Psychopharmacology最新文献

Rationale: Despite decades of research and medical development, relapse to drug seeking continues to be a significant challenge in the treatment of substance use disorders. GABA_B receptor (GABA_B-R) agonists have been shown preclinically to inhibit relapse by acting on midbrain dopamine (DA) neurons and are sometimes used off-label for the treatment of alcohol use disorder. Studies in rodent models show reduced GABA_B-R signaling in DA neurons after exposure to stimulants. Similarly, our recent data demonstrated reduced GABA_B-R currents in DA neurons during prolonged abstinence from fentanyl vapor self-administration (SA). However, the mechanism of opioid-induced changes in GABA_B-R currents is not well understood. In addition, GABA_B-R agonists are plagued with a plethora of side effects limiting their potential clinical use.

Objectives: In this study we aimed to answer the following questions: first, can we use GABA_B-R positive allosteric modulators (PAMs) to inhibit relapse to opioid seeking? Secondly, how do opioids result in reduced GABA_B-R signaling during prolonged abstinence?

Approach: To this end, we tested the effects of a novel GABA_B-R PAM (KK-92A) on reinstatement of drug seeking in a rat model of intravenous (IV) fentanyl SA. Using in situ hybridization with RNAscope, we examined the effects of opioids on mRNA levels of various genes involved in GABA_B-R signaling, in two rodent models of opioid addiction including a rat model of IV fentanyl SA and a mouse model of fentanyl vapor SA.

Results: Our results show that KK-92A inhibits relapse to fentanyl but not sucrose-seeking in rats, and fentanyl SA results in reduced mRNA levels of the G protein-coupled inwardly rectifying potassium channel subtypes 2 and 3 (GIRK_2/3).

Conclusion: These findings suggest that PAMs like KK-92A are a potential therapeutic strategy for opioid use disorder and their effect is likely due to rectifying GABA_B-R mediated inhibition of midbrain DA neurons, which is reduced after opioid SA due to reduced GIRK_2/3 expression.

Introduction: Enhanced creativity is often cited as an effect of microdosing (taking repeated low doses of a psychedelic drug). There have been recent efforts to validate the reported effects of microdosing, however creativity remains a difficult construct to quantify.

Objectives: The current study aimed to assess microdosing's effects on creativity using a multimodal battery of tests as part of a randomised controlled trial of microdosing lysergic acid diethylamide (LSD).

Methods: Eighty healthy adult males were given 10 µg doses of LSD or placebo every third day for six weeks (14 total doses). Creativity tasks were administered at a drug-free baseline session, at a first dosing session during the acute phase of the drug's effects, and in a drug-free final session following the six-week microdosing regimen. Creativity tasks were the Alternate Uses Test (AUT), Remote Associates Task (RAT), Consensual Assessment Technique (CAT), and an Everyday Problem-Solving Questionnaire (EPSQ).

Results: No effect of drug by time was found on the AUT, RAT, CAT, or EPSQ. Baseline vocabulary skill had a significant effect on AUT and RAT scores.

Conclusions: Despite participants reporting feeling more creative on dose days, objective measurement found no acute or durable effects of the microdosing protocol on creativity. Possible explanations of these null findings are that laboratory testing conditions may negatively affect ability to detect naturalistic differences in creative performance, the tests available do not capture the facets of creativity that are anecdotally affected by microdosing, or that reported enhancements of creativity are placebo effects.

Rationale: Adolescent cannabis use is linked to later-life changes in cognition, learning, and memory. Rodent experimental studies suggest Δ⁹-tetrahydrocannabinol (THC) influences development of circuits underlying these processes, especially in the prefrontal cortex, which matures during adolescence.

Objective: We determined how 14 daily THC injections (5 mg/kg) during adolescence persistently impacts medial prefrontal cortex (mPFC) dopamine-dependent cognition.

