Drugs prescribed for Phelan-McDermid syndrome differentially impact sensory behaviors in shank3 zebrafish models.

Background: Altered sensory processing is a pervasive symptom in individuals with Autism Spectrum Disorders (ASD); people with Phelan McDermid syndrome (PMS), in particular, show reduced responses to sensory stimuli. PMS is caused by deletions of the terminal end of chromosome 22 or point mutations in Shank3. People with PMS can present with an array of symptoms including ASD, epilepsy, gastrointestinal distress, and reduced responses to sensory stimuli. People with PMS are often medicated to manage behaviors like aggression and/or self-harm and/or epilepsy, and it remains unclear how these medications might impact perception/sensory processing. Here we test this using zebrafish mutant shank3ab PMS models that likewise show reduced sensory responses in a visual motor response (VMR) assay, in which increased locomotion is triggered by light to dark transitions. Methods: We screened three medications, risperidone, lithium chloride (LiCl), and carbamazepine (CBZ), prescribed to people with PMS and one drug, 2-methyl-6-(phenylethynyl) pyridine (MPEP) tested in rodent models of PMS, for their effects on a sensory-induced behavior in two zebrafish PMS models with frameshift mutations in either the N- or C- termini. To test how pharmacological treatments affect the VMR, we exposed larvae to selected drugs for 24 hours and then quantified their locomotion during four ten-minute cycles of lights on-to-off stimuli. Results: We found that risperidone normalized the VMR in shank3 models. LiCl and CBZ had no effect on the VMR in any of the three genotypes. MPEP reduced the VMR in wildtype (WT) to levels seen in shank3 models but caused no changes in either shank3 model. Finally, shank3 mutants showed resistance to the seizure-inducing drug pentylenetetrazol (PTZ), at a dosage that results in hyperactive swimming in WT zebrafish. Conclusions: Our work shows that the effects of drugs on sensory processing are varied in ways that can be highly genotype- and drug-dependent.

Evidence of G-Protein-Coupled Receptors (GPCR) in the Parasitic Protozoa Plasmodium falciparum-Sensing the Host Environment and Coupling within Its Molecular Signaling Toolkit.

Throughout evolution, the need for single-celled organisms to associate and form a single cluster of cells has had several evolutionary advantages. In complex, multicellular organisms, each tissue or organ has a specialty and function that make life together possible, and the organism as a whole needs to act in balance and adapt to changes in the environment. Sensory organs are essential for connecting external stimuli into a biological response, through the senses: sight, smell, taste, hearing, and touch. The G-protein-coupled receptors (GPCRs) are responsible for many of these senses and therefore play a key role in the perception of the cells' external environment, enabling interaction and coordinated development between each cell of a multicellular organism. The malaria-causing protozoan parasite, Plasmodium falciparum, has a complex life cycle that is extremely dependent on a finely regulated cellular signaling machinery. In this review, we summarize strong evidence and the main candidates of GPCRs in protozoan parasites. Interestingly, one of these GPCRs is a sensor for K+ shift in Plasmodium falciparum, PfSR25. Studying this family of proteins in P. falciparum could have a significant impact, both on understanding the history of the evolution of GPCRs and on finding new targets for antimalarials.

Sensory Perception of an Oral Rehydration Solution during Exercise in the Heat.

