sistema Límbico/imunologia , Sistema Límbico/metabolismo , Neuroglia/fisiologia , Neuroimunomodulação/efeitos dos fármacos , Neurotransmissores/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/metabolismo
7.
Brain Behav Immun ; 67: 181-193, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28864261

RESUMO

Circadian rhythm affects drug-induced reward behaviour and the innate immune system. Peaks in reward-associated behaviour and immune responses typically occur during the active (dark) phase of rodents. While the role of the immune system, specifically, Toll-like receptor 4 (TLR4, an innate immune receptor) in drug-induced reward is becoming increasingly appreciated, it is unclear whether its effects vary according to light-cycle. Therefore, the aim of this study was to characterise the effects of the phase of the light-cycle and the state of the innate immune system on alcohol reward behaviour and subsequently determine whether the efficacy of targeting the immune component of drug reward depends upon the light-cycle. This study demonstrates that mice exhibit greater alcohol-induced conditioned place preference and alcohol two-bottle choice preference during the dark cycle. This effect overlapped with elevations in reward-, thirst- and immune-related genes. Administration of (+)-Naltrexone, a TLR4 antagonist, reduced immune-related gene mRNA expression and alcohol preference with its effects most pronounced during the dark cycle. However, (+)-Naltrexone, like other TLR4 antagonists exhibited off-target side effects, with a significant reduction in overall saccharin intake - an effect likely attributable to a reduction in tyrosine hydroxylase (Th) mRNA expression levels. Collectively, the study highlights a link between a time-of-day dependent influence of TLR4 on natural and alcohol reward-like behaviour in mice.


Assuntos
Comportamento de Escolha/efeitos dos fármacos , Ritmo Circadiano , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/administração & dosagem , Imunidade Inata , Naltrexona/administração & dosagem , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Fotoperíodo , Recompensa , Receptor 4 Toll-Like/metabolismo
8.
Front Psychol ; 8: 1521, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28955264

RESUMO

Oxytocin is often portrayed as a hormone specific to social behavior, reflective of positive welfare states, and linked to mental states. Research on oxytocin in domesticated animal species has been few to date but is rapidly increasing (in dog, pig, cattle, sheep), with direct implications for animal welfare. This review evaluates the evidence for the specificity of oxytocin as an indicator of: 1. Social, 2. Positive, and 3. Psychological well-being. Oxytocin has most often been studied in socially relevant paradigms, with a lack of non-social control paradigms. Oxytocin research appears biased toward investigating positive valence, with a lack of control in valence or arousal. Oxytocin actions are modulated by the environmental and social contexts, which are important factors to consider. Limited evidence supports that oxytocin's actions are linked to psychological states; nevertheless whether this is a direct effect of oxytocin per se remains to be demonstrated. Overall, it is premature to judge oxytocin's potential as an animal welfare indicator given the few and discrepant findings and a lack of standardization in methodology. We cover potential causes for discrepancies and suggest solutions through appropriate methodological design, oxytocin sampling or delivery, analysis and reporting. Of particular interest, the oxytocinergic system as a whole remains poorly understood. Appreciation for the differences that social contact and group living pose in domesticated species and the way they interact with humans should be key considerations in using oxytocin as a psychosocial indicator of well-being.

9.
Behav Pharmacol ; 27(8): 659-671, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27755016

RESUMO

The endogenous oxytocin system plays a vital role in facilitating parturition, lactation and social interaction in humans and other mammals. It also impacts on a number of important endocrine, immune and neurotransmitter systems. A well-regulated oxytocin system has been proposed to increase resilience, and therefore reduce the likelihood of an individual developing mental illness or substance dependence. This review discusses the adverse external influences that can modulate oxytocin receptor and protein levels and impact on substance use and mental health. The paper highlights the impact of adversity such as poor maternal care, parental substance use and child abuse or neglect. We review clinical and preclinical data on the impact of adversity on the basis of the time of exposure from infancy and early childhood, to adolescence, adulthood to older age. Previous research suggests that dysregulation of the endogenous oxytocin system may be implicated in determining susceptibility to stress, anxiety, addiction and mental health conditions. The impact of external influence seems to be strongest in specific time periods where the system shows experience-based development or natural fluctuations in oxytocin levels. Interventions that target the oxytocin system during or soon after exposure to adversity may prove protective.


