scholarly journals Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

2021 ◽  
Author(s):  
Jonathan W. Kanen ◽  
Annemieke M. Apergis-Schoute ◽  
Robyn Yellowlees ◽  
Fréderique E. Arntz ◽  
Febe E. van der Flier ◽  
...  
Keyword(s):  
Reversal Learning ◽  
Skin Conductance Response ◽  
Tryptophan Depletion ◽  
Trial And Error ◽  
Double Blind ◽  
Autonomic Responses ◽  
Stimulus Response ◽  
Healthy Humans ◽  
Threatening Stimulus ◽  
Reversal Phase

AbstractSerotonin is involved in updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, autonomic responses to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and autonomic inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes, respectively, in two independent experiments (N = 97). Experiment 1 assessed instrumental (stimulus-response-outcome) reversal learning whereby individuals learned through trial and error which action was most optimal for obtaining reward or avoiding punishment initially, and the contingencies subsequently reversed serially. Experiment 2 examined Pavlovian (stimulus-outcome) reversal learning assessed by the skin conductance response: one innately threatening stimulus predicted receipt of an uncomfortable electric shock and another did not; these contingencies swapped in a reversal phase. Upon depleting the serotonin precursor tryptophan—in a double-blind randomised placebo-controlled design—healthy volunteers showed impairments in updating both actions and autonomic responses to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. Initial Pavlovian conditioning, moreover, which involved innately threatening stimuli, was potentiated by depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.

scholarly journals Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

2020 ◽  
Author(s):  
Jonathan W. Kanen ◽  
Annemieke M. Apergis-Schoute ◽  
Robyn Yellowlees ◽  
Frederique E. Arntz ◽  
Febe E. van der Flier ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Psychiatric Disorders ◽  
Reversal Learning ◽  
Emotional Reactions ◽  
Tryptophan Depletion ◽  
Double Blind ◽  
Experimental Animals ◽  
Serotonin Depletion ◽  
Healthy Humans ◽  
Aversive Processing

AbstractSerotonin is implicated in aversive processing and updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, emotional reactions to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and emotional inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes in two independent experiments (N = 97), using instrumental and aversive Pavlovian reversal learning paradigms, respectively. Upon depleting the serotonin precursor tryptophan – in a double-blind randomised placebo-controlled design – healthy volunteers showed impairments in updating both behaviour and emotion to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.

scholarly journals Probabilistic reversal learning under acute tryptophan depletion in healthy humans: a conventional analysis

2020 ◽  
Vol 34 (5) ◽  
pp. 580-583
Author(s):  
Jonathan W Kanen ◽  
Frederique E Arntz ◽  
Robyn Yellowlees ◽  
Rudolf N Cardinal ◽  
Annabel Price ◽  
...  
Keyword(s):  
Reversal Learning ◽  
Negative Feedback ◽  
Acute Tryptophan Depletion ◽  
Tryptophan Depletion ◽  
Serotonin Synthesis ◽  
Male And Female ◽  
Healthy Humans ◽  
Enhanced Sensitivity ◽  
Conventional Analysis ◽  
Probabilistic Reversal Learning

The involvement of serotonin in responses to negative feedback is well established. Acute serotonin reuptake inhibition has enhanced sensitivity to negative feedback (SNF), modelled by behaviour in probabilistic reversal learning (PRL) paradigms. Whilst experiments employing acute tryptophan depletion (ATD) in humans, to reduce serotonin synthesis, have shown no clear effect on SNF, sample sizes have been small. We studied a large sample of healthy volunteers, male and female, and found ATD had no effect on core behavioural measures in PRL. These results indicate that ATD effects can differ from other manipulations of serotonin expected to have a parallel or opposing action.

scholarly journals Influence of intranasal oxytocin on fear consolidation in healthy humans

2019 ◽  
Vol 32 (6) ◽  
pp. e100131 ◽  
Author(s):  
Elizabeth Hoge ◽  
Eric Bui ◽  
Peter Rosencrans ◽  
Scott Orr ◽  
Rachel Ross ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Repeated Measures ◽  
Skin Conductance Response ◽  
De Novo ◽  
Fear Learning ◽  
Drug Trials ◽  
Conditioning Procedure ◽  
Double Blind ◽  
Healthy Humans ◽  
Main Effects

