The role of microglia in neuronal and cognitive function during high altitude acclimatization.

Due to their interactions with the neurovasculature, microglia are implicated in maladaptive responses to hypobaric hypoxia at high altitude (HA). To explore these interactions at HA, pharmacological depletion of microglia with the colony-stimulating factor-1 receptor inhibitor, PLX5622, was employed in male C57BL/6J mice maintained at HA or sea level (SL) for 3-weeks, followed by assessment of ex-vivo hippocampal long-term potentiation (LTP), fear memory recall and microglial dynamics/physiology. Our findings revealed that microglia depletion decreased LTP and reduced glucose levels by 25% at SL but did not affect fear memory recall.

Kappa opioid receptor mediated operant performance in male and female rats.

Anhedonia and avolition are emotions frequently endorsed by individuals with stress related disorders. Kappa opioid receptor (KOR) activation can induce negative emotions and recent clinical evidence suggests that KOR antagonism can alleviate anhedonia in a transdiagnostic cohort of patients. However, the behavioral consequences of KOR activation and antagonism in modulating motivation, as assessed by schedule-controlled behavioral performance without preexisting conditions (stress or substance use), have not been formally assessed.

(2R,6R)-hydroxynorketamine (HNK) reverses mechanical hypersensitivity in a model of localized inflammatory pain.

The ketamine metabolite (2R,6R)-hydroxynorketamine, or (2R,6R)-HNK, was recently reported to evoke antinociception in response to a noxious thermal stimulus in healthy mice and reverse mechanical hypersensitivity in a murine model of neuropathic pain. This study reports the behavioral effects of (2R,6R)-HNK in male and female C57BL/6J mice exposed to a localized inflammatory pain condition and the broad pharmacological mechanism underlying this effect. Hind paw intraplantar injection of λ-carrageenan (CARR) caused inflammation and mechanical hypersensitivity in mice within 2 h, lasting at least 48 h.

Buprenorphine as a Treatment for Major Depression and Opioid Use Disorder.

Rates of major depressive disorder (MDD) are disproportionally high in subjects with opioid use disorder (OUD) relative to the general population. MDD is often more severe in OUD patients, leading to compliance issues with maintenance therapies and poor outcomes. A growing body of literature suggests that endogenous opioid system dysregulation may play a role in the emergence of MDD.

Antinociceptive and Analgesic Effects of (2,6)-Hydroxynorketamine.

Commonly used pain therapeutics, such as opioid medications, exert dangerous side effects and lack effectiveness in treating some types of pain. Ketamine is also used to treat pain, but side effects limit its widespread use. (2,6)-hydroxynorketamine (HNK) is a ketamine metabolite that potentially shares some beneficial behavioral effects of its parent drug without causing significant side effects.

Distinct post-sepsis induced neurochemical alterations in two mouse strains.

Sepsis associated encephalopathy, occurs in 70% of severe septic cases, following which survivors exhibit long-term cognitive impairment or global loss of cognitive function. Currently there is no clearly defined neurochemical basis of septic encephalopathy. Moreover, the lingering neurological complications associated with the severe acute respiratory syndrome CoV 2 (SARS-CoV-2) and the significant worsening in outcomes for those individuals with SARS-Cov-2 following sepsis underscore the need to define factors underlying the susceptibility to acute toxic encephalitis.

Mediation of the behavioral effects of ketamine and (2R,6R)-hydroxynorketamine in mice by kappa opioid receptors.

Emerging evidence has implicated the endogenous opioid system in mediating ketamine's antidepressant activity in subjects with major depressive disorder. To date, mu opioid receptors have been suggested as the primary opioid receptor of interest. However, this hypothesis relies primarily on observations that the opioid antagonist naltrexone blocked the effects of ketamine in humans and rodents.

Long-term increase in sensitivity to ketamine's behavioral effects in mice exposed to mild blast induced traumatic brain injury.

