Kappa-opioid receptor blockade in the inferior colliculus of prey threatened by pit vipers decreases anxiety and panic-like behaviour.

The dorsal midbrain comprises dorsal columns of the periaqueductal grey matter and corpora quadrigemina. These structures are rich in beta-endorphinergic and leu-enkephalinergic neurons and receive GABAergic inputs from substantia nigra pars reticulata. Although the inferior colliculus (IC) is mainly involved in the acoustic pathways, the electrical and chemical stimulation of central and pericentral nuclei of the IC elicits a vigorous defensive behaviour. The defensive immobility and escape elicited by IC activation is commonly related to panic-like emotional states. To investigate the role of κ-opioid receptor of the IC in the antiaversive effects of endogenous opioid receptor blockade in a dangerous situation, male Wistar rats were pretreated in the IC with the κ-opioid receptor-selective antagonist nor-binaltorphimine at different concentrations and submitted to the non-enriched polygonal arena for a snake panic test in the presence of a rattlesnake and, after 24 h, prey were resubmitted to the experimental context. The snakes elicited in prey a set of antipredatory behaviours, such as the anxiety-like responses of defensive attention and risk assessment, and the panic-like reactions of defensive immobility and either escape or active avoidance during the elaboration of unconditioned and conditioned fear-related responses. Pretreatment of the IC with microinjections of nor-binaltorphimine at higher concentrations significantly decreased the frequency and duration of both anxiety- and panic-attack-like behaviours. These findings suggest that κ-opioid receptor blockade in the IC causes anxiolytic- and panicolytic-like responses in threatening conditions, and that kappa-opioid receptor-selective antagonists can be a putative coadjutant treatment for panic syndrome treatment.

Moderators of ayahuasca's biological antidepressant action.

Introduction: The understanding of biological responses to psychedelics with antidepressant potential is imperative. Here we report how a set of acute parameters, namely emotional (depressive symptoms), cognitive (psychedelic experience), and physiological (salivary cortisol), recorded during an ayahuasca dosing session, modulated serum brain-derived neurotrophic factor (BDNF), serum cortisol (SC), serum interleukin 6 (IL-6), plasma C-reactive protein (CRP), and salivary cortisol awakening response (CAR). Methods: Results were analyzed 2 days after the psychedelic intervention (ayahuasca) versus placebo in both patients with treatment-resistant depression and healthy volunteers. These measures were assessed as part of a randomized double-blinded, placebo-controlled trial (n = 72). Results: Results revealed that larger reductions of depressive symptoms during the dosing session significantly moderated higher levels of SC in patients. Whereas lesser changes in salivary cortisol levels during the ayahuasca intervention were related to higher BDNF levels in patients with a larger clinical response in the reduction in depressive symptoms. No moderator was found for patient's CAR, IL-6, and CRP responses to ayahuasca and for all biomarker responses to ayahuasca in healthy controls and in the placebo group. Discussion: In summary, some specific emotional and physiological parameters during experimental ayahuasca session were revealed as critical moderators of the improvement of major depression biomarkers, mainly BDNF and SC two days after ayahuasca intake. These findings contribute to paving the way for future studies investigating the biological antidepressant response to psychedelic therapy.

Prophylactic action of ayahuasca in a non-human primate model of depressive-like behavior.

Observational studies of long-term users of ayahuasca, an Amazonian psychedelic brew, suggest an increase in resilience via improvements in emotion and cognition. Ayahuasca has also demonstrated clinical antidepressant effects in human and animal studies; however, its potential prophylactic action in depression has not been previously studied. Therefore, this experimental study sought to evaluate the potential prophylactic effects of repeated and long-term ayahuasca use, via the modulation of resilience, in a non-human primate animal model, Callithrix jacchus, subjected to a protocol for induction of depressive-like behavior. For the formation of the study groups, some juvenile marmosets were kept in their family groups (GF = 7), while for the two experimental groups, the animals were removed from the family and kept socially isolated. Then, part of the isolated animals made up the group in which ayahuasca was administered (AG, n = 6), while for others, no intervention was made (IG, n = 5). AG animals took ayahuasca (1.67 mL/300g body weight) at weeks 4 (before isolation), 8, and 12 (during isolation) of the study. More adaptive stress response was observed for the AG when compared to the IG. The AG showed higher cortisol reactivity and fecal cortisol levels than IG, while both measures were similar to FG. Moreover, AG animals showed no signs of anhedonia and no increase in chronic stress-related behaviors, which were expressed by the IG. Thus, ayahuasca seems to promote the expression of resilient responses, indicating a prophylactic action, buffering the emergence of depressive-like behaviors and cortisol alterations associated with major depression. These results are encouraging for further research on the prophylactic use of psychedelics to prevent psychopathologies associated with chronic stress.

