M1/M4-Preferring Muscarinic Cholinergic Receptor Agonist Xanomeline Reverses Wake and Arousal Deficits in Nonpathologically Aged Mice.

Degeneration of the cholinergic basal forebrain is implicated in the development of cognitive deficits and sleep/wake architecture disturbances in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Indirect-acting muscarinic cholinergic receptor agonists, such as acetylcholinesterase inhibitors (AChEIs), remain the only FDA-approved treatments for the cognitive impairments observed in AD that target the cholinergic system. Novel direct-acting muscarinic cholinergic receptor agonists also improve cognitive performance in young and aged preclinical species and are currently under clinical development for AD. However, little is known about the effects of direct-acting muscarinic cholinergic receptor agonists on disruptions of sleep/wake architecture and arousal observed in nonpathologically aged rodents, nonhuman primates, and clinical populations. The purpose of the present study was to provide the first assessment of the effects of the direct-acting M1/M4-preferring muscarinic cholinergic receptor agonist xanomeline on sleep/wake architecture and arousal in young and nonpathologically aged mice, in comparison with the AChEI donepezil, when dosed in either the active or inactive phase of the circadian cycle. Xanomeline produced a robust reversal of both wake fragmentation and disruptions in arousal when dosed in the active phase of nonpathologically aged mice. In contrast, donepezil had no effect on either age-related wake fragmentation or arousal deficits when dosed during the active phase. When dosed in the inactive phase, both xanomeline and donepezil produced increases in wake and arousal and decreases in nonrapid eye movement sleep quality and quantity in nonpathologically aged mice. Collectively, these novel findings suggest that direct-acting muscarinic cholinergic agonists such as xanomeline may provide enhanced wakefulness and arousal in nonpathological aging, MCI, and AD patient populations.

The power of Dionysus-Effects of red wine on consciousness in a naturalistic setting.

There is lack of research on effects of red wine on consciousness when drank in wine bars designed to enhance the pleasurableness of the wine drinking experience. Effects of a moderate dose of red wine (≈ 40.98 g of ethanol) on consciousness were examined in a naturalistic study taking place in a wine bar located in one of the most touristic areas of Lisbon, Portugal. One hundred two participants drank in one of three conditions: alone, in dyad, or in groups up to six people. Red wine increased pleasure and arousal, decreased the awareness of time, slowed the subjective passage of time, increased the attentional focus on the present moment, decreased body awareness, slowed thought speed, turned imagination more vivid, and made the environment become more fascinating. Red wine increased insightfulness and originality of thoughts, increased sensations of oneness with the environment, spiritual feelings, all-encompassing love, and profound peace. All changes in consciousness occurred regardless of volunteers drinking alone, in dyad or in group. Men and women did not report different changes in consciousness. Older age correlated with greater increases in pleasure. Younger age correlated with greater increases in fascination with the environment of the wine bar. Drinking wine in a contemporaneous Western environment designed to enhance the pleasurableness of the wine drinking experience may trigger changes in consciousness commonly associated with mystical-type states.

Ambient-task combined lighting to regulate autonomic and psychomotor arousal levels without compromising subjective comfort to lighting.

BACKGROUND: Although evidence of both beneficial and adverse biological effects of lighting has accumulated, biologically favorable lighting often does not match subjectively comfortable lighting. By controlling the correlated color temperature (CCT) of ambient lights, we investigated the feasibility of combined lighting that meets both biological requirements and subjective comfort. METHODS: Two types of combined lightings were compared; one consisted of a high-CCT (12000 K) light-emitting diode (LED) panel as the ambient light and a low-CCT (5000 K) LED stand light as the task light (high-low combined lighting), and the other consisted of a low-CCT (4500 K) LED panel as the ambient light and the same low-CCT (5000 K) stand light as the task light (low-low combined lighting) as control. Ten healthy subjects (5 young and 5 elderly) were exposed to the two types of lighting on separate days. Autonomic function by heart rate variability, psychomotor performances, and subjective comfort were compared. RESULTS: Both at sitting rest and during psychomotor workload, heart rate was higher and the parasympathetic index of heart rate variability was lower under the high-low combined lighting than the low-low combined lighting in both young and elderly subject groups. Increased psychomotor alertness in the elderly and improved sustainability of concentration work performance in both age groups were also observed under the high-low combined lighting. However, no significant difference was observed in the visual-analog-scale assessment of subjective comfort between the two types of lightings. CONCLUSIONS: High-CCT ambient lighting, even when used in combination with low-CCT task lighting, could increase autonomic and psychomotor arousal levels without compromising subjective comfort. This finding suggests the feasibility of independent control of ambient and task lighting as a way to achieve both biological function regulation and subjective comfort.