Prolonged exercise in the heat elicits a number of physiological changes as glycogen stores are low and water and electrolytes are lost through sweat. However, it is unclear whether these changes provoke an increase in liking of saltiness and, therefore, palatability of an oral rehydration solution (ORS). Twenty-seven recreationally active participants (n = 13 males; n = 14 females) completed sensory analysis of an ORS, a traditional sports drink (TS), and a flavored water placebo (PL) at rest and during 60 min (3 × 20-min bouts) of cycling exercise at 70% age-predicted maximum heart rate (HRmax) at 35.3 ± 1.4 °C and 41 ± 6% relative humidity. Before and after every 20 min of exercise, drinks were rated (using 20-mL beverage samples) based on liking of sweetness, liking of saltiness, thirst-quenching ability, and overall liking on a nine-point hedonic scale. Hydration status was assessed by changes in semi-nude body mass, saliva osmolality (SOsm), and saliva total protein concentration (SPC). After 60 min of exercise, participants lost 1.36 ± 0.39% (mean ± SD) of body mass and there were increases in SOsm and SPC. At all time points, liking of sweetness, saltiness, thirst-quenching ability, and overall liking was higher for the TS and PL compared to the ORS (p < 0.05). However, the saltiness liking and thirst-quenching ability of the ORS increased after 60 min of exercise compared to before exercise (p < 0.05). There was also a change in predictors of overall liking with pre-exercise ratings mostly determined by liking of sweetness, saltiness, and thirst-quenching ability (p < 0.001), whereas only liking of saltiness predicted overall liking post-exercise (R2 = 0.751; p < 0.001). There appears to be a hedonic shift during exercise in which the perception of saltiness becomes the most important predictor of overall liking. This finding supports the potential use of an ORS as a valuable means of hydration during the latter stages of prolonged and/or intense exercise in the heat.

Intranasal oxytocin enhances the perception of ambiguous averted gaze in women but not in men.

BACKGROUND: Perceiving accurately that others are looking away from us (averted gaze) is as important, for social interactions, as perceiving that others are looking at us (direct gaze). However, previous studies have revealed that when the deflection angle of averted gaze is small, individuals tend to falsely perceive it as direct gaze. Oxytocin (OXT) has been shown to increase orientation to the eye region. Therefore, a critical question is whether and how OXT would facilitate the perception of ambiguous averted gaze. OBJECTIVES: The present study aimed to measure the effects of OXT on the performance of males and females in distinguishing ambiguous averted gaze from direct gaze of different emotional faces. METHODS: In a double-blind placebo-controlled crossover experiment, 48 participants were presented successively two emotional faces with direct gaze (defined as 0, indicating the center of the eye) or averted gaze (defined as ±4, indicating the corner of the eye; +4 means that the iris moves 4 steps to the right; and -4 means that the iris moves 4 steps to the left) following intranasal oxytocin or placebo treatment and asked to make judgments on whether or not the two faces were the same in terms of identity. The interference effect of gaze direction was calculated by subtracting the mean accuracy and reaction time in the congruent gaze condition from those in the incongruent gaze condition. The logic of the measurement was if intranasal OXT would facilitate the detection of ambiguous averted gaze, we would observe a larger interference effect in the gaze incongruent condition compared with the gaze congruent condition, leading to longer RT or/and lower accuracy for identification judgment in the gaze incongruent condition. RESULTS: While there were no OXT effects in accuracy, we found a significant interaction between treatment, sex, and gaze congruency in reaction times. That is, following OXT as compared to placebo, women displayed stronger interference of gaze direction, whereas in men no significant difference was observed. Besides, this interaction did not vary across different emotional expressions. CONCLUSIONS: Our findings provide the first evidence for sex-dependent effects of OXT on the perception of ambiguous averted gaze. Given potential therapeutic applications of OXT to patients with developmental and psychiatric disorders, who are characterized as atypical in encoding gaze features, the findings suggest that rather different treatment outcomes could be anticipated in males and females.

THC and CBD produce divergent effects on perception and panic behaviours via distinct cortical molecular pathways.

Clinical and pre-clinical evidence demonstrates divergent psychotropic effects of THC vs. CBD. While THC can induce perceptual distortions and anxiogenic effects, CBD displays antipsychotic and anxiolytic properties. A key brain region responsible for regulation of cognition and affect, the medial prefrontal cortex (PFC), is strongly modulated by cannabinoids, suggesting that these dissociable THC/CBD-dependent effects may involve functional and molecular interplay within the PFC. The primary aim of this study was to investigate potential interactions and molecular substrates involved in PFC-mediated effects of THC and CBD on differential cognitive and affective behavioural processing. Male Sprague Dawley rats received intra-PFC microinfusions of THC, CBD or their combination, and tested in the latent inhibition paradigm, spontaneous oddity discrimination test, elevated T-maze and open field. To identify local, drug-induced molecular modulation in the PFC, PFC samples were collected and processed with Western Blotting. Intra-PFC THC induced strong panic-like responses that were counteracted with CBD. In contrast, CBD did not affect panic-like behaviours but blocked formation of associative fear memories and impaired latent inhibition and oddity discrimination performance. Interestingly, these CBD effects were dependent upon 5-HT1A receptor transmission but not influenced by THC co-administration. Moreover, THC induced robust phosphorylation of ERK1/2 that was prevented by CBD, while CBD decreased phosphorylation of p70S6K, independently of THC. These results suggest that intra-PFC infusion of THC promotes panic-like behaviour associated with increased ERK1/2 phosphorylation. In contrast, CBD impairs perceptive functions and latent inhibition via activation of 5-HT1A receptors and reduced phosphorylation of p70S6K.