Decreased hippocampal serotonin 5HT1A expression in mesial temporal lobe of epilepsy patients.

INTRODUCTION: Mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) is a surgically remediable epilepsy with a relatively high prevalence and psychiatric comorbidities. Depressive disorders may occur in up to 25% of MTLE-HS patients suggesting a common molecular mechanism underlying both conditions. OBJECTIVE: To compare the gene expression comprising serotonin 5HT1A and 5HT2A, noradrenaline (NA) ADRA1A, and ADRA2A receptors in the hippocampus of MTLE-HS patients with and without major depression. METHODS: A cross-sectional study allocated 31 patients in three groups: MTLE-HS without psychiatric diagnosis (MTLE-HS group), MTLE-HS with major depression (MTLE-HS-D group) and a control group consisting of healthy volunteers without any neurological or psychiatric disorders. Demographic and clinical characteristics were compared among groups. Gene expression of receptors were analyzed using general linear mixed models (GLMM), with an unstructured matrix, normal link. RESULTS: The three groups showed a similar distribution regarding age, gender (p > 0.16), history of initial precipitating injury, family history of epilepsy, monthly frequency of seizures, side of hippocampal sclerosis, interictal spike distribution and anti-seizure medications did not differ between MTLE-HS and MTLE-HS-D groups (p > 0.05). We observed a greater expression of the 5HT1A receptor in the control group when compared to the MTLE-HS (P = .004) and MTLE-HS-D (P = .007). Nevertheless, we did not observe any difference when MTLE-HS and MTLE-HS-D groups were compared to the controls for the ADRA1A (P = .931; P = .931), ADRA2A (P = .120; P = .121) and 5HT2A (P = .638; P = .318, respectively) gene expression. CONCLUSION: Mesial temporal lobe epilepsy related to hippocampal sclerosis and MTLE-HS-D patients showed a lowered expression of the 5HT1A receptors when compared with the controls adjusted for age and schooling. Data suggest that temporal lobe epilepsy plasticity may affect serotonin receptors, which may lead to more frequent cases of major depression in this population. More studies comprising wider samples are necessary to confirm these results; they also should investigate serotonin reuptake drugs as an adjuvant therapeutic option for MTLE-HS disorder.

Welfare Improvement by Enrichment Programs in Common Marmoset Females Under Social Isolation.

Animal welfare is critical to buffer stress in captive animals and to ensure the reliability of data from studies. The most usual environmental enrichment technique (EE) for social non-human primates is the social enrichment. However, some experimental protocols require keeping individuals isolated, thus demanding other types of EE. We tested in six adult Callithrix jacchus females, single housed for experimental purpose, the stress buffering efficacy of a structural enrichment protocol (SEP) and SEP in combination with a foraging enrichment (FSEP) using  fecal cortisol and behaviors to infer stress levels. Both types of EE improved welfare in different ways, while cortisol levels decreased with both EE as compared to the baseline, autogrooming, and piloerection increased after FSEP probably due to the new foods. Therefore, these findings support alternative practices of EE when social animals are living in isolation and reinforce the positive role of structural and food enrichment for decreasing stress markers. It also encourages studies on welfare with females, since its use as an animal model has increased.

Theta and gamma oscillations in the rat hippocampus support the discrimination of object displacement in a recognition memory task.

