Psychopharmacology最新文献

Rationale: Etomidate is a short-acting general anesthetic for clinical use and has been used as alternative to propofol or added to the powdered drug and e-cigarette cartridges recently, leading to an increase in abuse. But there have been no studies conducted on the abuse potential of etomidate.

Objectives and methods: This study aimed to evaluate the abuse potential of etomidate via conditioned place preference (CPP) and self-administration tests, reflecting its rewarding and reinforcing effects. In addition, righting reflex and open-field tests were conducted to evaluate the anesthetic and sedative effects of etomidate.

Results: In male mice, the ED₅₀ after intraperitoneal (i.p.) injection of anesthetic effect for etomidate was 9.156 mg/kg and the ED₅₀ of the sedative effect 5 min after intraperitoneal injection was 2.389 mg/kg. Etomidate induced CPP in male mice at the minimum dose of 3 mg/kg i.p. and supported stable self-administration in male rats at the dose of 0.075 mg/kg/intravenous infusion. The dose-response curve of etomidate was an inverted U-shape, which showed significant self-administrations compared with the vehicle group at doses of 0.05-0.1 mg/kg/infusion etomidate and the highest intake of 21.1 ± 0.64 infusions per 4 h-session.

Conclusions: These results clearly demonstrate that etomidate has rewarding and reinforcing effects in male rodents, as well as effects on anesthesia and motor inhibition. These findings indicate the possibility of abuse potential in humans using etomidate.

Rationale: Oxytocin has been shown to modulate behavior related to processing of monetary incentives and to regulate social and reproductive behavior, yet little is known about how oxytocin differentially influences neural responses to social and non-social incentives.

Objectives: We aimed to evaluate the effects of oxytocin administration on behavioral and neural responses to social and monetary incentives.

Methods: Twenty-eight healthy adults (age 18-45 years) performed both monetary and social incentive tasks during blood oxygenation level dependent (BOLD) imaging. Intranasal oxytocin or placebo was administered before each scan using a double blind, randomized, cross-over design. Task performance and self-reported motivation and mood states were collected. Time-series analysis was conducted to assess the influence of oxytocin on the hemodynamic response in the ventral tegmental area and substantia nigra (VTA/SN) and nucleus accumbens (NAc).

Results: Oxytocin demonstrated a multifaceted effect on VTA/SN and NAc when processing reward incentives, with it increasing BOLD response in VTA/SN and decreasing BOLD response in NAc during social incentive anticipation. A reversal of this was shown with decreased BOLD responses in the VTA/SN and increased BOLD response in the NAc during monetary incentive anticipation.

Conclusions: Our findings suggest a more nuanced purpose of oxytocin when evaluating reward incentive decision making. It is possible that while oxytocin does increase salience to rewards, that it is more important for cognitive control when determining short-term versus long-term benefits in rewards. Future studies should more closely examine the relationship between oxytocin and delay discounting.

Rationale: Environmental cues guide animals towards resources vital for survival but can also drive maladaptive reward-seeking behaviours, as in gambling and eating disorders. While conditioned stimuli (CSs) are paired with reward delivery after reward-seeking actions, discriminative stimuli (DSs) signal reward availability independently of behaviour.

Objective: We introduce a procedure to compare CS and DS effects on reward-seeking behaviour, in the same subjects within a single session.

Methods: Female and male Sprague-Dawley rats learned to self-administer sucrose. During each session, DS+ trials signaled that lever pressing would produce sucrose paired with a CS+ , and DS- trials signaled no sucrose and a CS-. Next, in the absence of sucrose, we assessed the ability of the cues to i) reinforce lever pressing and ii) increase sucrose seeking when presented response-independently. We also assessed the effects of the mGlu_2/3 receptor agonist LY379268 and d-amphetamine on cue-induced sucrose seeking.

Results: By the end of self-administration training, lever pressing peaked during DS+ trials and dropped during DS- trials. The DS+ was a conditioned reinforcer of sucrose seeking in both sexes, whereas the CS+ was more effective in males. Response-independent presentations of the DS+ invigorated sucrose seeking in both sexes, whereas the CS+ was effective only in males. LY379268 suppressed DS+ -triggered sucrose seeking in females, with no effect in males. D-amphetamine enhanced sucrose seeking non-specifically across cue conditions in males, with no effect in females.

Conclusions: Our new trial-based procedure can be used to identify unique and similar mechanisms underlying DS and CS influences on appetitive behaviour.