Assuntos
Transtornos Mentais/fisiopatologia , Ocitocina/metabolismo , Receptores de Ocitocina/metabolismo , Adolescente , Adulto , Fatores Etários , Idoso , Animais , Criança , Suscetibilidade a Doenças , Humanos , Lactente , Transtornos Mentais/etiologia , Transtornos Relacionados ao Uso de Substâncias/etiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Fatores de Tempo
10.
Artigo em Inglês | MEDLINE | ID: mdl-25814979

RESUMO

Endogenous oxytocin plays an important role in a wide range of human functions including birth, milk ejection during lactation, and facilitation of social interaction. There is increasing evidence that both variations in the oxytocin receptor (OXTR) and concentrations of oxytocin are associated with differences in these functions. The causes for the differences that have been observed in tonic and stimulated oxytocin release remain unclear. Previous reviews have suggested that across the life course, these differences may be due to individual factors, e.g., genetic variation (of the OXTR), age or sex, or be the result of early environmental influences, such as social experiences, stress, or trauma partly by inducing epigenetic changes. This review has three aims. First, we briefly discuss the endogenous oxytocin system, including physiology, development, individual differences, and function. Second, current models describing the relationship between the early life environment and the development of the oxytocin system in humans and animals are discussed. Finally, we describe research designs that can be used to investigate the effects of the early environment on the oxytocin system, identifying specific areas of research that need further attention.

11.
Front Behav Neurosci ; 8: 360, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25360094

RESUMO

The role of endogenous oxytocin as neuromodulator of birth, lactation and social behaviors is well-recognized. Moreover, the use of oxytocin as a facilitator of social and other behaviors is becoming more and more accepted. Many positive effects have been attributed to intranasal oxytocin administration in animals and humans; with current research highlighting encouraging advances in its potential for use in mental health disorders. The new frontier will be investigating the effective use of oxytocin in pediatric populations. Limited animal data is available on this. Large-scale human studies focusing on autism are currently under way, but many other possibilities seem to lie in the future. However, we need to know more about the risks and effects of repeated use on the developing brain and body. This paper will provide an overview of the current understanding of the role of endogenous oxytocin and its related neuropeptide systems in influencing behaviors, in particular attachment, and will review (a) the literature on the use of intranasal oxytocin in young animals, children (age range birth-12 years) and adolescents (age range 13-19 years), (b) the expected benefits and risks based on the current research, and (c) the risks of oxytocin in children with severe psychopathology and early life trauma. The paper will conclude with a clinical perspective on these findings.

12.
Pain Med ; 15(4): 647-60, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24517126

RESUMO

OBJECTIVE: Sensory illusions may reveal fundamental features of the nervous system. The thermal grill illusion is such a pain illusion, where interlaced warm and cool temperature bars (thermal grill) produce a paradoxical burning sensation. Previous studies have only systematically investigated the thermal grill illusion in pain-free volunteers. The objective of this study was to investigate whether the response to the thermal grill illusion was tolerable in patients with chronic pain and whether the response differed between patients with chronic pain and pain-free volunteers. SUBJECTS: Sixteen pain-free participants and 18 chronic pain patients (seven not receiving opioids and 11 receiving opioids). METHODS: The thermal grill response was investigated using a custom-built thermal grill. Heat and cold pain thresholds were also determined. RESULTS: Chronic pain patients reported less intense pain, heat, and unpleasantness to the thermal grill compared with pain-free participants; in particular, there was an overall main effect for significantly less heat from the thermal grill compared with pain-free participants (P = 0.016). At the 22/38°C combination, although the majority of pain-free participants experienced the illusion to some degree, the majority of pain patients in both groups did not (median pain score 0). Although perceived heat from the thermal grill was significantly lower in chronic pain patients, both heat and cold pain thresholds did not differ among the three populations. CONCLUSIONS: This preliminary data suggest that the thermal grill response may provide insights into pain sensitivity that are not detected by conventional thermal quantitative sensory testing.