Arousal-Inducing Effect of Garcinia cambogia Peel Extract in Pentobarbital-Induced Sleep Test and Electroencephalographic Analysis.

Caffeine, a natural stimulant, is known to be effective for weight loss. On this basis, we screened the arousal-inducing effect of five dietary supplements with a weight loss effect (Garcinia cambogia, Coleus forskohlii, Camellia sinensis L., Irvingia gabonensis, and Malus pumila M.), of which the G. cambogia peel extract (GC) showed a significant arousal-inducing effect in the pentobarbital-induced sleep test in mice. This characteristic of GC was further evaluated by analysis of electroencephalogram and electromyogram in C57L/6N mice, and it was compared to that of the positive control, caffeine. Administration of GC (1500 mg/kg) significantly increased wakefulness and decreased non-rapid eye movement sleep, similar to that of caffeine (25 mg/kg), with GC and caffeine showing a significant increase in wakefulness at 2 and 6 h, respectively. Compared to that of caffeine, the shorter duration of efficacy of GC could be advantageous because of the lower possibility of sleep disturbance. Furthermore, the arousal-inducing effects of GC (1500 mg/kg) and caffeine (25 mg/kg) persisted throughout the chronic (3 weeks) administration study. This study, for the first time, revealed the arousal-inducing effect of GC. Our findings suggest that GC might be a promising natural stimulant with no side effects. In addition, it is preferential to take GC as a dietary supplement for weight loss during the daytime to avoid sleep disturbances owing to its arousal-inducing effect.

Dorsal raphe serotonergic neurons promote arousal from isoflurane anesthesia.

AIMS: General anesthesia has been widely applied in surgical or nonsurgical medical procedures, but the mechanism behind remains elusive. Because of shared neural circuits of sleep and anesthesia, whether serotonergic system, which is highly implicated in modulation of sleep and wakefulness, regulates general anesthesia as well is worth investigating. METHODS: Immunostaining and fiber photometry were used to assess the neuronal activities. Electroencephalography spectra and burst-suppression ratio (BSR) were used to measure anesthetic depth and loss or recovery of righting reflex to indicate the induction or emergence time of general anesthesia. Regulation of serotonergic system was achieved through optogenetic, chemogenetic, or pharmacological methods. RESULTS: We found that both Fos expression and calcium activity were significantly decreased during general anesthesia. Activation of 5-HT neurons in the dorsal raphe nucleus (DRN) decreased the depth of anesthesia and facilitated the emergence from anesthesia, and inhibition deepened the anesthesia and prolonged the emergence time. Furthermore, agonism or antagonism of 5-HT 1A or 2C receptors mimicked the effect of manipulating DRN serotonergic neurons. CONCLUSION: Our results demonstrate that 5-HT neurons in the DRN play a regulative role of general anesthesia, and activation of serotonergic neurons could facilitate emergence from general anesthesia partly through 5-HT 1A and 2C receptors.

Glucocorticoid Receptor Antagonist Mifepristone Does Not Alter Innate Anxiety-Like Behavior in Genetically-Selected Marchigian Sardinian (msP) Rats.