Methods: In adult Long Evans rats treated as adolescents with THC (AdoTHC), we quantify performance on two mPFC dopamine-dependent reward-based tasks-strategy set shifting and probabilistic discounting. We also determined how acute dopamine augmentation with amphetamine (0, 0.25, 0.5 mg/kg), or specific chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons and their projections to mPFC impact probabilistic discounting.

Results: AdoTHC sex-dependently impacts acquisition of cue-guided instrumental reward seeking, but has minimal effects on set-shifting or probabilistic discounting in either sex. When we challenged dopamine circuits acutely with amphetamine during probabilistic discounting, we found reduced discounting of improbable reward options, with AdoTHC rats being more sensitive to these effects than controls. In contrast, neither acute chemogenetic stimulation of VTA dopamine neurons nor pathway-specific chemogenetic stimulation of their projection to mPFC impacted probabilistic discounting in control rats, although stimulation of this cortical dopamine projection slightly disrupted choices in AdoTHC rats.

Conclusions: These studies confirm a marked specificity in the cognitive processes impacted by AdoTHC exposure. They also suggest that some persistent AdoTHC effects may alter amphetamine-induced cognitive changes in a manner independent of VTA dopamine neurons or their projections to mPFC.

Rationale: Zuranolone is an oral positive allosteric modulator of GABA_A receptors. Due to its central nervous system (CNS) activity, zuranolone may impact activities requiring complex cognition, including driving.

Objective: Evaluate the effect of zuranolone on simulated driving performance.

Methods: In this randomized, double-blind, active- and placebo-controlled, four-period crossover study, treatments included once-nightly zuranolone 50 mg on days 1-7, zuranolone 50 mg on days 1-6 and zuranolone 100 mg on day 7, zopiclone 7.5 mg on days 1 and 7, and placebo on days 1-7. Driving was assessed using a validated simulator. Primary endpoint was standard deviation of lateral position (SDLP), evaluated 9 h post-dose on days 2 and 8. Secondary endpoints included additional driving assessments, cognitive tests, pharmacokinetics, and safety.

Results: Healthy adults (N = 67) enrolled and received ≥ 1 dose. Zuranolone 50 mg increased SDLP versus placebo on days 2 (least squares mean difference [LSMD]: 7.4 cm; p < 0.0001) and 8 (LSMD: 4.6 cm; p = 0.0106). Zuranolone 100 mg evoked a larger increase in SDLP versus placebo on day 8 (LSMD 18.9 cm; p < 0.0001). Reduced performance in other driving assessments and cognition were observed with zuranolone 50 mg on day 2; many resolved by day 8. Despite the SDLP observations, most participants judged themselves capable of driving. Frequent adverse events (≥ 20%) were CNS-related; most were mild/moderate.

Conclusion: Zuranolone impaired simulated driving and reduced cognitive function versus placebo 9 h after administration. Although many impairments resolved after 7 days of dosing, driving remained impaired. These results may inform prescriber decision-making.

Rationale: positive social interactions are essential for mental health, by offering emotional support, reducing stress levels, and promoting resilience against drugs of abuse effects. However, not all individuals perceive social interaction as rewarding.

Objectives: the goal of this study was to investigate whether the modulation of the orexin system can shift passive coping and non-social behavior (vulnerable) to active coping and social behavior (resilient). This knowledge is primordial for stress- and addiction-related disorders, and for other psychiatric disorders involving impairment in social interaction.

Methods: male C57/BL6N mice categorized into social and non-social groups, received injections of SB334867, a selective orexin 1 receptor (OX1R) antagonist, before the conditioning sessions with a male conspecific of the same weight and age.

Results: our results from the conditioned place preference test (CPP) show that SB334867 has no effect on social preference in non-social mice, but it reduces their stress levels and depression-like behavior. These effects appear to be due to a higher OX1R expression in the basolateral amygdala (BLA), a stress-related brain area, of non-social mice compared to their social counterparts.

Conclusions: these data suggest that the orexin system may be a target to alleviate stress and depression-like behavior in non-social individuals rather than to promote social reward.