Rationale: Despite improved life expectancy of people with HIV (PWH), HIV-associated neurocognitive impairment (NCI) persists, alongside deficits in sensorimotor gating and neuroinflammation. PWH exhibit high smoking rates, possibly due to neuroprotective, anti-inflammatory, and cognitive-enhancing effects of nicotine, suggesting potential self-medication.

Objectives: Here, we tested the effects of acute nicotine vapor exposure on translatable measures of sensorimotor gating and exploratory behavior in the HIV-1 transgenic (HIV-1Tg) rat model of HIV.

Methods: Male and female HIV-1Tg (n = 28) and F344 control rats (n = 29) were exposed to acute nicotine or vehicle vapor. Sensorimotor gating was assessed using prepulse inhibition (PPI) of the acoustic startle response, and exploratory behavior was evaluated using the behavioral pattern monitor (BPM).

Results: Vehicle-treated HIV-1Tg rats exhibited PPI deficits at low prepulse intensities compared to F344 controls, as seen previously. No PPI deficits were observed in nicotine-treated HIV-1Tg rats, however. Nicotine vapor increased locomotor activity across genotypes. Cotinine analyses confirmed comparable levels of the primary metabolite of nicotine across genotypes.

Conclusions: Previous findings of PPI deficits in HIV-1Tg rats were replicated and, importantly, attenuated by acute nicotine vapor administration. Evidence for similar cotinine levels suggest a nicotine-specific effect in HIV-1Tg rats. Therefore, acute nicotine administration may be beneficial for attenuating sensorimotor deficits in PWH. Future studies should determine the long-term effects of nicotine vapor on similar HIV/NCI-relevant behaviors.

Background: Sensitivity to alcohol's stimulating and rewarding properties is associated with increased risk for future heavy drinking and the development and maintenance of alcohol use disorder (AUD). Further, pace of alcohol consumption varies across individuals and affects level of intoxication and subjective alcohol responses. The present study used smartphone-based high-resolution ecological momentary assessment (HR-EMA) of a heavy drinking episode in young adult risky drinkers' natural environments to examine associations between pace of drinking and subjective responses to alcohol.

Method: Young adult risky drinkers (N = 248; 42% female) completed a 3-hour HR-EMA of alcohol use and subjective responses to alcohol (stimulation, sedation, feeling, liking, and wanting more) during a drinking episode in their natural environment. Analyses examined associations between drinking pace trajectories and subjective responses to alcohol, accounting for drinking context (location/presence of others) and depression.

Results: Trajectory analysis revealed three drinking pace subgroups based on total drinks consumed during the 3-hour monitoring period: fast risers (~ 4 standard drinks/hour), moderate risers (~ 2.6 standard drinks/hour), and slow risers (~ 1.4 standard drinks/hour). Overall, faster pace of drinking was associated with greater alcohol stimulation and reward (liking and wanting more) and more alcohol-related negative consequences during and after the episode.

Conclusions: Results further underscore the heterogeneous nature of young adult risky drinkers and suggest the possibility that these individuals may drink rapidly to experience the stimulating and rewarding effects of alcohol sooner. Resulting increases in the positive effects of alcohol may reinforce future rapid drinking behavior.

The study aimed to investigate to what extent blockade of muscarinic receptors affects the speed of endogenous versus exogenous attentional shift times, and how it affects learning of attention shifting, cue detection and signal readout. Subjects viewed an array of 10 moving clocks and reported the time a clock indicated when cued. Target clocks were indicated by peripheral or central cues, including conditions of pre-cuing. For peripheral and central cuing, it yielded a compound measure of how long it took to detect the cue, shift attention to the relevant clock and read the time on the clock. For the pre-cue condition it yielded a measure of how long it took to detect the cue and read the time on the clock when attention could have been pre-allocated to the target clock. In study 1, each subject participated in 2 sessions (scopolamine/placebo), whereby the order of drug intake was counterbalanced across subjects, and subjects were blinded to conditions. Scopolamine/placebo was administered before a psychophysical experiment was conducted. In study 2, the effect of muscarinic blockade on learning induced improvements of cue detection, attention shift times (for exogenous and endogenous conditions), and signal readout was investigated. Here scopolamine/placebo was administered immediately after the first (of two) psychophysical sessions, whereby a given subject either received scopolamine or placebo pills. Confirming previous results, we show that pre-cuing resulted in the shortest read-out delays, followed by exogenous cuing, with endogenous read-out delays being slowest. Scopolamine application increased readout-delays in a dose dependent manner. This was mainly driven by increased readout-delays for pre-cue conditions, and to some extent for exogenous cue conditions. It suggests that muscarinic blockade affected the ability to pre-allocated attention to a cued location, as well as to react to peripheral cues. Additionally, blockade of muscarinic receptors immediately after the first session reduced learning dependent improvement of read-out delays. These results demonstrate that muscarinic receptors play an important in detecting cues, and fast read-out of cued information, and they contribute to the learning thereof.