Cholinergic modulation of hippocampally mediated attention and perception.

Attention to the relations between visual features modulates hippocampal representations. Moreover, hippocampal damage impairs discrimination of spatial relations. We explore a mechanism by which this might occur: modulation by the acetylcholine system. Acetylcholine enhances afferent input to the hippocampus and suppresses recurrent connections within it. This biases hippocampal processing toward environmental input, and should improve externally oriented, hippocampally mediated attention and perception. We examined cholinergic modulation on an attention task that recruits the hippocampus. On each trial, participants viewed two images (rooms with paintings). On "similar room" trials, they judged whether the rooms had the same spatial layout from a different perspective. On "similar art" trials, they judged whether the paintings could have been painted by the same artist. On "identical" trials, participants simply had to detect identical paintings or rooms. We hypothesized that cholinergic modulation would improve performance on the similar room task, given past findings that hippocampal representations predicted, and hippocampal damage impaired, behavior on this task. To test this, nicotine cigarette smokers took part in two sessions: one before which they abstained from nicotine for 12 hours, and one before which they ingested nicotine in the past hour. Individual differences in expired breath carbon monoxide levels-a measure of how recently or how much someone smoked-predicted performance improvements on the similar room task. This finding provides novel support for computational models that propose that acetylcholine enhances externally oriented attentional states in the hippocampus. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Carbohydrate and Glutamine Supplementation Attenuates the Increase in Rating of Perceived Exertion during Intense Exercise in Hypoxia Similar to 4200 m.

The rating of perceived exertion (RPE) indicates the feeling of fatigue. However, hypoxia worsens the condition and can worsen RPE. We evaluated whether carbohydrate and glutamine supplementation alters RPE and physiological markers in running at 70% peak oxygen uptake until exhaustion in a simulated altitude of 4500 m. Nine volunteers underwent three running tests at 70% peak oxygen uptake until exhaustion: (1) hypoxia and placebo, (2) hypoxia and 8% maltodextrin, and (3) hypoxia after six days of glutamine supplementation (20 g/day) and 8% maltodextrin. The exercise and supplementation were randomized and double-blinded. Lactate, heart rate, haemoglobin O2 saturation (SpO2%), and RPE (6-20 scale) were analyzed at the 15th and 30th min. The level of significance was set at p ≤ 0.05. SpO2% decreased at the 15th and 30th minutes compared to resting in placebo, carbohydrate, and glutamine supplementation. RPE increased at the 30th minute compared to the 15th minute in placebo and carbohydrate supplementation; however, there was no difference in the glutamine supplementation condition. Heart rate and lactate increased after the 15th and 30th minutes compared to resting, similar to the three conditions studied. We conclude that previous supplementation with glutamine and carbohydrate during intense exercise in hypoxia similar to 4500 m can attenuate the increase in RPE by the increase in glycemia and can be a useful strategy for people who exercise in these conditions.

The influence of menthol dose on human temperature regulation and perception.