Marchigian Sardinian alcohol-preferring (msP) rats serve as a unique model of heightened alcohol preference and anxiety disorders. Their innate enhanced stress and poor stress-coping strategies are driven by a genetic polymorphism of the corticotropin-releasing factor receptor 1 (CRF1) in brain areas involved in glucocorticoid signaling. The activation of glucocorticoid receptors (GRs) regulates the stress response, making GRs a candidate target to treat stress and anxiety. Here, we examined whether mifepristone, a GR antagonist known to reduce alcohol drinking in dependent rats, decreases innate symptoms of anxiety in msPs. Male and female msPs were compared to non-selected Wistar counterparts across three separate behavioral tests. We assessed anxiety-like behavior via the novelty-induced hypophagia (NIH) assay. Since sleep disturbances and hyperarousal are common features of stress-related disorders, we measured sleeping patterns using the comprehensive lab monitoring system (CLAMS) and stress sensitivity using acoustic startle measures. Rats received an acute administration of vehicle or mifepristone (60 mg/kg) 90 min prior to testing on NIH, acoustic startle response, and CLAMS. Our results revealed that both male and female msPs display greater anxiety-like behaviors as well as enhanced acoustic startle responses compared to Wistar counterparts. Male msPs also displayed reduced sleeping bout duration versus Wistars, and female msPs displayed greater acoustic startle responses versus male msPs. Importantly, the enhanced anxiety-like behavior and startle responses were not reduced by mifepristone. Together, these findings suggest that increased expression of stress-related behaviors in msPs are not solely mediated by acute activation of GRs.

A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy.

BACKGROUND & AIMS: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis. METHODS: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks' dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days. RESULTS: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well. CONCLUSION: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone. LAY SUMMARY: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2016-003651-30.

Activation of anterior thalamic reticular nucleus GABAergic neurons promotes arousal from propofol anesthesia in mice.

Propofol is widely used for the induction and maintenance of anesthesia, which causes a rapid loss of consciousness. However, the mechanisms underlying the hypnosis effect of propofol are still not fully understood. The thalamic reticular nucleus (TRN) is crucial for regulating wakefulness, sleep rhythm generation, and sleep stability, while the role of TRN in the process of propofol-induced anesthesia is still unknown. Here, we investigated the function of the anterior TRN in propofol general anesthesia. Our results demonstrated that the neural activity of anterior TRN is suppressed during propofol anesthesia, whereas it is robustly activated from anesthesia by recording the calcium signals using fiber photometry technology. The results showed that the activation of anterior TRN neurons by chemogenetic and optogenetic methods shortens the emergency time without changing the induction time. Conversely, chemogenetic or optogenetic inhibition of the TRN neurons leads to a delay in the recovery time. Our study showed that anterior TRN is crucial for behavioral arousal without affecting the induction time of propofol anesthesia.

Subjective responses predict d-amphetamine choice in healthy volunteers.

BACKGROUND: It is commonly believed that drugs, including stimulants, are used recreationally because of their ability to induce pleasurable subjective effects. However, recreational drug use sometimes occurs in the absence of positive subjective effects, suggesting that other factors contribute. Here, we examine the extent to which the direct subjective effects of amphetamine, a commonly misused stimulant, predict subsequent choice of the drug vs placebo. METHODS: Healthy adults (N = 112) participated in a five-session amphetamine choice study. On the first four sessions, participants sampled either 20 mg d-amphetamine or placebo in color-coded capsules two times each. On the fifth session, they chose which color (d-amphetamine or placebo) they preferred. We examined the choice of drug vs placebo in relation to demographic characteristics, baseline mood states, personality and subjective and cardiovascular responses to acute administration of the drug. RESULTS: Eighty-one participants chose amphetamine (Choosers) while 31 chose placebo (Non-choosers). Overall, amphetamine produced typical stimulant-like effects on subjective questionnaires, and it elevated heart rate and blood pressure vs placebo. Choosers reported greater positive mood, elation and stimulant-like effects following amphetamine compared to Non-choosers. The Choosers also exhibited a greater increase in systolic blood pressure, but not heart rate. The groups did not differ on demographic characteristics, mood states before drug administration or personality. CONCLUSIONS: These findings support the idea that pleasurable subjective responses to amphetamine, including positive mood, elation, and stimulant-like effects influence behavioral choice of the drug.

Activation of Dopamine Signals in the Olfactory Tubercle Facilitates Emergence from Isoflurane Anesthesia in Mice.