Rationale: Anecdotal reports suggest that psychedelic drugs can improve psychological wellbeing and social engagement in autistic people. However, there are few contemporary studies on this topic.

Objectives: To examine autistic participants' experiences with psychedelic drugs and the extent to which they attributed changes in mental health and social engagement to their most 'impactful' psychedelic experience. We also explored associations between these changes and mechanistically important variables (e.g., aspects of the acute psychedelic experience and changes in 'psychological flexibility').

Methods: Self-selecting autistic participants (n = 233) with high autism quotient scores completed an online survey relating to their most impactful psychedelic experience. Questionnaires assessed the acute psychedelic experience and perceived psychedelic-induced changes in distress, social engagement and psychological flexibility, among other relevant variables.

Results: The majority of participants attributed reductions in psychological distress (82%) and social anxiety (78%) and increases in social engagement (70%) to their most 'impactful' psychedelic experience. A substantial minority (20%) also reported undesirable effects such as increases in anxiety with some describing their psychedelic experience as among the most negatively impactful experiences of their lives. The only substantial predictor of reductions in psychological distress was increased psychological flexibility.

Conclusion: Autistic people attributed changes in mental health and social engagement to a single highly impactful psychedelic experience. The results and their implications are discussed with caution considering the use of a non-experimental design and biased sampling.

Background: Previous studies have reported conflicting findings regarding the efficacy of esketamine in managing postoperative depression. While the positive effects of subanesthetic doses esketamine have been observed in treatment-resistant depression, the response to this medication in patients experiencing depression following surgery has not been consistent. Building upon the known impact of anesthesia on brain function, we have formulated a hypothesis suggesting that the timing of esketamine administration in relation to anesthesia may significantly affect its efficacy in managing postoperative depression. The aim of this study was to investigate the effect of esketamine administered at different time points before and after anesthesia.

Methods: Our randomized, double-blind, controlled study involved 120 patients undergoing laparoscopic bariatric surgery, randomly divided into three groups. Group Post- ESK received an intravenous injection of esketamine at a dose of 0.2 mg/kg after anesthesia induction. Group Pre- ESK received the same esketamine dosage 2 h prior to anesthesia induction. Group Placebo served as the control group and received a 0.9% saline solution after induction. The primary outcome measures of the study were depression scores as measured by Patient Health Questionnaire-9 (PHQ-9) and plasma brain-derived neurotrophic factor (BDNF) levels.

Results: On the first postoperative day, the PHQ-9 scores, incidence and severity of postoperative depression in the Pre-ESK group were significantly lower than those in the Post-ESK and placebo groups (P < 0.05). Additionally, plasma BDNF levels in the Pre-ESK group were significantly higher than those in the Post-ESK and placebo groups (P < 0.05). Notably, there was a negative correlation between PHQ-9 scores and plasma BDNF levels.

Conclusions: Our study supports the potential for subanesthetic dose esketamine to alleviate postoperative depression symptoms following laparoscopic bariatric surgery, and anesthetic drugs have a significant effect on its efficacy. The use of subanesthetic dose esketamine after anesthesia does not improve postoperative depression symptoms in patients undergoing laparoscopic bariatric surgery, while the use of sub-anesthetic dose esketamine before anesthesia can improve postoperative depression symptoms.

Rationale: In the socially transmitted food preference (STFP) paradigm, rats change their preference for food rewards after socially interacting with a conspecific who has been fed with the originally non-preferred food. Here, we asked if oxytocin (OXT), a neuropeptide known for its role in social affiliation and social behavior, plays a role in STFP. Since OXT's influences on social behavior can be familiarity-dependent, we further asked if OXT effects on STFP are moderated by the familiarity between rats.

Objectives: Does OXT modulate rats' socially transmitted food choices in a familiarity-dependent way.