Neurobehavioral deficits emerge in nearly 50% of patients following a mild traumatic brain injury (TBI) and may persist for months. Ketamine is used frequently as an anesthetic/analgesic and for management of persistent psychiatric complications. Although ketamine may produce beneficial effects in patients with a history of TBI, differential sensitivity to its impairing effects could make the therapeutic use of ketamine in TBI patients unsafe.

Translational relevance of fear conditioning in rodent models of mild traumatic brain injury.

Mild traumatic brain injury (mTBI) increases the risk of posttraumatic stress disorder (PTSD) in military populations. Utilizing translationally relevant animal models is imperative for establishing a platform to delineate neurobehavioral deficits common to clinical PTSD that emerge in the months to years following mTBI. Such platforms are required to facilitate preclinical development of novel therapeutics.

Kappa Opioid Receptors in the Pathology and Treatment of Major Depressive Disorder.

The kappa opioid receptor (KOR) is thought to regulate neural systems associated with anhedonia and aversion and mediate negative affective states that are associated with a number of psychiatric disorders, but especially major depressive disorder (MDD). Largely because KOR antagonists mitigate the effects of stress in preclinical studies, KOR antagonists have been recommended as novel drugs for treating MDD. The purpose of this review is to examine the role of KORs and its endogenous ligand dynorphins (DYNs) in the pathology and treatment of MDD derived from different types of clinical studies.

The kappa opioid receptor antagonist aticaprant reverses behavioral effects from unpredictable chronic mild stress in male mice.

Rationale: Major depressive disorder is a leading cause of disability worldwide and is likely precipitated by chronic stress. Although many antidepressants are currently available, these drugs require weeks to months of daily administration before reduction of symptoms occurs and many patients remain treatment-resistant despite several courses of treatment. There is a pressing need for new treatments for stress-related disorders.

Sex differences in the modulation of mouse nest building behavior by kappa opioid receptor signaling.

Emerging evidence suggests that females are less sensitive than males to the effects of kappa opioid receptor (KOR) ligands across multiple behavioral measures. The effects of the KOR agonist U50,488 and the KOR antagonist aticaprant were assessed on nest building behavior, an ethologically relevant indicator of overall well-being and affect, in adult male and female C57BL/6J mice. Females required a higher dose of U50,488 to suppress nesting, and a higher dose of aticaprant to restore U50,488-induced impairment of nesting.

Behavioral effects of the kappa opioid receptor partial agonist nalmefene in tests relevant to depression.

Compounds with high affinity at kappa and mu opioid receptors may have clinical utility in treating major depressive disorder. Nalmefene (NMF) is a partial kappa opioid receptor agonist and potent mu opioid receptor antagonist, but there has been no preclinical evaluation of NMF in rodent tests relevant to depression and anxiety. To address this, the effects of NMF on neurochemical and behavioral endpoints in C57BL/6J mice were examined and contrasted with a structurally related analog, naltrexone (NTX).

Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders.

Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants.

Targeting opioid dysregulation in depression for the development of novel therapeutics.

Since the serendipitous discovery of the first class of modern antidepressants in the 1950's, all pharmacotherapies approved by the Food and Drug Administration for major depressive disorder (MDD) have shared a common mechanism of action, increased monoaminergic neurotransmission. Despite the widespread availability of antidepressants, as many as 50% of depressed patients are resistant to these conventional therapies. The significant length of time required to produce meaningful symptom relief with these medications, 4-6 weeks, indicates that other mechanisms are likely involved in the pathophysiology of depression which may yield more viable targets for drug development.

Dysregulation of the Lateral Habenula in Major Depressive Disorder.

Clinical and preclinical evidence implicates hyperexcitability of the lateral habenula (LHb) in the development of psychiatric disorders including major depressive disorder (MDD). This discrete epithalamic nucleus acts as a relay hub linking forebrain limbic structures with midbrain aminergic centers. Central to reward processing, learning and goal directed behavior, the LHb has emerged as a critical regulator of the behaviors that are impaired in depression.