Episodic memory depends on the recollection of spatial and temporal aspects of past experiences in which the hippocampus plays a critical role. Studies on hippocampal lesions in rodents have shown that dentate gyrus (DG) and CA3 are necessary to detect object displacement in memory tasks. However, the understanding of real-time oscillatory activity underlying memory discrimination of subtle and pronounced displacements remains elusive. Here, we chronically implanted microelectrode arrays in adult male Wistar rats to record network oscillations from DG, CA3, and CA1 of the dorsal hippocampus while animals executed an object recognition task of high and low spatial displacement tests (HD: 108 cm, and LD: 54 cm, respectively). Behavioral analysis showed that the animals discriminate between stationary and displaced objects in the HD but not LD conditions. To investigate the hypothesis that theta and gamma oscillations in different areas of the hippocampus support discrimination processes in a recognition memory task, we compared epochs of object exploration between HD and LD conditions as well as displaced and stationary objects. We observed that object exploration epochs were accompanied by strong rhythmic activity in the theta frequency (6-12 Hz) band in the three hippocampal areas. Comparison between test conditions revealed higher theta band power and higher theta-gamma phase-amplitude coupling in the DG during HD than LD conditions. Similarly, direct comparison between displaced and stationary objects within the HD test showed higher theta band power in CA3 during exploration of displaced objects. Moreover, the discrimination index between displaced and stationary objects directly correlated with CA1 gamma band power in epochs of object exploration. We thus conclude that theta and gamma oscillations in the dorsal hippocampus support the successful discrimination of object displacement in a recognition memory task.

Potential biomarkers of major depression diagnosis and chronicity.

BACKGROUND: Molecular biomarkers are promising tools to be routinely used in clinical psychiatry. Among psychiatric diseases, major depression disorder (MDD) has gotten attention due to its growing prevalence and morbidity. METHODS: We tested some peripheral molecular parameters such as serum mature Brain-Derived Neurotrophic Factor (mBDNF), plasma C-Reactive Protein (CRP), serum cortisol (SC), and the salivary Cortisol Awakening Response (CAR), as well as the Pittsburgh sleep quality inventory (PSQI), as part of a multibiomarker panel for potential use in MDD diagnosis and evaluation of disease's chronicity using regression models, and ROC curve. RESULTS: For diagnosis model, two groups were analyzed: patients in the first episode of major depression (MD: n = 30) and a healthy control (CG: n = 32). None of those diagnosis models tested had greater power than Hamilton Depression Rating Scale-6. For MDD chronicity, a group of patients with treatment-resistant major depression (TRD: n = 28) was tested across the MD group. The best chronicity model (p < 0.05) that discriminated between MD and TRD included four parameters, namely PSQI, CAR, SC, and mBDNF (AUC ROC = 0.99), with 96% of sensitivity and 93% of specificity. CONCLUSION: These results indicate that changes in specific biomarkers (CAR, SC, mBDNF and PSQI) have potential on the evaluation of MDD chronicity, but not for its diagnosis. Therefore, these findings can contribute for further studies aiming the development of a stronger model to be commercially available and used in psychiatry clinical practice.

Pathophysiology of Major Depression by Clinical Stages.

The comprehension of the pathophysiology of the major depressive disorder (MDD) is essential to the strengthening of precision psychiatry. In order to determine the relationship between the pathophysiology of the MDD and its clinical progression, analyzed by severity of the depressive symptoms and sleep quality, we conducted a study assessing different peripheral molecular biomarkers, including the levels of plasma C-reactive protein (CRP), serum mature brain-derived neurotrophic factor (mBDNF), serum cortisol (SC), and salivary cortisol awakening response (CAR), of patients with MDD (n = 58) and a control group of healthy volunteers (n = 62). Patients with the first episode of MDD (n = 30) had significantly higher levels of CAR and SC than controls (n = 32) and similar levels of mBDNF of controls. Patients with treatment-resistant depression (TRD, n = 28) presented significantly lower levels of SC and CAR, and higher levels of mBDNF and CRP than controls (n = 30). An increased severity of depressive symptoms and worse sleep quality were correlated with levels low of SC and CAR, and with high levels of mBDNF. These results point out a strong relationship between the stages clinical of MDD and changes in a range of relevant biological markers. This can assist in the development of precision psychiatry and future research on the biological tests for depression.

Pranayamas and Their Neurophysiological Effects.