Activation of dopamine (DA) neurons is essential for the transition from sleep to wakefulness and maintenance of awakening, and sufficient to accelerate the emergence from general anesthesia in animals. Dopamine receptors (DR) are involve in arousal mediation. In the present study, we showed that the olfactory tubercle (OT) was active during emergence from isoflurane anesthesia, local injection of dopamine D1 receptor (D1R) agonist chloro-APB (1 mg/mL) and D2 receptor (D2R) agonist quinpirole (1 mg/mL) into OT enhanced behavioural and cortical arousal from isoflurane anesthesia, while D1R antagonist SCH-23390 (1 mg/mL) and D2R antagonist raclopride (2.5 mg/mL) prolonged recovery time. Optogenetic activation of DAergic terminals in OT also promoted behavioural and cortical arousal from isoflurane anesthesia. However, neither D1R/D2R agonists nor D1R/D2R antagonists microinjection had influences on the induction of isoflurane anesthesia. Optogenetic stimulation on DAergic terminals in OT also had no impact on the anesthesia induction. Our results indicated that DA signals in OT accelerated emergence from isoflurane anesthesia. Furthermore, the induction of general anesthesia, different from the emergence process, was not mediated by the OT DAergic pathways.

An interoceptive basis for alcohol priming effects.

RATIONALE: Alcohol priming can modulate the value of rewards, as observed through the effects of acute alcohol administration on cue reactivity. However, little is known about the psychophysiological mechanisms driving these effects. Here, we examine how alcohol-induced changes in bodily states shape the development of implicit attentional biases and explicit cue reactivity. OBJECTIVES: To characterize the interoceptive correlates of alcohol priming effects on alcohol attentional biases and cue reactivity. METHODS: In a two-session double-blind alcohol administration procedure, participants (n=31) were given a 0.4-g/kg dose of alcohol or a placebo drink. Cardiovascular responses were measured before and after alcohol administration to observe the effects of alcohol on viscero-afferent reactivity, as indexed through changes in heart rate variability (HRV) at or near 0.1 Hz (0.1-Hz HRV). Next, participants completed a modified flanker task to examine implicit alcohol attentional biases and provided subjective valence and arousal ratings of alcohol cues to examine explicit cue reactivity. RESULTS: We found that changes in 0.1-Hz HRV after alcohol administration positively correlated with attentional biases, and negatively correlated with alcohol valence ratings; blood alcohol content was a null predictor. CONCLUSIONS: This is novel evidence that suggests alcohol-induced changes in bodily states may mediate the occurrence of alcohol priming effects and highlights the potentially generative role of interoceptive mechanisms in alcohol-related behaviors. The differential patterns revealed by implicit biases and explicit response tendencies are considered within the context of the dissociation between wanting and liking.

Intranasal oxytocin may help maintain romantic bonds by decreasing jealousy evoked by either imagined or real partner infidelity.

BACKGROUND: While romantic jealousy may help to maintain relationships, following partner infidelity and an irretrievable loss of trust it can also promote break-ups. The neuropeptide oxytocin can enhance the maintenance of social bonds and reduce couple conflict, although its influence on jealousy evoked by imagined or real infidelity is unclear. AIMS: This study aimed to investigate the effects of intranasal oxytocin (24 IU) on romantic jealousy in both males and females in imagined and real contexts. METHODS: Seventy heterosexual couples participated in this double-blind, placebo-controlled, between-subject design study. Jealousy was firstly quantified in the context of subjects imagining partner infidelity and secondly in a Cyberball game where their partner interacted preferentially with an opposite-sexed rival stranger to simulate partner exclusion, or rejected a neutral stranger but not the partner. RESULTS: Oxytocin primarily decreased jealousy and arousal ratings towards imagined emotional and sexual infidelity by a partner in both sexes. During the Cyberball game, while male and female subjects in both groups subsequently threw the ball least often to the rival stranger, under oxytocin they showed reduced romantic jealousy and arousal ratings for stranger players, particularly the rival one, and reported reduced negative and increased positive feelings while playing the game. CONCLUSIONS: Together, our results suggest that oxytocin can reduce the negative emotional impact of jealousy in established romantic partners evoked by imagined or real infidelity or exclusive social interactions with others. This provides further support for oxytocin promoting maintenance of relationships.