Ketamine Reverses Lateral Habenula Neuronal Dysfunction and Behavioral Immobility in the Forced Swim Test Following Maternal Deprivation in Late Adolescent Rats.

Mounting evidence suggests that the long-term effects of adverse early life stressors on vulnerability to drug addiction and mood disorders are related to dysfunction of brain monoaminergic signaling in reward circuits. Recently, there has been a growing interest in the lateral habenula (LHb) as LHb dysfunction is linked to the development of mental health disorders through monoaminergic dysregulation within brain reward/motivational circuits and may represent a critical target for novel anti-depressants, such as ketamine. Here, we show that maternal deprivation (MD), a severe early life stressor, increases LHb intrinsic excitability and LHb bursting activity, and is associated with the development of increased immobility in the forced swim test (FST) in late-adolescent male rats.

Opioid modulation of cognitive impairment in depression.

The failure of traditional antidepressant medications to adequately target cognitive impairment is associated with poor treatment response, increased risk of relapse, and greater lifetime disability. Opioid receptor antagonists are currently under development as novel therapeutics for major depressive disorder (MDD) and other stress-related illnesses. Although it is known that dysregulation of the endogenous opioid system is observed in patients diagnosed with MDD, the impact of opioidergic neurotransmission on cognitive impairment has not been systematically evaluated.

How do we facilitate international clinical placements for nursing students: A cross-sectional exploration of the structure, aims and objectives of placements.

Background: International clinical placements provide undergraduate students with a unique and complex clinical learning environment, to explore cultural awareness, experience different health care settings and achieve clinical competencies. Higher education institutions need to consider how to structure these placements to ensure appropriate and achievable aims and learning outcomes.

Objectives: In this study we described the structure, aims and learning outcomes associated with international clinical placement opportunities currently undertaken by Australian undergraduate nursing students in the Asia region.

A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress.

Centrally released corticotropin-releasing factor or hormone (extrahypothalamic CRF or CRH) in the brain is involved in the behavioral and emotional responses to stress. The lateral habenula (LHb) is an epithalamic brain region involved in value-based decision-making and stress evasion. Through its inhibition of dopamine-mediated reward circuitry, the increased activity of the LHb is associated with addiction, depression, schizophrenia, and behavioral disorders.

Reversal of Stress-Induced Social Interaction Deficits by Buprenorphine.

Background: Patients with post-traumatic stress disorder frequently report persistent problems with social interactions, emerging after a traumatic experience. Chronic social defeat stress is a widely used rodent model of stress that produces robust and sustained social avoidance behavior. The avoidance of other rodents can be reversed by 28 days of treatment with selective serotonin reuptake inhibitors, the only pharmaceutical class approved by the U.

Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism.

Pharmacogenetic studies have identified the non-synonymous single nucleotide polymorphism (A118G) in the human mu opioid receptor (MOR) gene (OPRM1) as a critical genetic variant capable of altering the efficacy of opioid therapeutics. To date few studies have explored the potential impact of the OPRM1 A118G polymorphism on the pharmacological effects of buprenorphine (BPN), a potent MOR partial agonist and kappa opioid receptor antagonist, which is approved by the FDA for the treatment of opioid addiction and chronic pain. The goal of these studies was to determine whether the MOR-mediated behavioral effects of BPN were altered in the Oprm1 A112G mouse model of the human OPRM1 A118G SNP.

Hair corticosterone measurement in mouse models of type 1 and type 2 diabetes mellitus.

In diabetes, glucocorticoid secretion increases secondary to hyperglycemia and is associated with an extensive list of disease complications. Levels of cortisol in humans, or corticosterone in rodents, are usually measured as transitory biomarkers of stress in blood or saliva. Glucocorticoid concentrations accumulate in human or animal hair over weeks and could more accurately measure the cumulative stress burden of diseases like chronic diabetes.