INTRODUCTION: The millenarian breathing exercises from Yoga, commonly called Pranayamas, are known to induce meditative states, reduce stress, and increase lung capacity. However, the physiological mechanisms by which these practices modulate the human nervous system still need to be unveiled. OBJECTIVES: The aim of this work was to review studies describing the influence of breathing exercises on the brain/mind of humans. METHODOLOGY: We reviewed articles written in English and published between 2008 and 2018. Inclusion and exclusion criteria were based on the PRISMA recommendations to filter articles from Science Direct, PubMed, and Virtual Health Library databases. Patient/Population, Intervention, Comparison, and Outcome technique and Prospective Register of Systematic Reviews registration were also considered. RESULTS: From a total of 1588 articles, 14 attended the criteria. They were critically compared to each other and presented in a table divided into study; country; sample size; gender; age; objective; technique; outcome. DISCUSSION: In general, the 14 papers highlight the impact of yogic breathing techniques on emotional and cognitive performance. CONCLUSION: In-depth studies focusing on specific aspects of the practices such as retentions, prolonged expiration, attention on fluid respiration, and abdominal/thoracic respiration should better elucidate the effects of Yogic Breathing Techniques (YBT).

The Dream of God: How Do Religion and Science See Lucid Dreaming and Other Conscious States During Sleep?

Lucid dreaming (LD) began to be scientifically studied in the last century, but various religions have highlighted the importance of LD in their doctrines for a much longer period. Hindus' manuscripts dating back over 2,000 years ago, for example, divide consciousness in waking, dreaming (including LD), and deep sleep. In the Buddhist tradition, Tibetan monks have been practicing the "Dream Yoga," a meditation technique that instructs dreamers to recognize the dream, overcome all fears when lucid, and control the oneiric content. In the Islamic sacred scriptures, LD is regarded as a mental state of great value, and a special way for the initiated to reach mystical experiences. The Christian theologian Augustine of Hippo (354-430 AD) mentions LD as a kind of preview of the afterlife, when the soul separates from the body. In the nineteenth century, some branches of the Spiritism religion argue that LD precedes out-of-body experiences during sleep. Here we reviewed how these religions interpret dreams, LD and other conscious states during sleep. We observed that while Abrahamic monotheisms (Judaism, Christianity, and Islam) recognize dreams as a way to communicate with God to understand the present and predict the future, the traditional Indian religions (Buddhism and Hinduism) are more engaged in cultivating self-awareness, thus developed specific techniques to induce LD and witnessing sleep. Teachings from religious traditions around the world offer important insights for scientific researchers today who want to understand the full range of LD phenomenology as it has emerged through history.

Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca.

BACKGROUND: Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients (n = 28) and healthy controls (n = 45). AIMS: We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Åsberg Depression Rating Scale. RESULTS: At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed (rho = -0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Åsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation (rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Åsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed. CONCLUSIONS: These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression.

Specific Increase of Hippocampal Delta Oscillations Across Consecutive Treadmill Runs.

Running speed affects theta (6-10 Hz) oscillations, the most prominent rhythm in the rat hippocampus. Many reports have found a strong positive correlation between locomotion speed and the amplitude and frequency of theta oscillations. However, less is known about how other rhythms such as delta (0.5-4 Hz) and gamma (25-100 Hz) are affected, and how consecutive runs impact oscillatory activity in hippocampal networks. Here, we investigated whether the successive execution of short-term runs modulates local field potentials (LFPs) in the rat hippocampus. To do this, we trained Long-Evans rats to perform voluntary 15-s runs at 30 cm/s on a treadmill placed on the central stem of an eight-shape maze, in which they subsequently performed a spatial alternation task. We bilaterally recorded CA1 LFPs while rats executed at least 35 runs on the treadmill-maze apparatus. Within running periods, we observed progressive increases in delta band power along with decreases in the power of the theta and gamma bands across runs. Concurrently, the inter-hemispheric phase coherence in the delta band significantly increased, while in the theta and gamma bands exhibited no changes. Delta power and inter-hemispheric coherence correlated better with the trial number than with the actual running speed. We observed no significant differences in running speed, head direction, nor in spatial occupancy across runs. Our results thus show that consecutive treadmill runs at the same speed positively modulates the power and coherence of delta oscillations in the rat hippocampus.

