Psychopharmacology最新文献

Background: The endocannabinoid system, which regulates fear- and anxiety-related behaviors, is dysregulated in adults with posttraumatic stress disorder (PTSD), as indicated by higher circulating anandamide (AEA) concentrations. The C385A (rs324420) polymorphism in the fatty acid amide hydrolase (FAAH) gene, which catabolizes AEA, is linked to higher AEA concentrations and greater PTSD symptoms in adults. Given that adolescence is a critical period during which trauma and psychiatric disorders emerge, understanding this relationship in youth is essential. This study examines PTSD symptoms, AEA concentrations, and FAAH genotype in a diverse adolescent sample.

Methods: This study included 102 Detroit-area adolescents (M ± SD = 13.33 ± 2.21 years, 54.9% female) and their parents/guardians. The sample consisted of 40.2% White Non-Hispanic, 34.3% Black Non-Hispanic, 6.9% White Hispanic, 4.9% Asian/Pacific Islander, and 12.7% Biracial adolescents. Trauma exposure and PTSD symptoms were assessed using the UCLA PTSD Reaction Index for DSM-5. Plasma concentrations of AEA were measured by liquid chromatography-tandem mass spectrometry, and FAAH genotype was determined from saliva samples and high-throughput screening.

Results: The majority (90%) of adolescents reported trauma exposure, and 20% met PTSD criteria. Higher AEA concentrations were associated with more severe PTSD symptoms (p = 0.009), especially hyperarousal. The FAAH A-allele (present in 52.5% of participants) was associated with higher AEA concentrations (2.11 ± 0.69 pmol/ml, p = 0.013) and greater PTSD severity (22.65 ± 15.931, p = 0.027), particularly those with the reexperiencing cluster, compared to the CC genotype (1.79 ± 0.66 pmol/ml and 15.87 ±+ 13.043, respectively).

Conclusion: Elevated AEA concentrations and the FAAH A-allele were associated with greater PTSD symptom severity in urban adolescents. These findings suggest endocannabinoid dysregulation may play a role in adolescent PTSD, highlighting the need for further research and targeted interventions.

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: Anticipation is a critical antecedent to drug use, in which the prospect of imminent drug availability can potently motivate instrumental actions directed to procure it. Models that capture the behavioral dynamics that precede drug access may allow for the dissociation of key neural mechanisms underlying appetitive or consummatory processes in drug self-administration.

Objectives: We aimed to isolate measurements attributed to the procurement and consumption of a reward by defining distinct actions for each using a chain-schedule of reinforcement.

Methods: Male Long-Evans rats were trained to self-administer cocaine or saccharin under a chained schedule of reinforcement (FI-FR) in order to dissociate appetitive ('seeking') from consummatory ('taking') behaviors. Completion of a fixed-interval (5 min) was followed by 5 min of continuously reinforced responding (FR1) on another lever.

Results: The FI-FR chain procedure appears to provide sensitive and dissociable dimensions of cocaine self-administration within a single experimental session. Importantly, we demonstrate that responding during the FI (i.e., seeking) link tracks with the incentive value of anticipated reward access - whereby response rates corresponded to expected reward magnitude, degree of reward-specific satiety, and general motivational state.

Conclusions: The FI component is a sensitive and reliable index of motivational changes induced by either the extrinsic incentive value of reinforcement (i.e., anticipated dose) or intrinsic motive states (i.e., satiety or deprivation). This procedure provides a valuable tool for interrogating the neural dynamics of drug-seeking and -taking behavior, in isolation.

Rationale: Chronic cannabis users frequently report stress relief as their primary reason for use. The endocannabinoid system is involved in the neuroendocrine stress response, and diurnal cortisol rhythms may be disrupted in chronic cannabis users.

Objectives: The objectives were to determine whether cannabis users demonstrate disruptions in diurnal stress rhythms and examine the acute effects of cannabis on stress-related outcomes in cannabis users' natural environments.

Methods: Eighty-two participants (39 cannabis users, 43 non-users) collected saliva samples to quantify cortisol concentrations and provided subjective stress ratings at 8 time points throughout the day. They wore a medical-grade wearable device for 24 h that recorded physiological indicators of stress (heart rate variability, electrodermal activity). Cannabis users collected additional saliva samples before and after cannabis use to examine acute effects of cannabis use.

Results: Cannabis users exhibited significant dysregulations in diurnal cortisol rhythms, including a blunted cortisol awakening response, flattened diurnal cortisol slope, and elevated afternoon cortisol concentrations. There were no differences in diurnal heart rate variability or electrodermal activity except for elevated evening heart rate in cannabis users. Finally, there were significant decreases in cortisol, subjective stress, and electrodermal activity following acute cannabis use in cannabis users' natural environment.

Conclusions: These results provide evidence of dysregulated diurnal cortisol rhythms in cannabis users that were related to later waking times and acute stress-relieving properties of cannabis use in naturalistic environments. Future research should examine the direction of the relationship between cannabis use and diurnal cortisol rhythms and potential implications for other psychological disorders.

Rationale: The effect of caffeine mouth rinsing (CAF-MR) on cognitive performance has not been thoroughly investigated.

Objectives: To evaluate the effects of different concentrations of CAF-MR on selective attention in relation to perceived taste intensity.

