Emergence Of Negative Emotional State Research Articles

Proteomic analysis of central amygdala systems regulated by the glucocorticoid receptor antagonist mifepristone in the context of alcohol dependence

Alcohol use disorder (AUD) is a chronic psychiatric disorder characterized by escalated alcohol use and emergence of negative emotional states during withdrawal. Studies show a dysregulation of glucocorticoid signaling in AUD, affecting the hypothalamic-pituitary-adrenal (HPA) axis and the central amygdala (CeA). Excessive activation of glucocorticoid receptors (GRs) is hypothesized to promote cognitive dysfunction, negative emotional states, and escalated drinking. Previous work demonstrates a functional increase in GR activity in the CeA during alcohol withdrawal in alcohol-dependent animal models. Importantly, the GR antagonist mifepristone reduces alcohol-seeking and drinking behaviors in rodents and humans. The aims of this study were to determine differential CeA protein expression in alcohol-dependent rats and examine the effects of mifepristone treatment. We hypothesized that male and female rats will show sex differences in their CeA protein expression and that alcohol-induced reductions in brain anti-stress signaling (e.g., endocannabinoid system) will be normalized by mifepristone treatment. Male and female Wistar rats were exposed to chronic intermittent ethanol vapor (CIEV) or air (control) for 10 weeks. In week 7, half of each group received subcutaneous placebo pellets while the other half received mifepristone pellets (150mg, 21-day slow release). At the end of Week 10, the rats were sacrificed during acute (6-hour) CIEV withdrawal (and identical time in control groups). The CeA was analyzed using proteomics and ingenuity pathway analysis (IPA). In males, a total of 3050 proteins were detected in the CeA. Of these, 142 proteins were altered by alcohol (but not mifepristone), whereas an additional 253 proteins were altered by alcohol and “normalized” by mifepristone. In females, among the 2632 detected proteins, 46 were affected by alcohol (but not mifepristone), and 25 were altered by alcohol and restored by mifepristone. IPA revealed significant changes in canonical pathways, including the endocannabinoid neuronal synapse pathway and oxidative phosphorylation, affected by alcohol but normalized by mifepristone. Future studies will incorporate alcohol self-administration procedures in male and female rats to functionally examine proteins within these pathways as promising “druggable” targets that offer novel therapeutic avenues for AUD. Supported by NIH-NIAAA R01AA025996, P60AA009803, T32AA007577. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The state of hemodynamics of trainees of vocational training during a fire training class

The activities of employees of internal affairs bodies associated with the performance of official duties in extreme conditions dangerous to life and health, leads to the emergence of negative emotional states. Such conditions have an impact on the entire physiological system of the body. This often leads to affective or aggressive-chaotic actions, or to the refusal to perform those actions that, if necessary, will allow you to successfully complete the official task. This often leads to injuries and deaths of law enforcement officers. Problem statement: the study of the functioning of the body systems of employees of the internal affairs bodies, their behavior in situations of risk to life and health shows that employees often have poor self-regulation techniques to overcome negative conditions and are not able to quickly bring their body to a normal functional state. The purpose of the study: to establish the relationship between hemodynamic and respiratory indicators of trainees of vocational training in a fire training class.Research methods: the authors have applied both theoretical research methods (analysis, comparison, generalization, systematization). Empirical data were systematized on the basis of mathematical statistics methods and presented using the graphical method. Results and key conclusions: based on the developed private methodology of functional diagnostics, the indicators of hemodynamics and external respiration of employees of internal affairs bodies during fire training classes were studied. In addition, the results of the study can be used when conducting fire training classes for the development and implementation of individually differentiated technologies for self-regulation of employees during professional training.

Job insecurity and emotional disturbance of Polish employees during pandemic COVID-19.