Contextual influences on subjective alcohol response.

Prior research demonstrates contextual influences on drug responses in both animals and humans, although studies in humans typically focus on only one aspect of context (e.g., social) and examine a limited range of subjective experiences. The current study sought to address these limitations by examining the impact of both social and physical context on the full range of subjective alcohol effects. The sample included 448 young adult social drinkers (57% male, 66.5% White) randomly assigned to consume alcohol (target blood alcohol concentration of .08 g%) or placebo in 1 of 4 contexts (solitary lab, group lab, solitary bar, group bar). Results indicated that high arousal positive (HAP) effects of alcohol (e.g., talkative, lively) were stronger in nonbar relative to bar contexts and that low arousal positive (LAP) effects (e.g., relaxed, calm) were only present in the group lab context. There were also main effects of social context such that high arousal effects (both positive and negative) were stronger in group contexts, regardless of beverage condition. These findings highlight the importance of considering context when examining alcohol effects. Studies designed to isolate pharmacological HAP effects may benefit from a nonbar setting, and studies of LAP effects might be most effective in a simulated living room or home environment, although future studies are needed to directly address this possibility. Further, studies with an explicit focus on expectancies or that need strong control for expectancies might benefit from a group context, particularly when studying high arousal effects. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Ketamine anesthesia enhances fear memory consolidation via noradrenergic activation in the basolateral amygdala.

Trauma patients treated with ketamine during emergency care present aggravated early post- traumatic stress reaction which is highly predictive of post-traumatic stress disorder (PTSD) development and severity. The use of ketamine in the acute trauma phase may directly or indirectly interfere with neural processes of memory consolidation of the traumatic event, thus leading to the formation of maladaptive memories, a hallmark symptom of PTSD. We have recently shown that ketamine anesthesia, immediately after a traumatic event, enhances memory consolidation and leads to long-lasting alterations of social behavior in rats. Based on the evidence that ketamine induces a robust central and peripheral adrenergic/noradrenergic potentiation and that activation of this system is essential for the formation of memory for stressful events, we explored the possibility that the strong sympathomimetic action of ketamine might underlie its memory enhancing effects. We found that rats given immediate, but not delayed, post-training ketamine anesthesia (125 mg/kg) presented enhanced 48-h memory retention in an inhibitory avoidance task and that these effects were blocked by adrenal medullectomy, lesions of the locus coeruleus, systemic or intra-basolateral amygdala ß-adrenergic receptor antagonism. Thus, the memory enhancing effects of ketamine anesthesia are time-dependent and mediated by a combined peripheral-central sympathomimetic action. We elucidated a mechanism by which ketamine exacerbates acute post-traumatic reaction, possibly leading to development of PTSD symptomatology later in life. These findings will help guide for a better management of sedation/anesthesia in emergency care to promote the prophylaxis and reduce the risk of developing trauma-related disorders in trauma victims.

Approach to Cognitive Impairment in Parkinson's Disease.

Cognitive dysfunction is common in Parkinson's disease (PD) and predicts poor clinical outcomes. It is associated primarily with pathologic involvement of basal forebrain cholinergic and prefrontal dopaminergic systems. Impairments in executive functions, attention, and visuospatial abilities are its hallmark features with eventual involvement of memory and other domains. Subtle symptoms in the premotor and early phases of PD progress to mild cognitive impairment (MCI) which may be present at the time of diagnosis. Eventually, a large majority of PD patients develop dementia with advancing age and longer disease duration, which is usually accompanied by immobility, hallucinations/psychosis, and dysautonomia. Dopaminergic medications and deep brain stimulation help motor dysfunction, but may have potential cognitive side effects. Central acetylcholinesterase inhibitors, and possibly memantine, provide modest and temporary symptomatic relief for dementia, although there is no evidence-based treatment for MCI. There is no proven disease-modifying treatment for cognitive impairment in PD. The symptomatic and disease-modifying role of physical exercise, cognitive training, and neuromodulation on cognitive impairment in PD is under investigation. Multidisciplinary approaches to cognitive impairment with effective treatment of comorbidities, proper rehabilitation, and maintenance of good support systems in addition to pharmaceutical treatment may improve the quality of life of the patients and caregivers.