BackgroundAlthough recent data in healthy humans suggestthat treatment with intranasal oxytocin (OT) may facilitate extinction recall,to date, little is known about the effects of OT on memory consolidationprocesses.AimTo examine the effect of intranasal administration of OT compared with placebo on memory consolidation blockade of a de novo fear memory in a classical 2-day fear conditioning procedure.ResultsThere were no significant differences between the OT and the placebo groups on the first two extinction trials (mean (SD)=0.01 (0.39) vs 0.15 (0.31), t=−1.092, p=0.28). Similarly, during early extinction, analysis of variance for repeated measures failed to show significant main effects of extinction trials: trials (F(4, 112)=1.58, p=0.18), drug (F(1, 112)=0.13, p=0.72) or drug × trials interaction (F(4, 112)=0.76, p=0.56).ConclusionOur results suggest that OT administered in a double-blind fashion immediately after fear conditioning does not significantly reduce consolidation of fear learning as measured by a differential skin conductance response tested at the beginning of extinction.

Rapid Tryptophan Depletion Improves Decision-Making Cognition in Healthy Humans without Affecting Reversal Learning or Set Shifting

2005 ◽  
Vol 31 (7) ◽  
pp. 1519-1525 ◽  
Author(s):  
Peter S Talbot ◽  
David R Watson ◽  
Suzanne L Barrett ◽  
Stephen J Cooper
Keyword(s):  
Decision Making ◽  
Reversal Learning ◽  
Tryptophan Depletion ◽  
Set Shifting ◽  
Healthy Humans

scholarly journals Sex-dependent effects of chronic intermittent voluntary alcohol consumption on attentional, not motivational, measures during probabilistic learning and reversal

2020 ◽  
Author(s):  
Claudia G. Aguirre ◽  
Alexandra Stolyarova ◽  
Kanak Das ◽  
Sriya Kolli ◽  
Vincent Marty ◽  
...  
Keyword(s):  
Sex Differences ◽  
Reversal Learning ◽  
Response Times ◽  
Neural Mechanisms ◽  
Group Differences ◽  
Probabilistic Learning ◽  
Final Phase ◽  
Future Studies ◽  
Stimulus Response ◽  
Reversal Phase

AbstractBackgroundForced alcohol (ethanol, EtOH) exposure has been shown to cause significant impairments on reversal learning, a widely-used assay of cognitive flexibility, specifically on fully-predictive, deterministic versions of this task. However, previous studies have not adequately considered voluntary EtOH consumption and sex effects on probabilistic reversal learning. The present study aimed to fill this gap in the literature.MethodsMale and female Long-Evans rats underwent either 10 weeks of voluntary intermittent 20% EtOH access or water only (H2O) access. Rats were then pretrained to initiate trials and learn stimulus-reward associations via touchscreen response, and subsequently required to select between two visual stimuli, rewarded with probability 0.70 or 0.30. In the final phase, reinforcement contingencies were reversed.ResultsWe found significant sex differences on several EtOH-drinking variables, with females reaching a higher maximum EtOH consumption, exhibiting more high-drinking days, and escalating their EtOH at a quicker rate compared to males. During early abstinence, EtOH drinkers made more initiation omissions and were slower to initiate trials than H2O drinking controls, particularly during pretraining. EtOH drinking females were most affected. A similar pattern in trial initiations was also observed in discrimination, but not in reversal learning. EtOH drinking rats were unaffected in their reward collection and stimulus response times, indicating intact motivation and motor responding. Although there were sex differences in discrimination and reversal phases, performance improved over time. We also observed sex-independent drinking group differences in win-stay and lose-shift strategies specific to the reversal phase.ConclusionsFemales exhibit increased vulnerability to EtOH effects in early learning: there were sex-dependent EtOH effects on attentional measures during pretraining and discrimination phases. We also found sexindependent EtOH effects on exploration strategies during reversal. Future studies should aim to uncover the neural mechanisms for changes in attention and exploration in both acute and prolonged EtOH withdrawal.

scholarly journals Relative absorption of silicon from different formulations of dietary supplements: a pilot randomized, double-blind, crossover post-prandial study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
N. Boqué ◽  
R. M. Valls ◽  
A. Pedret ◽  
F. Puiggrós ◽  
L. Arola ◽  
...  
Keyword(s):  
Dietary Supplements ◽  
Inductively Coupled Plasma ◽  
Aloe Vera ◽  
Emission Spectrometry ◽  
Orthosilicic Acid ◽  
Post Dose ◽  
Double Blind ◽  
Gold Standard Method ◽  
Healthy Humans ◽  
Relative Absorption