The pandemic, as an event that is new and dangerous to the health and life of the population, has put employees at risk of losing their job and experiencing deteriorating working and employment conditions. In this situation, authors were particularly concerned with the extent to which job insecurity (both quantitative and qualitative) contributed to the deterioration of workers' well-being. The study was carried out on 382 Polish employees in April and May 2020. The following research tools were used: the Job Insecurity in Pandemic Scale by Chirkowska-Smolak and Czumak and the Depression, Anxiety, Stress Scale (DASS-21) by Levibond and Levibond. The quantitative and qualitative job insecurity were significant predictors of depression and stress, but they did not explain anxiety symptoms. The scope of the explained variance of these negative emotional states by concerns related to work and employment was not large (from 11% to 17.6%). The moderating role of perceived employability was confirmed only in the case of the relationship between qualitative job insecurity and depression, as well as quantitative job insecurity and stress. However, the increase in the explained variance was very small. Uncertainty related to the maintenance of employment and concerns about the deterioration of working conditions due to the COVID-19 pandemic had an impact on emotional disturbances of employees, but they only explained some of the variance of depression and stress and did not affect the perceived level of anxiety. The smaller role of economic stress in the emergence of negative emotional states could be associated with the occurrence of much more serious threats to the health and life of the population in this period. The very low level of unemployment in Poland, which remained at a similar level throughout the pandemic despite the catastrophic forecasts of economists, could also have played an important role. Med Pr. 2021;72(6):645-52.

Prevention of glutamate excitotoxicity in lateral habenula alleviates ethanol withdrawal-induced somatic and behavioral effects in ethanol dependent mice

Ethanol withdrawal commonly leads to anxiety-related disorder, a central factor toward negative reinforcement leading to relapse. The lateral habenula (LHb), an epithalamic nucleus, has emerged to be critical for both reward and aversion processing. Recent studies have also implicated the hyperactivity of LHb, adding to the emergence of negative emotional states during withdrawal from addictive drugs. Herein, we have studied the effects of glutamate transporter inhibitor (PDC), GluN2B-containing NMDAR antagonist (Ro25-6981), and intracellular calcium chelator (BAPTA-AM) injection in LHb on ethanol withdrawal symptoms. We found that ethanol 4 g/kg 20 % w/v intragastric (i.g.) for 10 days followed by 24 h of withdrawal showed a significant increase in somatic signs characterized by vocalization, shaking, and scratching. It also increased locomotor activity and anxiety-like behavior, collectively showing expression of ethanol withdrawal symptoms. The intra-LHb administration of PDC (0.5 ng) worsened the effect of ethanol withdrawal, whereas Ro25-6981 (2 and 4 ng) and BAPTA-AM (6.5 and 13 ng) significantly reversed ethanol withdrawal-induced behavior evident by a decrease in somatic signs, locomotor activity, and anxiety-like behavior. Further, pretreatment of Ro25-6981 and BAPTA-AM reduced the neuronal loss, whereas PDC increased it compared to the vehicle-treated group, as evidenced by NeuN staining. Altogether, our results suggest that increased glutamate, GluN2B activation, and likely calcium increase indicative of glutamate excitotoxicity-induced neuronal loss in LHb possibly endorse the emergence of ethanol withdrawal symptoms, while their inhibition might help in alleviating the ethanol withdrawal symptoms.

Glutamatergic and gabaergic neuronal populations in the dorsal Periacqueductual Gray have different functional roles in aversive conditioning

The dorsal periacqueductal gray (dPAG) is a midbrain structure having an essential role in coordinating defensive behaviors in response to aversive stimulation. However, the question of whether dPAG neurons can respond to aversive conditioning and retrieval, properties involved in emergence of negative emotional state, is still under debate.Here we used calcium imaging by fiber photometry to record the activity of dPAGVGluT2+ and dPAGGAD2+ neuronal populations during unconditioned and conditioned aversive stimulation. Then, following an unconditioned stimulation we performed a retrieval experiment to quantify memory-like responses of dPAG neurons. This shown that whilst both dPAGVGluT2+ and dPAGGAD2+ neuronal populations respond to direct US stimulation, and to CS stimulation during conditioning, only the dPAGVGluT2+ population persisted in responding to the CS stimulation during retrieval. Finally to better understand these divergences in dPAGVGluT2+ and dPAGGAD2+ responses, we investigated their respective connectivity patterns by performing a cell specific monosynaptic retrograde rabies virus tracing experiment. This revealed that different patterns of fibers projects to dPAGVGluT2+ and dPAGGAD2+, which could explain part of their response specificities. This may indicate that glutamatergic subpopulation is a main contributor of aversive memories in dPAG.

Cocaine withdrawal reduces GABAB R transmission at entopeduncular nucleus - lateral habenula synapses.

