It’s Tea Time: Interference of Ayahuasca Brew on Discriminative Learning in Zebrafish

Ayahuasca is a psychoactive brew traditionally used in shamanistic and vegetalistic rituals and has recently received lot of attention due to potential cognitive benefits. Ayahuasca effects are caused by the synergistic interaction of β-carbolines (harmine, harmaline and tetrahydroarmine) contained in Banisteriopsis caapi stalks combined with the N,N-dimethyltryptamine (DMT) from Psychotria viridis leaves, a potent agonist to serotonin (5-HT) receptors. The present study approaches the effects of chronic and acute exposure to two Ayahuasca concentrations (0.1 and 0.5 ml/L) on the cognitive ability to discriminate objects in a one-trial learning task in zebrafish. Based on the combination of concentrations and exposure regimens, we divided adult zebrafish in five treatment groups: acute 0.1 and 0.5 ml/L, chronic 0.1 and 0.5 ml/L, and control 0.0 (n = 20 for each group). Then we tested them in a memory task of object discrimination. Acute Ayahuasca exposed groups performed similarly to the control group, however chronically treated fish (13 days) presented both impaired discriminative performance and locomotor alterations. Overall, these results indicate that Ayahuasca is a potent psychoactive drug that, in chronic exposure, negatively affects mnemonic parameters in zebrafish. In single exposure it does not affects cognitive performance, but the higher concentration (0.5) affected locomotion. Moreover, we reinforce the importance of the zebrafish for behavioral pharmacological studies of drug screening, in special to psychedelic drug research

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)

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

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

Behavioral Changes Over Time Following Ayahuasca Exposure in Zebrafish

The combined infusion of Banisteriopsis caapi stem and Psychotria viridis leaves, known as ayahuasca, has been used for centuries by indigenous tribes. The infusion is rich in N, N-dimethyltryptamine (DMT) and monoamine oxidase inhibitors, with properties similar to those of serotonin. Despite substantial progress in the development of new drugs to treat anxiety and depression, current treatments have several limitations. Alternative drugs, such as ayahuasca, may shed light on these disorders. Here, we present time-course behavioral changes induced by ayahuasca in zebrafish, as first step toward establishing an ideal concentration for pre-clinical evaluations. We exposed adult zebrafish to five concentrations of the ayahuasca infusion: 0 (control), 0.1, 0.5, 1, and 3 ml/L (n = 14 each group), and behavior was recorded for 60 min. We evaluated swimming speed, distance traveled, freezing and bottom dwelling every min for 60 min. Swimming speed and distance traveled decreased with an increase in ayahuasca concentration while freezing increased with 1 and 3 ml/L. Bottom dwelling increased with 1 and 3 ml/L, but declined with 0.1 ml/L. Our data suggest that small amounts of ayahuasca do not affect locomotion and reduce anxiety-like behavior in zebrafish, while increased doses of the drug lead to crescent anxiogenic effects. We conclude that the temporal analysis of zebrafish behavior is a sensitive method for the study of ayahuasca-induced functional changes in the vertebrate brain

Cellular prion protein modulates defensive attention and innate fear-induced behaviour evoked in transgenic mice submitted to an agonistic encounter with the tropical coral snake Oxyrhopus guibei

The cellular prion protein (PrPC) is a neuronal anchored glycoprotein that has been associated with distinct functions in the CNS, such as cellular adhesion and differentiation, synaptic plasticity and cognition. Here we investigated the putative involvement of the PrPC in the innate fear-induced behavioural reactions in wild-type (WT), PrPC knockout (Prnp(0/0)) and the PrPC overexpressing Tg-20 mice evoked in a prey versus predator paradigm. The behavioural performance of these mouse strains in olfactory discrimination tasks was also investigated. When confronted with coral snakes, mice from both Prnp(0/0) and Tg-20 strains presented a significant decrease in frequency and duration of defensive attention and risk assessment, compared to WT mice. Tg-20 mice presented decreased frequency of escape responses, increased exploratory behaviour, and enhancement of interaction with the snake, suggesting a robust fearlessness caused by PrPC overexpression. Interestingly, there was also a discrete decrease in the attentional defensive response (decreased frequency of defensive alertness) in Prnp(0/0) mice in the presence of coral snakes. Moreover, Tg-20 mice presented an increased exploration of novel environment and odors. The present findings indicate that the PrPC overexpression causes hyperactivity, fearlessness, and increased preference for visual, tactile and olfactory stimuli-associated novelty, and that the PrPC deficiency might lead to attention deficits. These results suggest that PrPC exerts an important role in the modulation of innate fear and novelty-induced exploration. (C) 2008 Published by Elsevier B.V.CNPq[470119/2004-7]FAPESP[03/07202-6]FAPESP[03/01768-8]FAPESP[04/09139-2]FAPESP[07/01174-1]FAEPA[68/2001]FAEPA[70/2002]FAEPA[15/2003]FAEPA[6/2004