Differences in midazolam premedication effects on recovery after short-duration ambulatory anesthesia with propofol or sevoflurane for gynecologic surgery in young patients: A randomized controlled trial.

BACKGROUND: Anxiolytic premedication requires careful consideration owing to potential side effects including delayed recovery after ambulatory anesthesia. We aimed to compare the effect of midazolam on recovery profiles postoperatively, depending on whether propofol or sevoflurane was the primary anesthetic. METHODS: We enrolled 226 patients (age, 18-50 years) undergoing ambulatory gynecologic laparoscopic surgery. Patients were categorized into propofol without midazolam (P), propofol with midazolam (MP), sevoflurane without midazolam (S), and sevoflurane with midazolam (MS) groups. As premedication, placebo or 0.02 mg/kg intravenous midazolam was used. The primary outcome was the difference in the time from anesthetic discontinuation to eye opening in response to verbal command. Secondary outcomes included postoperative nausea and pain occurrence and time to reach the discharge score. RESULTS: The time from anesthetic discontinuation to eye opening was longer in the MP group (n = 49) than in the P group (n = 50; P < .001) but was not significantly different between the MS (n = 50) and S groups (n = 49; P = .1). Midazolam premedication did not significantly affect postoperative nausea in the MP group compared with that in the P group (P = .3) but had a nausea prevention effect in the MS group compared with that in the S group (P < .001). The time to reach the discharge score was similar in all patients regardless of midazolam administration. CONCLUSION: In the recovery from short-duration ambulatory gynecologic surgery in young patients, intravenous midazolam premedication showed positive effects on postoperative nausea without affecting the time from anesthetic discontinuation to eye opening with sevoflurane-based anesthesia but prolonged the time from anesthetic discontinuation to eye opening with propofol-based anesthesia. Because this difference between the propofol groups is not clinically significant, the results support midazolam premedication in young women. Further studies assessing larger populations are needed.

The effects of caffeine on olfactory function and mood: an exploratory study.

Caffeine has been demonstrated to enhance olfactory function in rodents, but to date, the sparse research in humans has not shown any equivalent effects. However, due to the methodological nature of those human studies, a number of questions remain unanswered, which the present study aimed to investigate. Using a double-blind experimental design, participants (n = 40) completed baseline mood measures, standardised threshold and identification tests and were then randomly allocated to receive a capsule containing either 100 mg of caffeine or placebo, followed by the same olfactory tests and mood measures. Results revealed that despite a trend toward elevated arousal following caffeine for habitual caffeine consumers, there were no changes in odour function. In contrast, for non-caffeine consumers, caffeine acted to enhance odour (threshold) sensitivity but reduce odour identification. Overall, these findings demonstrate a complex profile of effects of caffeine on odour function and, given the evidence from the wider caffeine literature, it is proposed that the effects of caffeine might be limited to older populations.

An Exploratory Factor Analysis of the Stimulant, Sedative, and Affective Responses to Alcohol.

BACKGROUND: Subjective response (SR) to acute alcohol reflects individual variance to the sensitivity of alcohol's pharmacological effects. It has been argued that measures of stimulation and sedation may not fully capture the full-range SR, with 2 novel domains proposed: high arousal negative and low arousal positive. While substantial progress has been made in the field of SR and alcohol use risk, it remains unknown how these novel domains correspond to traditional SR measures. Therefore, the current study examined the latent structure of traditional and novel SR measures at rising breath alcohol concentrations (BrACs) during alcohol administration. METHODS: Heavy drinkers (n = 67; 36M/31F) participated in an intravenous alcohol administration. Questionnaires assessing stimulation, sedation, mood, valence and arousal, and craving were assessed at baseline and at BrACs of 20, 40, and 60 mg%. A series of exploratory factor analyses were conducted to examine the latent factor structure of SR at each time point. Correlations examined the association between the generated factors and measures of problematic alcohol use. RESULTS: The analysis generated a 3-factor solution, consistent across all time points. The factors measured the following effects of SR: (i) stimulation and positive mood, (ii) sedation and aversive effects, and (iii) tension reduction. The tension reduction factor was most commonly associated with problematic alcohol use in this sample. CONCLUSION: This study extends upon the literature evaluating the biobehavioral effects of alcohol by examining a novel combination of SR to alcohol measures. This study demonstrates that the proposed low arousal positive domain, which loaded onto the tension reduction factor, provides novel information not captured by previous SR measures. Going forward, studies of alcohol's subjective effects should use this dimensional approach to reduce multiple comparisons across a wide range of scales and to build a literature grounded on the underlying structure of SR as a translational phenotype for AUD.