Lateral habenula (LHb) hyperactivity plays a pivotal role in the emergence of negative emotional states, including those occurring during withdrawal from addictive drugs. We have previously implicated cocaine‐driven adaptations at synapses from the entopeduncular nucleus (EPN) to the LHb in this process. Specifically, ionotropic GABAA receptor (R)‐mediated neurotransmission at EPN‐to‐LHb synapses is reduced during cocaine withdrawal, due to impaired vesicle filling. Recent studies have shown that metabotropic GABABR signaling also controls LHb activity, although its role at EPN‐to‐LHb synapses during drug withdrawal is unknown. Here, we predicted that cocaine treatment would reduce GABABR‐mediated neurotransmission at EPN‐to‐LHb synapses. We chronically treated mice with saline or cocaine, prepared brain slices after two days of withdrawal and performed voltage‐clamp recordings from LHb neurons whilst optogenetically stimulating EPN terminals. Compared with controls, mice in cocaine withdrawal exhibited reduced GABAAR‐mediated input to LHb neurons, and a reduced occurrence of GABABR‐signaling at EPN‐to‐LHb synapses. We then assessed the underlying mechanism of this decrease. Application of GABABR agonist baclofen evoked similar postsynaptic responses in EPN‐innervated LHb neurons in saline‐ and cocaine‐treated mice. Release probability at EPN‐to‐LHb GABAergic synapses was also comparable between groups. However, incubating brain slices in glutamine to facilitate GABA vesicle filling, normalized GABABR‐currents at EPN‐to‐LHb synapses in cocaine‐treated mice. Overall, we show that during cocaine withdrawal, together with reduced GABAAR transmission, also GABABR‐mediated inhibitory signaling is diminished at EPN‐to‐LHb synapses, likely via the same presynaptic deficit. In concert, these alterations are predicted to contribute to the emergence of drug withdrawal symptoms, facilitating drug relapse.

Dysregulation of c-Jun N-terminal kinase phosphorylation in alcohol dependence.

Alcohol use disorder (AUD) is a chronic, relapsing psychiatric disease characterized by the emergence of negative emotional states and the development of motivational deficits that manifest during alcohol withdrawal. Accordingly, alcohol may be sought after and taken in excessive amounts to alleviate withdrawal-related symptoms. To develop more effective treatments for AUD, it is necessary to identify potential molecular targets that underlie the transition from initial alcohol use to alcohol dependence, and our previous work has implicated a role for potentiated glucocorticoid receptor (GR) signaling in this regard. As a key negative regulator of GR-mediated signaling, the current study first measured c-Jun N-terminal kinase (JNK) phosphorylation in animals following an acute alcohol challenge. We found that JNK phosphorylation (pJNK) was significantly increased in the hippocampus, frontal cortical regions, and striatum of adult male Wistar rats following alcohol challenge, indicating that initial alcohol exposure increases JNK activity across several brain regions. A separate group of adult male Wistar rats were made dependent via chronic, intermittent ethanol vapor exposure and were trained to self-administer alcohol. We found that alcohol-dependent animals consumed significantly more alcohol and escalated their drinking over time compared to non-dependent animals. We then measured alterations in JNK phosphorylation in this alcohol-dependent group during acute withdrawal and found that pJNK was selectively decreased in the dorsal hippocampus, dorsomedial prefrontal cortex, and cingulate cortex. These findings demonstrate that withdrawal from chronic alcohol exposure leads to region-specific deficits in JNK phosphorylation. JNK signaling dysregulation may foster long-lasting behavioral and motivational impairments in alcohol dependence, either as a result of increased GR-mediated stress signaling or via other downstream mechanisms.

Glucocorticoid Receptor‐Dependent Gene Expression in the Central Amygdala of Alcohol‐Dependent Animals