INTRODUCTION: This study assessed the influence of High (H, 4.13%), Medium (M, 2.0%) and Low (L, 0.1%) doses of menthol on temperature perception and regulation, compared to a Placebo Condition (P). METHOD: Sixteen participants underwent the aforementioned conditions on four separate days. During each test participants rested supine (Environmental conditions: 30 °C, 50% rh) for 30-min before 40 mL of L, M, H or P gel was applied to the anterior upper body, then rested 30-min thereafter. Primary measures included thermal sensation (TS), thermal comfort (TC), irritation (IRR), rectal temperature (Tre), and skin temperature (chest, forearm, thigh, calf), and EMG (trapezius, pectoralis major, sternocleidomastoid). The area under the curve (AUC) from minute 30 to 60 was compared between conditions using relevant non/parametric tests (alpha level = 0.05). RESULTS: A cooling trend in Tre was observed following Placebo gel application, but this significantly (p < 0.05) reversed into a heat storage response in M and H. Both TS and TC significantly differed by condition (p < 0.001) in a dose-dependent manner, with L, M, and H doses eliciting significantly cooler sensations and more discomfort than P (p < 0.05). Irritation significantly differed by condition (p < 0.01) in a dose-dependent manner, with L and M eliciting significantly greater irritation than P (p < 0.01). No other differences were observed. CONCLUSIONS: Menthol exerts perceptual and thermoregulatory effects independent of skin temperature. A menthol dose-dependent perceptual cooling effect was evident with possible saturation at the moderate dose. A dose-dependent alteration in deep body temperature was also evident.

Hydrocortisone decreases metacognitive efficiency independent of perceived stress.

It is well established that acute stress produces negative effects on high level cognitive functions. However, these effects could be due to the physiological components of the stress response (among which cortisol secretion is prominent), to its psychological concomitants (the thoughts generated by the stressor) or to any combination of those. Our study shows for the first time that the typical cortisol response to stress is sufficient to impair metacognition, that is the ability to monitor one's own performance in a task. In a pharmacological protocol, we administered either 20 mg hydrocortisone or placebo to 46 male participants, and measured their subjective perception of stress, their performance in a perceptual task, and their metacognitive ability. We found that hydrocortisone selectively impaired metacognitive ability, without affecting task performance or creating a subjective state of stress. In other words, the single physiological response of stress produces a net effect on metacognition. These results inform our basic understanding of the physiological bases of metacognition. They are also relevant for applied or clinical research about situations involving stress, anxiety, depression, or simply cortisol use.

Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention.

Psychedelic drugs, including the serotonin 2a (5-HT2A) receptor partial agonist psilocybin, are receiving renewed attention for their possible efficacy in treating a variety of neuropsychiatric disorders. Psilocybin induces widespread dysregulation of cortical activity, but circuit-level mechanisms underlying this effect are unclear. The claustrum is a subcortical nucleus that highly expresses 5-HT2A receptors and provides glutamatergic inputs to arguably all areas of the cerebral cortex. We therefore tested the hypothesis that psilocybin modulates claustrum function in humans. Fifteen healthy participants (10M, 5F) completed this within-subjects study in which whole-brain resting-state blood-oxygenation level-dependent (BOLD) signal was measured 100 â€‹min after blinded oral administration of placebo and 10 mg/70 â€‹kg psilocybin. Left and right claustrum signal was isolated using small region confound correction. Psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. Subjective effects of psilocybin predicted changes in the amplitude of low frequency fluctuations and the variance of BOLD signal in the left and right claustrum. Observed effects were specific to claustrum, compared to flanking regions of interest (the left and right insula and putamen). This study used a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT2A receptor signaling in claustrum functioning, and supports a possible role of the claustrum in the subjective and therapeutic effects of psilocybin.

Combining sensory and texturometer parameters to characterize different type of cosmetic ingredients.

INTRODUCTION: Sensory properties have a great importance for cosmetics and personal care products. If literature permits to consult articles comparing different formulations on their sensory attributes, there are only a few articles concerning ingredients. OBJECTIVE: The overall objective of this study was to carry out an original study combining the sensory evaluation of different natures of ingredients, in order to initiate a sensory data set that could help researchers to identify differentiating sensory characteristics, as well as initiating a comparison between sensory data and texturometer instrumental measurements. METHODS: Oils, glycolic extracts, butter and starch were evaluated according to descriptive sensory analysis methodology with the help of panel of 25 experts. In order to compare responses obtained from the panel to instrumental measurements, texture analyzes were performed in compression traction model. RESULTS: Significant differences were detected in ten of the eleven evaluated sensory attributes, indicating that ingredients have distinct sensory profiles. The mainly discriminative attributes for the analyzed ingredients were: gloss, opacity, fluidity, freshness, whitening and oily residue. The oils are mostly related to oily residue and slipperiness while extracts are mostly related to gloss, fluidity and freshness attributes. Both Tapioca Starch and Shea Butter were related to non-fluidity, opacity, and Tapioca Starch was related to freshness too. This study was completed by a texturometer analysis which lead to show the opposite correlation between the sensory attribute fluidity and the consistent index.