Assuntos
Dor Crônica/fisiopatologia , Temperatura Baixa , Temperatura Alta , Ilusões/fisiologia , Distúrbios Somatossensoriais/fisiopatologia , Sensação Térmica/fisiologia , Adulto , Idoso , Analgésicos Opioides/uso terapêutico , Estudos de Casos e Controles , Dor Crônica/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Limiar da Dor/fisiologia
14.
Pharmacol Biochem Behav ; 119: 22-38, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24056025

RESUMO

Recent research shows that the effects of oxytocin are more diverse than initially thought and that in some cases oxytocin can directly influence the response to drugs and alcohol. Large individual differences in basal oxytocin levels and reactivity of the oxytocin system exist. This paper will review the literature to explore how individual differences in the oxytocin system arise and examine the hypothesis that this may mediate some of the individual differences in susceptibility to addiction and relapse. Differences in the oxytocin system can be based on individual factors, e.g. genetic variation especially in the oxytocin receptor, age or gender, or be the result of early environmental influences such as social experiences, stress or trauma. The paper addresses the factors that cause individual differences in the oxytocin system and the environmental factors that have been identified to induce long-term changes in the developing oxytocin system during different life phases. Individual differences in the oxytocin system can influence effects of drugs and alcohol directly or indirectly. The oxytocin system has bidirectional interactions with the stress-axis, autonomic nervous system, neurotransmitter systems (e.g. dopamine, serotonin and GABA/glutamate) and the immune system. These systems are all important, even vital, in different phases of addiction. It is suggested that early life adversity can change the development of the oxytocin system and the way it modulates other systems. This in turn could minimise the negative feedback loops that would normally exist. Individuals may show only minor differences in behaviour and function unless subsequent stressors or drug use challenges the system. It is postulated that at that time individual differences in oxytocin levels, reactivity of the system or interactions with other systems can influence general resilience, drug effects and the susceptibility to develop problematic drug and alcohol use.


Assuntos
Suscetibilidade a Doenças , Ocitocina/fisiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Animais
15.
Pharmacol Biochem Behav ; 119: 39-48, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23916423

RESUMO

The present article advances a neurobiological model of the reciprocal associations between social attachment and drug abuse, and social attachment and chronic stress, as overlapping systems are involved in stress coping and social attachment. In terms of coping, responding to a novel stressor or challenge involves initial novelty processing and activation of learning mechanisms that allow habituation to the stressor through familiarization. Similarly, social attachments are initially formed by being attracted by rewarding properties of an as-yet novel individual, and subsequently developing feelings of attachment towards the familiarized individual. Attachment and familiarization increase the availability of "internal working models" for the control of behavior and emotion, which may explain why secure attachments are associated with increased resilience in the face of stress, accompanied by less reactive reward responding (i.e., increased resilience against drug addiction). The present article seeks to illuminate the role of the neuropeptide oxytocin, which may be involved in the overlapping mechanisms of stable attachment formation and stress coping by shifting processing from novelty and reward seeking to appreciation of familiarity. Oxytocin may accomplish this by facilitating a ventral-to-dorsal shift in activation in corticostriatal loops, which produces a shift from a reactive reward drive (wanting) to stable appreciation of familiar social aspects ("liking" or "loving"). The authors suggest that through dopaminergic, serotonergic and endogenous opioid mechanisms, oxytocin is involved in shifting the balance between wanting and liking in corticostriatal loops by facilitating consolidation of social information from ventral reactive reward systems to dorsal internal working models that aid in prospectively selecting optimal actions in the future, increasing resilience in the face of stress and addiction.


Assuntos
Córtex Cerebral/fisiopatologia , Corpo Estriado/fisiopatologia , Ocitocina/fisiologia , Comportamento Social , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Humanos , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
16.
Front Psychiatry ; 3: 43, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22623919

RESUMO

Cortisol and oxytocin have been shown to interact in both the regulation of stress responses and in memory function. In the present study we administered cortisol to 35 healthy female subjects in a within-subject double-blind placebo-controlled design, while measuring oxytocin levels, adrenocorticotropic hormone (ACTH) levels, and free recall of pleasant and of unpleasant words. We found that cortisol administration suppressed ACTH levels and (1) induced a decrease in oxytocin associated with ACTH suppression and (2) an increase in oxytocin that was independent from ACTH suppression. This cortisol-induced increase in plasma oxytocin was associated with a selective decrease in immediate free recall of unpleasant words from primacy positions. The present results add to evidence that cortisol-induced increases in oxytocin could mediate some of the effects of stress and cortisol on memory, and possibly play a role in the regulation of the hypothalamo-pituitary-adrenal stress response. This mechanism could significantly impact affective and social behaviors, in particular during times of stress.

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