AbstractThe purpose of the present study was to compare the relative absorption of a new powder presentation of silicon (Si) as orthosilicic acid with maltodextrin (Orgono Powder) compared to usual Si liquid presentations as orthosilicic acid with Equisetum arvense and Rosmarinus officinalis (G5 Siliplant) and orthosilicic acid with aloe vera (G7 Aloe). All dietary supplements were administered at the same Si oral dose (21.6 mg) in a randomized, double-blind, crossover post-prandial study conducted in 5 healthy men. Urine was collected at baseline and over the 6-h post-dose period in 2 separate 3-h collections for the analysis of Si concentration, which was conducted by inductively coupled plasma optical emission spectrometry as the gold standard method. No significant differences in total urinary Si excretion were found after the intake of these 3 dietary supplements; 34.6%, 32.4% and 27.2% of the ingested Si from G7 Aloe, G5 Siliplant and Orgono Powder, respectively, was excreted in urine over the 6-h follow-up period. The 3 different oral Si formulations tested, in powder and liquid presentations, provide highly bioavailable Si and present an equivalent relative absorption in healthy humans.

506 Samelisant: Baseline Characteristics from a Phase 2 Study Evaluating Efficacy and Safety in Patients with Narcolepsy

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A199-A199
Author(s):  
Ramakrishna Nirogi ◽  
Jyothsna Ravula ◽  
Pradeep Jayarajan ◽  
Satish Jetta ◽  
Gopinadh Bhyrapuneni ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Demographic Data ◽  
Fixed Ratio ◽  
Study Drug ◽  
Eligibility Criteria ◽  
Double Blind ◽  
Healthy Humans ◽  
Parallel Group ◽  
Secondary Endpoints ◽  
Baseline Characteristics

Abstract Introduction histamine H3 receptor (H3R) antagonists/ inverse agonists increase histaminergic neurotransmission and offer a therapeutic option for the treatment of narcolepsy. Samelisant (SUVN-G3031) is a potent and selective H3R inverse agonist exhibited selectivity over 70 other targets. Samelisant showed wake-promoting and anticataplectic effects in orexin knockout mice suggesting its potential therapeutic utility in the treatment of EDS and cataplexy associated with narcolepsy. Safety and tolerability studies in animals and healthy humans suggested a favorable risk/benefit profile. Methods The current study is a 2 week treatment, multicenter, double-blind, placebo controlled, parallel-group study in patients with Narcolepsy with or without Cataplexy. Eligibility criteria include age between 18 to 50 years old, an ESS score of ≥ 12; and mean MWT time of < 12 minutes and a confirm diagnosis of narcolepsy as per ICSD-3. Further, the randomization will be stratified according to type of narcolepsy (Type-1 or Type-2). Each subject will receive either placebo or study drug once daily for 2 weeks in a fixed ratio of 1:1:1. The primary efficacy endpoint is change in maintenance of wakefulness test (MWT) score from baseline to week 2. Key secondary endpoints include change from baseline to week 2 in ESS and an improvement in CGI-S scores. Safety will be monitored by medical monitor and by an independent data safety monitoring committee. Baseline clinical and demographic data for the currently enrolled study is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion. Results As of data cutoff date of Dec 20, 2020, a total of 54 subjects were completed in the study. The median age of subjects was 30 years (range: 18 - 50 years) with mean BMI of 28.6 (range: 18.3 - 43.1 kg/m2). Overall, 74% of subjects were female and 83% were Caucasian. Mean (SD) baseline values of MWT and ESS are 5.65 (3.5) and 16.7 (2.5), respectively. Conclusion Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling the subjects with Narcolepsy with or without Cataplexy, and the Data readout is expected in the second half of 2021. Support (if any):

Acupuncture effects on autonomic responses to cold pressor and handgrip exercise in healthy humans

2004 ◽  
Vol 14 (2) ◽  
pp. 113-118 ◽  
Author(s):  
Holly R. Middlekauff ◽  
Janki B. Shah ◽  
Jun Liang Yu ◽  
Kakit Hui
Keyword(s):  
Cold Pressor ◽  
Handgrip Exercise ◽  
Autonomic Responses ◽  
Healthy Humans ◽  
Acupuncture Effects

scholarly journals Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation

2016 ◽  
Vol 48 (5) ◽  
pp. 1340-1350 ◽  
Author(s):  
Luigi Taranto-Montemurro ◽  
Scott A. Sands ◽  
Bradley A. Edwards ◽  
Ali Azarbarzin ◽  
Melania Marques ◽  
...  
Keyword(s):  
Crossover Trial ◽  
Positive Airway Pressure ◽  
Upper Airway ◽  
Sleep Apnoea ◽  
Double Blind ◽  
Healthy Humans ◽  
Dilator Muscle ◽  
Obstructive Sleep ◽  
Airway Collapsibility ◽  
Upper Airway Collapsibility