INTRODUCTION: Les propriétés sensorielles ont une grande importance pour les cosmétiques et les produits de soins. Si la littérature permet de consulter des articles comparant différentes formulations sur leurs attributs sensoriels, il n'y a que quelques articles concernant les ingrédients. OBJECTIF: L'objectif global de cette étude était de réaliser une étude originale combinant l'évaluation sensorielle de différentes natures d'ingrédients, afin d'initier un ensemble de données sensorielles qui pourrait aider les chercheurs à identifier les caractéristiques sensorielles discriminantes, ainsi qu'à initier une comparaison entre données sensorielles et mesures instrumentales du texturomètre. MÉTHODES: Les huiles, les extraits glycoliques, le beurre et l'amidon ont été évalués selon la méthodologie d'analyse sensorielle descriptive avec l'aide d'un panel de 25 experts. Afin de comparer les réponses obtenues à partir du panel aux mesures instrumentales, des analyses de texture ont été effectuées avec un texturométre selon la méthode traction-compression. RÉSULTATS: Des différences significatives ont été détectées sur dix des onze attributs sensoriels évalués, indiquant que les ingrédients ont des profils sensoriels distincts. Les attributs principalement discriminants pour les ingrédients analysés étaient : la brillance, l'opacité, la fluidité, la fraîcheur, le blanchiment et les résidus huileux. Les huiles sont principalement liées aux descripteurs résidus huileux et glissant tandis que les extraits sont principalement liés aux attributs de brillance, de fluidité et de fraîcheur. L'amidon de tapioca et le beurre de karité étaient tous deux liés à la non-fluidité, l'opacité et l'amidon de tapioca était également lié à la fraîcheur. Cette étude a été complétée par une analyse texturométrique qui a montré la corrélation opposée entre le descripteur sensoriel fluide et l'indice de consistance.

Perceived outcomes of psychedelic microdosing as self-managed therapies for mental and substance use disorders.

RATIONALE: The regular consumption of very small doses of psychedelic drugs (known as microdosing) has been a source of growing media and community attention in recent years. However, there is currently limited clinical and social research evidence on the potential role of microdosing as therapies for mental and substance use disorders. OBJECTIVES: This paper examined subjective experiences of microdosing psychedelics to improve mental health or to cease or reduce substance use, and examined sociodemographic and other covariates of perceived improvements in mental health that individuals attributed to microdosing. METHODS: An international online survey was conducted in 2018 and examined people's experiences of using psychedelics for self-reported therapeutic or enhancement purposes. This paper focuses on 1102 respondents who reported current or past experience of psychedelic microdosing. RESULTS: Twenty-one percent of respondents reported primarily microdosing as a therapy for depression, 7% for anxiety, 9% for other mental disorders and 2% for substance use cessation or reduction. Forty-four percent of respondents perceived that their mental health was "much better" as a consequence of microdosing. In a multivariate analysis, perceived improvements in mental health from microdosing were associated with a range of variables including gender, education, microdosing duration and motivations, and recent use of larger psychedelic doses. CONCLUSIONS: Given the promising findings of clinical trials of standard psychedelic doses as mental health therapies, clinical microdosing research is needed to determine its potential role in psychiatric treatment, and ongoing social research to better understand the use of microdosing as self-managed mental health and substance use therapies.

Psychological distress symptoms and illness perception in patients with epilepsy in Northwest Greece.