Methods: We systemically injected either vehicle, low-dose (0.25 mg/kg) of OXT, or large-dose (1.0 mg/kg) of OXT before social interaction with either a familiar cagemate (in-group) or an unfamiliar conspecific from a different cage (out-group).

Results: We found an intergroup bias in STFP: vehicle-treated rats showed larger socially transmitted changes in food preference in the out-group than the in-group condition. OXT modulated STFP in a familiarity-dependent way: OXT prevented the increase in the consumption of the non-preferred food in the out-group, and decreased the consumption of the preferred food in the in-group. These effects were dose-dependent and observed under acute OXT action, but also on the subsequent day when acute OXT effects dissipated, suggesting long-lasting social learning effects of OXT. Additional analyses suggest that the familiarity and dose-dependent effects of OXT on STFP cannot be attributed to OXT's anorexic actions or differences in the duration of the social interactions.

Conclusions: OXT modulates STFP in a familiarity-dependent way.

Rationale: Both the paraventricular nucleus of the thalamus (PVT) and the neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), are thought to be involved in food intake. Importantly, PACAP is expressed in cells of the PVT.

Objectives: To determine if PACAP in cells of the PVT might mediate some of the involvement of the PVT with palatable food intake.

Methods: In male and female C57BL/6 J mice and PACAP-Cre transgenic mice on a C57BL/6 J background, limited access to Milk Chocolate Ensure Plus® was used to establish a model of binge-type eating. Next, using quantitative real-time PCR, gene expression of PACAP in the PVT was measured in relation to this binge-type eating. Finally, using chemogenetics in PACAP-Cre transgenic mice, the effect of activation of PVT PACAP⁺ cells on binge-type eating was determined.

Results: Males and females both engaged in binge-type eating with Ensure, although females engaged in this behavior to a greater degree than males. While females also had a higher baseline level of PVT PACAP mRNA than males, only males showed an increase in levels of PACAP after a history of exposure to Ensure, and only males showed a reduction in levels of PACAP immediately prior to a binge session. Conversely, activation of PACAP⁺ cells in the PVT reduced binge-type eating of Ensure, specifically in male mice.

Conclusions: The present findings indicate that PVT PACAP⁺ cells influence and are influenced by binge-type eating. Thus, PACAP in the PVT might mediate some of the known involvement of the PVT with palatable food intake.

Rationale & objectives: A core symptom of alcohol use disorder (AUD) is a progressively increased choice of alcohol over alternative rewards despite negative consequences. Here, we investigated choice between personalized alcohol vs. natural rewards in a laboratory setting, and compared this behavior between non-treatment-seeking heavy drinkers and light social drinkers.

Methods: 30 light social drinkers (15 men drinking < 15 drinks/week and 15 women drinking < 10 drinks/week) and 30 heavy, non-treatment-seeking drinkers (drinking more than these levels; 15 women). In the Concurrent Choice Alcohol Food (CCAF) task, participants chose between individually tailored images of alcohol and snack rewards and collected points towards the respective reward. To assess cost sensitivity, points associated to the images varied so that they favored alcohol or snack, or were equal, creating three relative point levels.

Results: Choice preference for alcohol was strongly correlated with Alcohol Use Disorder Identification Test (AUDIT) scores, supporting the external validity of the choice procedure. Compared to light drinkers, heavy drinkers showed increased choice preference for alcohol, as indicated by a between-group difference in points of subjective equality, a metric that quantifies the relative point level at which alcohol and snacks were equally likely to be chosen. In both groups, choice preference strongly depended on the relative point level of alcohol compared to snacks, suggesting that responding for alcohol in heavy drinkers was sensitive to costs.

Conclusions: Our results replicate previous findings of a relationship between self-reported alcohol use and choice preference for alcohol. We also found that choice behavior was strongly dependent on relative cost of alcohol in both groups, although price sensitivity was lower in heavy compared to light drinkers. An increased choice preference for alcohol in heavy drinkers suggests that they attribute a higher relative reinforcing value to alcohol compared to natural rewards.