Effects of Yoga Respiratory Practice (Bhastrika pranayama) on Anxiety, Affect, and Brain Functional Connectivity and Activity: A Randomized Controlled Trial.

Pranayama refers to a set of yoga breathing exercises. Recent evidence suggests that the practice of pranayama has positive effects on measures of clinical stress and anxiety. This study explored the impact of a Bhastrika pranayama training program on emotion processing, anxiety, and affect. We used a randomized controlled trial design with thirty healthy young adults assessed at baseline and after 4 weeks of pranayama practices. Two functional magnetic resonance imaging (MRI) protocols were used both at baseline and post-intervention: an emotion task as well as a resting-state acquisition. Our results suggest that pranayama significantly decreased states of anxiety and negative affect. The practice of pranayama also modulated the activity of brain regions involved in emotional processing, particularly the amygdala, anterior cingulate, anterior insula, and prefrontal cortex. Resting-state functional MRI (fMRI) showed significantly reduced functional connectivity involving the anterior insula and lateral portions of the prefrontal cortex. Correlation analysis revealed that changes in connectivity between the ventrolateral prefrontal cortex and the right anterior insula were associated with changes in anxiety. Although it should be noted that these analyses were preliminary and exploratory, it provides the first evidence that 4 weeks of B. pranayama significantly reduce the levels of anxiety and negative affect, and that these changes are associated with the modulation of activity and connectivity in brain areas involved in emotion processing, attention, and awareness. The study was registered at https://www.ensaiosclinicos.gov.br/rg/RBR-2gv5c2/(RBR-2gv5c2).

Changes in Cortisol but Not in Brain-Derived Neurotrophic Factor Modulate the Association Between Sleep Disturbances and Major Depression.

Sleep disturbance is a symptom consistently found in major depression and is associated with a longer course of illness, reduced response to treatment, increased risk of relapse and recurrence. Chronic insomnia has been associated with changes in cortisol and serum brain-derived neurotrophic factor (BDNF) levels, which in turn are also changed in major depression. Here, we evaluated the relationship between sleep quality, salivary cortisol awakening response (CAR), and serum BDNF levels in patients with sleep disturbance and treatment-resistant major depression (n = 18), and in a control group of healthy subjects with good (n = 21) and poor (n = 18) sleep quality. We observed that the patients had the lowest CAR and sleep duration of all three groups and a higher latency to sleep than the healthy volunteers with a good sleep profile. Besides, low CAR was correlated with more severe depressive symptoms and worse sleep quality. There was no difference in serum BDNF levels between groups with distinct sleep quality. Taken together, our results showed a relationship between changes in CAR and in sleep quality in patients with treatment-resistant depression, which were correlated with the severity of disease, suggesting that cortisol could be a physiological link between sleep disturbance and major depression.

Prenatal restraint stress impairs recognition memory in adult male and female offspring.

OBJECTIVE: Accumulating evidence from preclinical and clinical studies indicates that prenatal exposure to stress impairs the development of the offspring brain and facilitates the emergence of mental illness. This study aims to describe the impact of prenatal restraint stress on cognition and exploration to an unfamiliar environment at adulthood in an outbred strain of mice. METHODS: Late pregnant mice were exposed to restraint stress and adult offspring (60 days of age) behaviours were assessed in the object recognition task and open field test. FINDINGS: Prenatal stress (PNS) impaired new object recognition in male and female mice. Importantly, the learning deficits in female PNS mice were linked to their estrous cycle. Actually, PNS females in metestrus/diestrus but not in proestrus/estrus phases displayed recognition deficits compared to controls. Concerning locomotion in an unfamiliar environment, male but not female PNS mice displayed significant increase, but showed no differences in the distance travelled within the centre zone of the arena. CONCLUSION: Present findings support the view that maternal restraint-stress during late pregnancy impairs recognition memory in both male and female offspring, and in females, this cognitive deficit is dependent on the estrous cycle phase. Ultimately, these data reinforce that PNS is an aetiological component of psychiatric disorders associated with memory deficits.