OBJECTIVE: The purpose of the present study was to compare psychological distress between patients with epilepsy and healthy controls and to evaluate potentially related factors to psychological distress in patients with epilepsy. Furthermore, we assessed how psychological distress and other potential factors mediate illness perception in patients with epilepsy in an urban area of Northwest Greece. MATERIALS AND METHODS: A case-control study was conducted in adult patients with epilepsy followed up at the University Hospital of Ioannina and in healthy controls. The Symptom Checklist-90 Revised (SCL-90R) for symptoms of psychological distress and the overall psychological distress Global Severity Index (GSI) evaluation, the brief illness perception questionnaire (B-IPQ), and the Adverse Event Profile (AEP) questionnaire for the antiepileptic drugs (AEDs) were used. RESULTS: Seventy patients with epilepsy and 70 controls were recruited in the study. Somatic, depression, and anxiety symptoms and the GSI were higher in patients than in controls. In patients with epilepsy, the AEP score was significantly associated with psychological distress. Illness perception was associated with the number and the total number of administered AEDs; the AEP score; somatic, obsessive, depressive, and anxiety symptoms; and the GSI. After regression analysis, epilepsy characteristics, AEDs, and psychological distress accounted for 11.7%, 28.7%, and 5.5% of variance in BIP-Q score, respectively. CONCLUSION: Screening for psychological distress in patients with epilepsy is of high importance in clinical practice as somatic, depression, and anxiety symptoms and overall psychological distress are more severe in patients with epilepsy than in healthy controls. The symptoms of psychological distress are strongly associated with the adverse effects of AEDs. The epilepsy characteristics, the AEDs, and the psychological distress could determine a large part of illness perception in epilepsy, with the adverse effects of AEDs being the strongest predictor.

The Effect of 1600 µg Inhaled Salbutamol Administration on 30 m Sprint Performance Pre and Post a Yo-Yo Intermittent Running Test in Football Players.

The purpose of the study was to investigate the effect of inhaling 1600 µg of salbutamol (SAL) on 30 m sprint before and after the Yo-Yo Intermittent Recovery test. In a randomised cross over single blind study 13 male non-asthmatic, football players volunteered (mean ± SD; age 18.1 ± 0.9 years; weight 69.5 ± 8.3 kg; height 1.78 ± 0.07 m). Participants completed two visits and were randomly assigned to either (SAL) or (PLA) treatment and performed a set of three sprints of 30 m before and after the Yo-Yo Intermittent Recovery Test (Yo-Yo IRT). Best sprint and mean sprint were analysed in addition to the distance covered during the Yo-Yo IRT; rating of perceived exertion and heart rate were collected at the end of each level completed. Repeated measures ANOVA were performed to investigate changes in performance between groups. Following the inhalation of supra-therapeutic salbutamol dose (1600 µg) neither 30 m sprint time (PLA 4.43 ± 0.14 s; SAL 4.44 ± 0.15 s, p = 0.76) nor distance covered in the Yo-Yo IRT test reported significant variation between PLA conditions (1660 ± 217 m) and SAL (1610 ± 229 m, p = 0.16). Moreover, lactate values, heart rate and RPE did not differ significantly between groups. The inhalation of 1600 µg salbutamol does not enhance 30 m sprint performance in non-fatigued and fatigue conditions. Our findings suggest when football players acutely inhale double the permitted dose of salbutamol, as indicated in the World Anti-Doping Agency List of Prohibited Substances and Methods, they will not experience improvements in sprint or endurance performance.

Differential cell-type dependent brain state modulations of sensory representations in the non-lemniscal mouse inferior colliculus.

Sensory responses of the neocortex are strongly influenced by brain state changes. However, it remains unclear whether and how the sensory responses of the midbrain are affected. Here we addressed this issue by using in vivo two-photon calcium imaging to monitor the spontaneous and sound-evoked activities in the mouse inferior colliculus (IC). We developed a method enabling us to image the first layer of non-lemniscal IC (IC shell L1) in awake behaving mice. Compared with the awake state, spectral tuning selectivity of excitatory neurons was decreased during isoflurane anesthesia. Calcium imaging in behaving animals revealed that activities of inhibitory neurons were highly correlated with locomotion. Compared with stationary periods, spectral tuning selectivity of excitatory neurons was increased during locomotion. Taken together, our studies reveal that neuronal activities in the IC shell L1 are brain state dependent, whereas the brain state modulates the excitatory and inhibitory neurons differentially.