Alcohol Use Disorder (AUD) is a chronic, relapsing psychiatric disorder that is characterized by the development of motivational symptoms (e.g., escalation of alcohol intake) and the parallel emergence of negative emotional states (e.g., dysphoria, anxiety, pain). Consequently, the transition from recreational, limited alcohol consumption to uncontrolled, escalated intake is proposed to involve a transition from positive to negative reinforcement mechanisms. Our previous research indicates that alcohol dependence is associated with potentiated glucocorticoid signaling in brain regions that mediate stress and nociception, namely the central amygdala (CeA). Glucocorticoid receptor (GR) antagonism with mifepristone has demonstrated promising efficacy in reducing alcohol consumption in humans with AUD and rodent models of alcohol dependence. However, mifepristone's mechanism of action remains unclear. Given the role of GR as a transcription factor, we hypothesized that potentiated GR activity increases the expression of downstream neuropeptide system genes, and mifepristone normalizes these transcriptional effects. We tested our hypothesis in a well‐ established rodent model of AUD that utilizes chronic intermittent ethanol vapor exposure (CIEV). One day prior to the start of vapor exposure, animals were implanted with either placebo or 30d chronic release mifepristone pellets. After the 4‐week treatment regimen, we utilized a fluorescent bead‐based multiplex assay to determine brain region‐specific changes in mRNA levels of expected GR‐regulated genes. Results were analyzed via two‐way ANOVA, with alcohol vapor exposure (modeling alcohol dependence) and mifepristone treatment as factors. We found that within the CeA, alcohol dependence was associated with increased mRNA coding for the nociceptin peptide as well as its receptor, opioid receptor‐like 1 (Orl1), while mifepristone treatment significantly attenuated this effect. The nociceptin system is a part of the endogenous opioid class of signaling molecules, and previous research has demonstrated a role for nociceptin in both chronic pain and the manifestation of negative affect during alcohol withdrawal. Our findings suggest that the therapeutic benefits of mifepristone could be associated with a blunting of the nociceptin system in the central amygdala.Support or Funding InformationOur research is supported by the following grants from the National Institute on Alcohol Abuse and Alcoholism: F31AA025812 (MAM) and R00AA020839 (SE).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Impact of Topic Characteristics and Threat on Willingness to Engage with Wikipedia Articles: Insights from Laboratory Experiments.

A growing body of research aims to identify the factors that motivate people to make contributions in Wikipedia. We conducted two laboratory experiments to investigate the connections between topic characteristics, perception of threat, and willingness to engage with Wikipedia articles. In Study 1 (N = 83), we examined how topic familiarity, topic controversiality, and mortality salience influenced participants’ willingness to engage with Wikipedia articles. We presented the introduction parts of 20 Wikipedia articles and asked participants to rate each article with respect to familiarity and controversiality. In addition, we experimentally manipulated participants’ level of mortality salience in terms of the amount of threat they experienced when reading the article. Participants also indicated their willingness to engage with a particular article. The results revealed that familiar and controversial topics increased the willingness to engage with Wikipedia articles. Although mortality salience increased accessibility of death-related thoughts, it did not result in any changes in people’s willingness to work with the articles. The aim of Study 2 (N = 90) was to replicate the effects of topic characteristics by following a similar procedure. We additionally manipulated uncertainty salience by assigning participants to three experimental conditions: uncertainty salience, certainty salience, and non-salience. As expected, familiar and controversial topics were of high interest in terms of willingness to contribute. However, the manipulation of uncertainty salience did not yield any significant results despite the emergence of negative emotional states. In sum, we demonstrated that topic characteristics were factors that substantially influenced people’s willingness to engage with Wikipedia articles whereas perceived threat was not.