Acute effects of ayahuasca in a juvenile non-human primate model of depression

Objective: The incidence rate of major depression in adolescents reaches approximately 14%. This disorder is usually recurrent, without remission of symptoms even after pharmacological treatment, and persists throughout adult life. Since the effects of antidepressants take approximately 2 weeks to begin, new pharmacological therapies are under continuous exploration. Recent evidence suggests that psychedelics could produce rapid antidepressant effects. In this study, we evaluated the potential antidepressant effects of ayahuasca in a juvenile non-human primate model of depression. Methods: While living with their families, juvenile marmosets (8 males; 7 females) were observed on alternate days for four weeks during a baseline phase. This was followed by 8 weeks of an induced depressive state protocol, the social isolated context (IC), in which the animals were monitored in the first and last weeks. Subsequently, five males and four females were randomly selected for treatment, first with a single administration of saline vehicle (1.67 mL/300 g of body weight, via gavage), followed by a single dose of ayahuasca (1.67 mL/300 g of body weight, via gavage). Both phases lasted 1 week and the animals were monitored daily. A third week of sampling was called the tardive-pharmacological effects phase. In all phases the marmosets were assessed for behavior, fecal cortisol levels, and body weight. Results: After IC, the animals presented typical hypocortisolemia, but cortisol recovered to baseline levels 24 h after an acute dose of ayahuasca; this recovery was not observed in vehicle-treated animals. Additionally, in males, ayahuasca, but not the vehicle, reduced scratching, a stereotypic behavior, and increased feeding. Ayahuasca treatment also improved body weight to baseline levels in both sexes. The ayahuasca-induced behavioral response had long-term effects (14 days). Thus, in this translational juvenile animal model of depression, ayahuasca presented beneficial effects. Conclusions: These results can contribute to the validation of ayahuasca as an antidepressant drug and encourage new studies on psychedelic drugs as a tool for treating mood disorders, including for adolescents with early-onset depression.

Dopamine D1 and D2 receptors mediate neuropeptide S-induced antinociception in the mouse formalin test.

Neuropeptide S (NPS) is the endogenous ligand of a G-protein coupled receptor named NPS receptor. The NPS system controls several biological functions, including anxiety, wakefulness, locomotor activity, food intake, and pain transmission. A growing body of evidence supports facilitatory effects for NPS over dopaminergic neurotransmission. The present study was aimed to investigate the role of dopamine receptors signaling in the antinociceptive effects of NPS in the mouse formalin test. The following dopamine receptor antagonists were employed: SCH 23390 (selective dopamine D1 antagonist, 0.05 mg/kg, ip), haloperidol (non-selective dopamine D2-like receptor antagonist; 0.03 mg/kg, ip), and sulpiride (selective dopamine D2-like receptor antagonist; 25 mg/kg, ip). Mice were pretreated with dopamine antagonists before the supraspinal administration of NPS (0.1 nmol, icv). Morphine (5 mg/kg, sc) and indomethacin (10 mg/kg, ip) were used as positive controls to set up the experimental conditions. Morphine-induced antinociceptive effects were observed during phases 1 and 2 of the test, while indomethacin was only active at phase 2. Central NPS significantly reduced formalin-induced nociception during both phases. The systemic administration of SCH 23390 slightly blocked the effects of NPS only during phase 2. Haloperidol prevented NPS-induced antinociceptive effects. Similar to haloperidol, sulpiride also counteracted the antinociceptive effects of NPS in both phases of the formalin test. In conclusion, the present findings suggest that the analgesic effects of NPS are linked with dopaminergic neurotransmission mainly through dopamine D2-like receptor signaling.

Modulation of the NOP receptor signaling affects resilience to acute stress.