Dopamine Enhances Item Novelty Detection via Hippocampal and Associative Recall via Left Lateral Prefrontal Cortex Mechanisms.

The involvement of fronto-striatal circuits in item and associative memory retrieval as well as in the stabilization of memories by retrieval practice suggests that both retrieval and re-encoding of stored memories might rely on dopaminergic mechanisms in humans. We tested these hypotheses in a placebo-controlled pharmacological fMRI study using 2 mg of the D2 antagonist haloperidol administered acutely before a cued associative recall task of previously encoded picture-word pairs in 53 healthy humans of both sexes. The cued associative recall was moreover repeated 3 d later outside the scanner without pharmacological intervention. Dopaminergic modulation significantly improved associative recall performance and recognition accuracy of verbal items. Moreover, we observed a significant dopamine effect on re-encoding in terms of increased specificity of associative memories from the first to the second cued associative recall. Better association memory under haloperidol was linked with higher activity in the left lateral prefrontal cortex and right parietal cortex, suggesting that dopamine facilitates associative retrieval through increased recruitment of frontoparietal monitoring processes. In contrast, improved recognition of verbal items under haloperidol was reflected by enhanced novelty detection in the hippocampus and increased activity in saliency networks. Together, these results show distinct but concomitant positive effects of dopamine on associative recall and item recognition and suggest that the specificity of associative recall through re-encoding mechanisms is likewise augmented by dopamine.SIGNIFICANCE STATEMENT Although the neurotransmitter dopamine has been linked with learning and memory for a long time, dopaminergic effects on item recognition in humans were demonstrated only recently. The involvement of fronto-striatal monitoring processes in association retrieval suggests that associative memory might be particularly affected by dopamine. Moreover, fronto-striatal dopaminergic signals have been hypothesized to determine the updating and re-encoding of previously retrieved memories. We here demonstrate clear facilitative effects of dopamine on associative recall and item recognition mediated by prefrontal and hippocampal mechanisms respectively. Additionally, effects on re-encoding were reflected by increased specificity of associative memories. These results augment our understanding of dopaminergic processes in episodic memory retrieval and offer new perspectives on memory impairments in dopamine-related disorders and their treatment.

Central Nervous System Correlates of "Objective" Neuropathy in Alcohol Use Disorder.

BACKGROUND: Among the neurological consequences of alcoholism is peripheral neuropathy. Relative to human immunodeficiency virus (HIV) or diabetes-related neuropathies, neuropathy associated with alcohol use disorders (AUD) is understudied. In both the diabetes and HIV literature, emerging evidence supports a central nervous system (CNS) component to peripheral neuropathy. METHODS: In seeking a central substrate for AUD-related neuropathy, the current study was conducted in 154 individuals with AUD (43 women, age 21 to 74 years) and 99 healthy controls (41 women, age 21 to 77 years) and explored subjective symptoms (self-report) and objective signs (perception of vibration, deep tendon ankle reflex, position sense, 2-point discrimination) of neuropathy separately. In addition to regional brain volumes, risk factors for AUD-related neuropathy, including age, sex, total lifetime ethanol consumed, nutritional indices (i.e., thiamine, folate), and measures of liver integrity (i.e., γ-glutamyltransferase), were evaluated. RESULTS: The AUD group described more subjective symptoms of neuropathy and was more frequently impaired on bilateral perception of vibration. From 5 correlates, the number of AUD-related seizures was most significantly associated with subjective symptoms of neuropathy. There were 15 correlates of impaired perception of vibration among the AUD participants: Of these, age and volume of frontal precentral cortex were the most robust predictors. CONCLUSIONS: This study supports CNS involvement in objective signs of neuropathy in AUD.

Exploring perceptions among people who drive after cannabis use: Collision risk, comparative optimism and normative influence.