Rationale: It is hypothesised that modulation of striatal dopaminergic signalling plays a key role in the rewarding effects of opioids. The monetary incentive delay (MID) task is a functional magnetic resonance imaging (fMRI) paradigm used to investigate striatal responses, which may reflect striatal dopamine release, during the anticipation of a financial reward.

Objectives: We hypothesised that fentanyl would modulate striatal MID task Blood Oxygenation Level Dependent (BOLD) responses, reflecting opioidergic modulation of striatal dopaminergic signalling.

Methods: 24 right-handed males who undertook four MRI scanning sessions, during which they completed an MID task 15 min after receiving an intravenous infusion of either one of two doses of fentanyl (50 µg/70kg), naloxone (400 µg) or placebo (saline 0.9%), were included in the analyses. End tidal CO₂ data were collected to control for respiratory depression.

Results: We demonstrated fentanyl induced increases in MID task reward and loss anticipation BOLD compared with placebo and naloxone in both region of interest (ROI) and whole brain analyses. These results were in cortical regions including the lingual gyrus, precuneus, posterior cingulate and frontal pole rather than the striatum.

Conclusions: Our results show the primary effects of fentanyl on MID anticipation BOLD in regions associated with the preparation of a motor response to a salient visual cue, rather than in regions typically associated with reward processing such as the striatum. This suggests that opioid agonists do not affect striatal activation during the MID task. Tasks using naturalistic rewards, for example feeding, sex or social contact which induce endogenous opioid signalling, may be more appropriate to probe the effects of fentanyl on reward processing. These results are from male participants' data and therefore may not be generalisable to female participants.

Rationale: Two prominent neurobiological models of addiction, the allostatic and incentive-sensitization models, have guided clinical research on alcohol use disorder (AUD). While these models are often viewed in isolation, it is plausible these theories are complimentary.

Objectives: Use naturalistic, daily diary reports to determine whether positive and negative mood states influence alcohol cue sensitivity in a clinical sample with AUD.

Methods: This is an exploratory analysis of daily diary data collected from a non-treatment seeking sample with current AUD over two weeks. Eligible adult participants (N = 50) were enrolled in a medication trial for AUD. Each morning, participants retrospectively reported on pre-drinking mood states, alcohol cue exposure, and craving levels, and subsequent alcohol intake occurring the previous day. Multilevel models tested the singular and interactive relationships between cue exposure and mood states with craving and drinking. Within-person and between-person outcomes were assessed. Exploratory analyses examined whether individuals with withdrawal-related dysphoria were more vulnerable to mood states and cue-reactivity.

Results: Greater cue exposure was associated with higher daily drinking levels (p = .001), but not daily alcohol craving. Higher negative mood (p < .0001) and lower positive mood (p = .012) were associated with higher daily alcohol craving, but not same-day drinking. As negative mood levels increased (p < .01) and positive mood levels decreased (p = .010), the relationship between cue exposure and same-day drinking became stronger. These findings were most pronounced among those with withdrawal-related dysphoria.

Conclusions: Findings provided concomitant support for the allostatic model and incentive-sensitization model as determinants of alcohol craving and drinking among individuals with AUD.

Medications for opioid use disorder (OUD) and overdose have been available for decades, yet nearly 70% of fatal drug overdoses in the United States are attributed to the opioid receptor agonist fentanyl and its analogs. There is a pressing need for more and better medications that reduce fentanyl use and prevent overdose. A humanized (h) monoclonal antibody (mAb) targeting fentanyl, hHY6-F9, was tested for attenuating intravenous fentanyl self-administration and reversing and preventing fentanyl-induced ventilatory depression in rhesus monkeys. A single administration of hHY6-F9 significantly decreased fentanyl, but not heroin or cocaine, self-administration. In some monkeys, fentanyl self-administration remained decreased for ~ 2 weeks. hHY6-F9 was as effective as 32 µg/kg naloxone in reversing fentanyl-induced ventilatory depression, with a single administration protecting against fentanyl-induced ventilatory depression for 2-3 weeks. Moreover, pharmacokinetic analyses indicate that hHY6-F9 continued to sequester fentanyl in the serum for 2 weeks. This study demonstrates that hHY6-F9 selectively attenuates the positive reinforcing and ventilatory depressant effects of fentanyl, indicating its possible utility for preventing relapse and overdose.