BACKGROUND: The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are implicated in the modulation of emotional states. Previous human and rodent findings support NOP antagonists as antidepressants. However, the role played by the N/OFQ-NOP receptor system in resilience to stress is unclear. AIMS: The present study investigated the effects of activation or blockade of NOP receptor signaling before exposure to acute stress. METHODS: The behavioral effects of the administration before stress of the NOP agonists Ro 65-6570 (0.01-1 mg/kg) and MCOPPB (0.1-10 mg/kg), and the NOP antagonist SB-612111 (1-10 mg/kg) were assessed in mice exposed to inescapable electric footshock and forced swim as stressors. The behavioral phenotype of mice lacking the NOP receptor (NOP(-/-)) exposed to inescapable electric footshock was also investigated. RESULTS: The activation of NOP receptor signaling with the agonists increased the percentage of mice developing helpless behavior and facilitated immobile posture. In contrast, the blockade of NOP receptor reduced the acquisition of depressive-like phenotypes, and similar resistance to develop helpless behaviors was observed in NOP(-/-) mice. Under the same stressful conditions, the antidepressant nortriptyline (20 mg/kg) did not change the acquisition of helpless behavior and immobile posture. CONCLUSIONS: These findings support the view that NOP activation during acute stress facilitates the development of depressive-related behaviors, whereas NOP blockade has a protective outcome. This study showed for first time that NOP antagonists are worthy of investigation as preemptive treatments in patients with severe risk factors for depression.

Modulation of Serum Brain-Derived Neurotrophic Factor by a Single Dose of Ayahuasca: Observation From a Randomized Controlled Trial.

Serotonergic psychedelics are emerging as potential antidepressant therapeutic tools, as suggested in a recent randomized controlled trial with ayahuasca for treatment-resistant depression. Preclinical and clinical studies have suggested that serum brain-derived neurotrophic factor (BDNF) levels increase after treatment with serotoninergic antidepressants, but the exact role of BDNF as a biomarker for diagnostic and treatment of major depression is still poorly understood. Here we investigated serum BDNF levels in healthy controls (N = 45) and patients with treatment-resistant depression (N = 28) before (baseline) and 48 h after (D2) a single dose of ayahuasca or placebo. In our sample, baseline serum BDNF levels did not predict major depression and the clinical characteristics of the patients did not predict their BDNF levels. However, at baseline, serum cortisol was a predictor of serum BDNF levels, where lower levels of serum BDNF were detected in a subgroup of subjects with hypocortisolemia. Moreover, at baseline we found a negative correlation between BDNF and serum cortisol in volunteers with eucortisolemia. After treatment (D2) we observed higher BDNF levels in both patients and controls that ingested ayahuasca (N = 35) when compared to placebo (N = 34). Furthermore, at D2 just patients treated with ayahuasca (N = 14), and not with placebo (N = 14), presented a significant negative correlation between serum BDNF levels and depressive symptoms. This is the first double-blind randomized placebo-controlled clinical trial that explored the modulation of BDNF in response to a psychedelic in patients with depression. The results suggest a potential link between the observed antidepressant effects of ayahuasca and changes in serum BDNF, which contributes to the emerging view of using psychedelics as an antidepressant. This trial is registered at http://clinicaltrials.gov (NCT02914769).

Hippocampal and cortical communication around micro-arousals in slow-wave sleep.

Sleep plays a crucial role in the regulation of body homeostasis and rhythmicity in mammals. Recently, a specific component of the sleep structure has been proposed as part of its homeostatic mechanism, named micro-arousal. Here, we studied the unique progression of the dynamic behavior of cortical and hippocampal local field potentials (LFPs) during slow-wave sleep-related to motor-bursts (micro-arousals) in mice. Our main results comprised: (i) an abrupt drop in hippocampal LFP amplitude preceding micro-arousals which persisted until the end of motor-bursts (we defined as t interval, around 4s) and a similar, but delayed amplitude reduction in cortical (S1/M1) LFP activity occurring at micro-arousal onset; (ii) two abrupt frequency jumps in hippocampal LFP activity: from Theta (6-12 Hz) to Delta (2-4 Hz), also t seconds before the micro-arousal onset, and followed by another frequency jump from Delta to Theta range (5-7 Hz), now occurring at micro-arousal onset; (iii) a pattern of cortico-hippocampal frequency communication precedes micro-arousals: the analysis between hippocampal and cortical LFP fluctuations reveal high coherence during τ interval in a broader frequency band (2-12 Hz), while at a lower frequency band (0.5-2 Hz) the coherence reaches its maximum after the onset of micro-arousals. In conclusion, these novel findings indicate that oscillatory dynamics pattern of cortical and hippocampal LFPs preceding micro-arousals could be part of the regulatory processes in sleep architecture.