Negative Emotional States Help Drive Alcohol Use Disorder, Koob Says

Back to table of contents Previous article Next article Professional NewsFull AccessNegative Emotional States Help Drive Alcohol Use Disorder, Koob SaysMark MoranMark MoranSearch for more papers by this authorPublished Online:30 Jun 2017https://doi.org/10.1176/appi.pn.2017.7a11AbstractThe NIAAA director is credited with significantly broadening knowledge of the adaptations within reward and stress neurocircuits that lead to addiction.Alcohol and drug addiction appears to impair not only brain areas critical to reward, but over time also sensitizes other brain areas involved in negative emotional states—dysphoria, anxiety, and irritability—when access to the drug or stimulus is prevented. George Koob, Ph.D., says he doubts that medication can “cure” alcoholism, but it can be an important tool in the biopsychosocial treatment of alcohol use disorder.David Hathcox“We can all agree that addiction is a chronic, relapsing disorder characterized by a compulsion to use a substance or stimulus,” said George F. Koob, Ph.D., director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), at APA’s 2017 Annual Meeting in San Diego. “But we now believe that a critical component of addiction is the emergence of negative emotional states when access to the substance is prevented. This is what I have called the ‘dark side of addiction.’ ” Koob described recent research indicating that negative emotional states are activated in parts of the brain outside the reward circuit that become sensitized as an individual’s addiction increases over time and appear to involve a number of stress-related neurotransmitters that cause anxiety and irritability when an addict’s drug of choice is denied or not available. These stress-related neurotransmitters include corticotropin-releasing factor (CRF), norepinephrine, dynorphin, vasopressin, glucocorticoids, or other neuroimmune factors.“Compulsive drug taking produces a reduction in reward neurotransmission in the basal ganglia and a recruitment of brain stress neurotransmission in the extended amygdala that contribute to dysphoric-like responses and a negative emotional state,” Koob said. “We believe that these brain systems mediating negative emotional states are activated by acute excessive drug intake, sensitized during repeated withdrawal, and persist into protracted withdrawal.”In combination with social and environmental cues that trigger the desire to use or drink, these negative emotional states drive drug seeking and relapse in addiction, Koob said. He described an individual who has faced workplace consequences due to alcoholism or addiction; driving home, he feels humiliated and agitated. “He sees his favorite bar, and the lights go off,” Koob said.Koob is an internationally recognized expert on alcohol and stress and the neurobiology of alcohol and drug addiction. As director of NIAAA, he oversees a broad portfolio of alcohol research ranging from basic science to epidemiology, diagnostics, prevention, and treatment. He began his career investigating the neurobiology of emotion, particularly how the brain processes reward and stress. He subsequently applied basic research on emotions, including on the anatomical and neurochemical underpinnings of emotional function, to alcohol and drug addiction, significantly broadening knowledge of the adaptations within reward and stress neurocircuits that lead to addiction.This work has advanced the understanding of the physiological effects of alcohol and other substance use and why some people transition from use to misuse to addiction while others do not. At the lecture, Koob reminded psychiatrists that despite the existence of three FDA-approved drugs to treat alcohol use disorder—disulfiram, naltrexone, and acamprosate—less than 20 percent of addicted individuals get treatment, and less than 10 percent get pharmacotherapy. Moreover, he said data now indicate that as many as 15 percent of deaths from opioid overdose also involved alcohol use. Koob’s research suggests hope for the development of medications that can diminish negative emotional states associated with withdrawal from alcohol or drugs, and he noted that anti-stress neurotransmitters such as oxytocin have shown promise. But he cautioned against hoping for a magic bullet. “I don’t think medication can ever cure addiction,” he said. “Rather, medication may be one piece in an armamentarium. Behavioral therapies, which many of you provide, will be needed to help patients achieve homeostasis in the rest of their lives.” ■ ISSUES NewArchived

Extended access to nicotine leads to a CRF1receptor dependent increase in anxiety-like behavior and hyperalgesia in rats

Tobacco dependence is associated with the emergence of negative emotional states during withdrawal, including anxiety and nociceptive hypersensitivity. However, the current animal models of nicotine dependence have focused on the mechanisms that mediate the acute reinforcing effects of nicotine and failed to link increased anxiety and pain during abstinence with excessive nicotine self-administration. Here, we tested the hypothesis that the activation of corticotropin-releasing factor-1 (CRF1 ) receptors and emergence of the affective and motivational effects of nicotine abstinence only occur in rats with long access (>21 hours/day, LgA) and not short (1 hour/day, ShA) access to nicotine self-administration. ShA and LgA rats were tested for anxiety-like behavior, nociceptive thresholds, somatic signs of withdrawal and nicotine intake after 3 days of abstinence. The role of CRF1 receptors during abstinence was tested using systemic or intracerebral infusion of MPZP (N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo(1,5α)pyrimidin-7-amine), a CRF1 receptor antagonist, in the central nucleus of the amygdala (CeA). LgA but not ShA rats exhibited abstinence-induced increases in anxiety-like behavior and nociceptive hypersensitivity, which both predicted subsequent excessive nicotine intake and were prevented by systemic administration of MPZP. Intra-CeA MPZP infusion prevented abstinence-induced increases in nicotine intake and nociceptive hypersensitivity. These findings demonstrate that the model of short access to nicotine self-administration has limited validity for tobacco dependence, highlight the translational relevance of the model of extended-intermittent access to nicotine self-administration for tobacco dependence and demonstrate that activation of CRF1 receptors is required for the emergence of abstinence-induced anxiety-like behavior, hyperalgesia and excessive nicotine intake.