INTRODUCTION AND AIMS: While the perceived risks of driving under the influence of cannabis (DUIC) have been a focus of recent drug-driving research, relevant concepts from the social cognition literature have rarely been applied to inform understanding of DUIC. This study aims to expand knowledge of perceived collision risk and social influences associated with DUIC and driving after other substance use. DESIGN AND METHODS: Semi-structured interviews were conducted with 20 participants of a remedial program for impaired drivers. Thematic analysis began with two independent coders. Early discussion of emergent themes resulted in the identification of applicable social cognition concepts, resulting in selective coding and interpretation. RESULTS: Many participants identified DUIC as less risky than driving under the influence of alcohol or other drugs. Mixed perceptions regarding the dangerousness of DUIC were expressed, with some participants denying increased collision risk except among novice cannabis users. Comparative optimism bias was also expressed by participants who perceived themselves as less likely than others to be involved in a collision when DUIC. In view of normative influence, friends were generally seen as more accepting of DUIC than family, and there were indications that the opinions of others who use cannabis were regarded as more credible than the opinions of those who do not use the drug. DISCUSSION AND CONCLUSIONS: Comparative optimism bias and normative influence may contribute to perceived risks associated with DUIC and may, therefore, be useful concepts to employ to increase the effectiveness of public health and road safety initiatives.

Effects of haloperidol on the delta-9-tetrahydrocannabinol response in humans: a responder analysis.

RATIONALE: Δ-9-Tetrahydrocannabinol (Δ-9-THC) produces psychotomimetic effects in humans. However, the role of dopamine signaling in producing such effects is unclear. We hypothesized that dopaminergic antagonism would reduce the psychotomimetic effect of Δ-9-THC. OBJECTIVE: The objective of this study was to evaluate whether pre-treatment with haloperidol would alter the psychotomimetic and perceptual-altering effects of Δ-9-THC, measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and the Clinician-Administered Dissociative Symptom Scale (CADSS) in humans. METHODS: In a two-test-day double-blind study, 28 healthy individuals were administered with active (0.057 mg/kg) or placebo oral haloperidol, followed 90 and 215 min later by intravenous administration of active (0.0286 mg/kg) Δ-9-THC and placebo, respectively. This secondary analysis was conducted because of the observation in other studies and in our data that a significant proportion of individuals may not have an adequate response to THC (floor effect), thus limiting the ability to test an interaction. Therefore, this analysis was performed including only responders to THC (n = 10), defined as individuals who had an increase of at least one point on the PANSS positive scale, consistent with prior human laboratory studies. RESULTS: In the 10 responders, Δ-9-THC-induced increases in PANSS positive scores were significantly lower in the haloperidol condition (1.1 + 0.35) compared with the placebo condition (2.9 + 0.92). CONCLUSION: This responder analysis showed that haloperidol did reduce the psychotomimetic effect of Δ-9-THC, supporting the hypothesis that dopaminergic signaling may participate in the psychosis-like effects of cannabinoids.

Microdosing psychedelics: personality, mental health, and creativity differences in microdosers.

RATIONALE: Microdosing psychedelics-the regular consumption of small amounts of psychedelic substances such as LSD or psilocybin-is a growing trend in popular culture. Recent studies on full-dose psychedelic psychotherapy reveal promising benefits for mental well-being, especially for depression and end-of-life anxiety. While full-dose therapies include perception-distorting properties, microdosing mayprovide complementary clinical benefits using lower-risk, non-hallucinogenic doses. OBJECTIVES: This pre-registered study aimed to investigate whether microdosing psychedelics is related to differences in personality, mental health, and creativity. METHODS: In this observational study, respondents recruited from online forums self-reported their microdosing behaviors and completed questionnaires concerning dysfunctional attitudes, wisdom, negative emotionality, open-mindedness, and mood. Respondents also performed the Unusual Uses Task to assess their creativity. RESULTS: Current and former microdosers scored lower on measures of dysfunctional attitudes (p < 0.001, r = - 0.92) and negative emotionality (p = 0.009, r = - 0.85) and higher on wisdom (p < 0.001, r = 0.88), openmindedness(p = 0.027, r = 0.67), and creativity (p < 0.001, r = 0.15) when compared to non-microdosing controls. CONCLUSIONS: These findings provide promising initial evidence that warrants controlled experimental research to directly test safety and clinical efficacy. As microdoses are easier to administer than full-doses, this new paradigm has the exciting potential to shape future psychedelic research.