We recently demonstrated that desipramine reduces the sleep-related loss of upper airway dilator muscle activity and reduces pharyngeal collapsibility in healthy humans without obstructive sleep apnoea (OSA). The aim of the present physiological study was to determine the effects of desipramine on upper airway collapsibility and apnoea–hypopnea index (AHI) in OSA patients.A placebo-controlled, double-blind, randomised crossover trial in 14 OSA patients was performed. Participants received treatment or placebo in randomised order before sleep. Pharyngeal collapsibility (critical collapsing pressure of the upper airway (Pcrit)) and ventilation under both passive (V′0,passive) and active (V′0,active) upper airway muscle conditions were evaluated with continuous positive airway pressure (CPAP) manipulation. AHI was quantified off CPAP.Desipramine reduced activePcrit(median (interquartile range) −5.2 (4.3) cmH2O on desipramineversus−1.9 (2.7) cmH2O on placebo; p=0.049) but not passivePcrit(−2.2 (3.4)versus−0.7 (2.1) cmH2O; p=0.135). A greater reduction in AHI occurred in those with minimal muscle compensation (defined asV′0,active−V′0,passive) on placebo (r=0.71, p=0.009). The reduction in AHI was driven by the improvement in muscle compensation (r=0.72, p=0.009).In OSA patients, noradrenergic stimulation with desipramine improves pharyngeal collapsibility and may be an effective treatment in patients with minimal upper airway muscle compensation.

scholarly journals A Single Administration of AZP-3601, a Novel, Long-Acting PTH Analog, Induces a Significant and Sustained Calcemic Response: Preliminary Data From a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A254-A254
Author(s):  
Soraya Allas ◽  
Michel Ovize ◽  
Michael D Culler ◽  
Clarisse Geraul ◽  
Jeroen van de Wetering ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Clinical Symptoms ◽  
Phase 1 ◽  
High Dose ◽  
Single Administration ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Healthy Humans ◽  
Dose Dependent

Abstract Hypoparathyroidism is a rare disease characterized by a deficiency in parathyroid hormone (PTH) that results in hypocalcemia and hyperphosphatemia. Current treatment approaches, including high dose oral calcium and active vitamin D, as well as recombinant human PTH (1–84), do not provide adequate or consistent control of either serum calcium or clinical symptoms over a full 24-hour period. AZP-3601 is a novel 36 amino-acid PTH analog that has been designed to potently bind to the R0 conformation of the PTH1 receptor, which results in prolonged signaling responses in vitro and prolonged calcemic responses in animals despite having a short circulating half-life. A Phase 1 double-blind, placebo-controlled, single and multiple ascending dose study is being conducted to evaluate the safety, tolerability and pharmacodynamics of AZP-3601 in healthy adults. Here we report data from the first cohorts of the single ascending dose portion of the study. Sequential cohorts of 4 (cohort 1) to 8 (cohort 2 to 4) healthy male subjects aged 18–60 years, with a body mass index of 19–28 kg/m2, were assigned to receive 5, 10, 20 or 40μg of AZP-3601 or placebo at a ratio of 3:1. The study drug was administered in the morning by subcutaneous injection in the abdominal wall and was well tolerated with no remarkable adverse events. As compared with placebo controls, AZP-3601 treatment produced a clear, dose-dependent increase in mean albumin-adjusted serum calcium values from baseline. The normal physiological diurnal variation of albumin-adjusted serum calcium was gradually attenuated with 5 and 10μg AZP-3601, and was completely eliminated with 20μg. With the dose of 40μg AZP-3601, mean albumin-adjusted serum calcium values were significantly increased but stayed within normal laboratory range and remained elevated through at least 24 hours post-administration. We observed a dose-dependent decrease in mean endogenous serum PTH that was significantly correlated with the concomitant increase in mean serum calcium. These data provide initial evidence of the pharmacodynamic effect of AZP-3601 in healthy humans characterized by a sustained calcemic response for at least 24 hours following a single administration.

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