Ethanol Alters Variability, But Not Rate, of Firing in Medial Prefrontal Cortex Neurons of Awake-Behaving Rats.

BACKGROUND: The medial prefrontal cortex (mPFC) is a brain region involved in the evaluation and selection of motivationally relevant outcomes. Neural activity in mPFC is altered following acute ethanol (EtOH) use and, in rodent models, doses as low as 0.75 g/kg yield cognitive deficits. Deficits in decision making following acute EtOH are thought to be mediated, at least in part, by decreases in mPFC firing rates (FRs). However, the data leading to this conclusion have been generated exclusively in anesthetized rodents. The present study characterizes the effects of acute EtOH injections on mPFC neural activity in awake-behaving rodents. METHODS: Awake-behaving and anesthetized in vivo electrophysiological recordings were performed. We utilized 3 groups: the first received 2 saline injections, the second received a saline injection followed by 1.0 g/kg EtOH, and the last received saline followed by 2 g/kg EtOH. One week later, an anesthetized recording occurred where a saline injection was followed by an injection of 1.0 g/kg EtOH. RESULTS: The anesthetized condition showed robust decreases in neural activity and differences in up-down states (UDS) dynamics. In the awake-behaving condition, FRs were grouped according to behavioral state: moving, not-moving, and sleep. The differences in median FRs were found for each treatment and behavioral state combination. A FR decrease was only found in the 2.0 g/kg EtOH treatment during not-moving states. However, robust decreases in FR variability were found across behavioral state in both the 1.0 and 2.0 g/kg EtOH treatment. Sleep was separately analyzed. EtOH modulated the UDS during sleep producing decreases in FRs. CONCLUSIONS: In conclusion, the changes in neural activity following EtOH administration in anesthetized animals are not conserved in awake-behaving animals. The most prominent difference following EtOH was a decrease in FR variability suggesting that acute EtOH may be affecting decision making via this mechanism.

Oxytocin enhances the recovery of eye-contact induced autonomic arousal: A treatment mechanism study with placebo-controlled design.

The neuropeptide oxytocin (OT) is suggested to exert a pivotal role in a variety of complex human behaviors, including trust, attachment, social perception and fear regulation. Previous studies have demonstrated that intranasal administration of OT reduces subjective and neuroendocrine stress responses and dampens amygdala reactivity. OT has also been proposed to modulate activity of the autonomic nervous system. Here, a randomized double-blind, placebo-controlled study (with parallel design) was conducted with 56 healthy adult men to investigate whether a single-dose of OT (24 IU) modulates sympathetic autonomic arousal upon live dyadic gaze interactions. To do so, electrodermal recordings of skin conductance were performed during the engagement of eye contact with a live model in a two-person social context. In accordance to prior research, direct eye gaze elicited a significant enhancement in skin conductance responses, but OT did not specifically enhance or dampen the overall magnitude (amplitude) of the skin conductance response. Administration of OT did facilitate the recovery of skin conductance responses back to baseline (reduced recovery time), indicating a role of OT in restoring homeostatic balance. Notably, the treatment-effect on autonomic recovery was most prominent in participants with low self-reported social responsiveness, indicating that person-dependent factors play an important role in determining OT treatment-responses. Exploratory, it was shown that OT also significantly reduced self-reported feelings of tension and (at trend-level) worrying about how one presents oneself. Together, these observations add further evidence to a role of OT in modulating activity of the autonomic nervous system, primarily by facilitating a restoration of homeostatic balance after stimulus-induced increases in sympathetically-driven autonomic arousal.