Predictability of arousal in mouse slow wave sleep by accelerometer data

<div><p>Arousals can be roughly characterized by punctual intrusions of wakefulness into sleep. In a standard perspective, using human electroencephalography (EEG) data, arousals are associated to slow-wave rhythms and K-complex brain activity. The physiological mechanisms that give rise to arousals during sleep are not yet fully understood. Moreover, subtle body movement patterns, which may characterize arousals both in human and in animals, are usually not detectable by eye perception and are not in general present in sleep studies. In this paper, we focus attention on accelerometer records (AR) to characterize and predict arousal during slow wave sleep (SWS) stage of mice. Furthermore, we recorded the local field potentials (LFP) from the CA1 region in the hippocampus and paired with accelerometer data. The hippocampus signal was also used here to identify the SWS stage. We analyzed the AR dynamics of consecutive arousals using recurrence technique and the determinism (DET) quantifier. Recurrence is a fundamental property of dynamical systems, which can be exploited to characterize time series properties. The DET index evaluates how similar are the evolution of close trajectories: in this sense, it computes how accurate are predictions based on past trajectories. For all analyzed mice in this work, we observed, for the first time, the occurrence of a universal dynamic pattern a few seconds that precedes the arousals during SWS sleep stage based only on the AR signal. The predictability success of an arousal using DET from AR is nearly 90%, while similar analysis using LFP of hippocampus brain region reveal 88% of success. Noteworthy, our findings suggest an unique dynamical behavior pattern preceding an arousal of AR data during sleep. Thus, the employment of this technique applied to AR data may provide useful information about the dynamics of neuronal activities that control sleep-waking switch during SWS sleep period. We argue that the predictability of arousals observed through DET(AR) can be functionally explained by a respiratory-driven modification of neural states. Finally, we believe that the method associating AR data with other physiologic events such as neural rhythms can become an accurate, convenient and non-invasive way of studying the physiology and physiopathology of movement and respiratory processes during sleep.</p></div

Temporal dynamics of sleep-wake cycle involving the determinism (DET) of AR—noninvasive method—and the variance (<i>σ</i>) of LFP of CA1 area—invasive method—during SWS stage.

<p>(a) The normalized temporal behavior of the determinism (DET) estimated from the AR. The same panel shows an increase and sharp decrease of DET associated with the sleep-wake cycle dynamics and arousal-burst events (dotted rectangle). The two consecutive dashed vertical lines mark the sharp decrease of DET and the following arousal event (precursor time). (b) The accelerometer record AR, the burst events represent the dynamic of arousals during the SWS sleep stage. (c) The normalized and filtered windowed variance of the amplitude of LFP CA1 activity. The panel shows the Large Variance Amplitude: <i>LσA</i> = <i>σ</i>_<i>max</i> − <i>σ</i>_<i>min</i> (defined as events that crosses the horizontal top and bottom dashed lines). We notice that the precursor time LDA of AR and <i>LσA</i> of CA1 are synchronized. (d) The raw LFP recorded at the hyppocampal CA1 area.</p

Venn Diagram representing events as arousal, LDA and L<i>σ</i>A phenomena.

<p>The figure shows the Venn diagram over all statistics that correlates the three phenomena: (i) large decreasing in determinism of accelerometer (LDA) in red; (ii) large decreasing in the fluctuation amplitude of LFP—CA1 (L<i>σ</i>A) in blue; and (iii) arousal episodes in black. The case where only one of those cited events—L<i>σ</i>A, arousal or LDA—appears is shown respectively in (A), (D) and (G) panels. We emphasize that these occurrences are rare. The most important case is (B) in which all three events take place simultaneously (true positive for both cases LDA and L<i>σ</i>A). The situation with L<i>σ</i>A preceding arousal is shown in panel (E), while LDA preceding arousal is in (G). Finally, the case with both LDA and L<i>σ</i>A without arousal is presented by panel (C) (false positive for both cases LDA and L<i>σ</i>A). The Venn diagram shows all possible events combined.</p