Methods: A total of 30 healthy and recreationally active male subjects were included in this randomized, double-blind, placebo-controlled crossover trial. Interventions included MR for 20 s at rest with three different caffeine solutions (0.24% [60 mg/25 mL], 0.6% [150 mg/25 mL], and 1.2% [300 mg/25 mL]), MR with 25 mL water (placebo), and no MR (control). Data on Victoria Stroop Test (VST) and the perceived taste intensity were recorded at five sessions.

Results: CAF-MR-300 mg intervention significantly decreased completion time (from 62.93 ± 19.07 to 57.01 ± 16.74 s, p = 0.002 in Part D), while CAF-MR-150 mg intervention significantly decreased number of errors in Part D (7.00 ± 6.21 vs. 5.63 ± 5.76, p = 0.04) and Part C (8.77 ± 8.80 vs. 7.10 ± 7.11, p = 0.02). Perceived difficulty was significantly decreased both after CAF-MR with 150 mg (5.57 ± 1.65 vs. 4.77 ± 1.98, p = 0.006) and 300 mg (5.95 ± 1.77vs. 4.67 ± 1.96, p < 0.001). Perceived taste intensity for 300 mg of caffeine was negatively correlated with completion time (r: ranged, 0.37 to 0.46, p ranged, 0.045 to 0.009) after 300 mg, 150 mg (p ranged, 0.04 to 0.005) and placebo (p ranged 0.044 to 0.03) interventions.

Conclusions: This study is the first to demonstrate that CAF-MR shows dose-dependent effects on selective attention in healthy recreational males, such as improved speed (for 300 mg caffeine), reduced error rate (for 150 mg caffeine) and decrease in perceived difficulty (for 150 and 300 mg caffeine).

Rationale: The Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) classifies attention deficit hyperactivity disorder (ADHD) as a neurodevelopmental disorder that interferes with human functioning and development. As the clinical presentation of ADHD involves a deficiency in executive function, neurocognitive deficits involving distinctive neuropathological changes must be present for clinical diagnosis.

Objectives: The vesicular monoamine transporter (VMAT), specifically VMAT-2, plays a role in ADHD pathogenesis. In addition, experimental data show that the stimulants (amphetamines and methylphenidate) are first-line treatments for the condition because of their extensive interaction with VMAT-2. The interactions of peptides, bupropion, and nutritional supplements with VMAT-2 receptors have been researched, but more evidence is needed to elucidate their pharmacodynamic properties. Therefore, this literature review evaluated the current pharmacological treatment modalities, peptides, and nutritional supplements for ADHD that target the VMAT-2 system.

Methods, results, and conclusions: We obtained relevant studies from several platforms, including the National Center for Biotechnology, Clinical Key, Access Medicine, and PubMed. From the results of these studies, we observed that stimulants interact highly with the VMAT-2 transporter, with omega-3 fatty acids, peptides, and bupropion exerting some modulatory activity on VMAT-2. These agents should be considered for the future treatment of ADHD, although clinical-level research involving human participants is necessary.

Rationale: Flavors can alter the orosensory properties of tobacco products. Specifically, flavors can serve as an oral cue for smokeless tobacco products.

Objectives: We aimed to investigate the impact of oral vanillin, the principal chemical of vanilla flavor in tobacco products, on nicotine's taste, and nicotine choice, intake, and seeking behaviors.

Methods: Experiments were performed in young adult Sprague Dawley rats. We employed a two-bottle free-choice test (2BC) to measure the preference for different concentrations of vanillin and its effect on nicotine preference. To explore the long-term effects of early exposure to sweetened vanillin, we utilized a combined 2BC and intraoral self-administration (IOSA) model. We assessed the nicotine taking and seeking behaviors in the presence or absence of vanillin. We performed a taste reactivity test (TRT) to quantify liking (ingestive) and disliking (aversive) taste responses to oral nicotine with or without vanillin.

Results: In 2BC, female rats preferred vanillin containing solutions more than their male counterparts. In IOSA, vanillin alone and in combination with nicotine led to greater IOSA compared to water. Female rats self-administered vanillin plus nicotine more than male rats. Vanillin increased motivation to nicotine taking, but only in females. In TRT, vanillin increased nicotine's ingestive responses but blocked aversive responses in both sexes.

Conclusions: These results indicate that vanilla flavor can increase oral nicotine intake. It can also increase liking and decrease disliking of nicotine's taste. Furthermore, the impact of vanilla flavor on nicotine taste and nicotine choice, intake, and seeking behaviors is concentration and sex dependent.

Rationale: Neuroinflammation may inhibit oligodendrocyte and astrocyte differentiation, which causes demyelination and synaptic degeneration. The myelin component nervonic acid (NA) may improve demyelinating and neurodegenerative diseases.

Objectives: This study firstly explored relationships between glial cell dysfunction and demyelination or synaptic degeneration in schizophrenia patients, and secondly determined nervonic acid therapeutic effects in a preclinical schizophrenia model of mice.

Methods: Plasma samples were collected from 18 male healthy controls and 18 male schizophrenic patients (diagnosed by DSM-V) at aged 18-55. Mouse brain samples were collected from a maternal immune activation (MIA) model of schizophrenia via injecting 5 mg/kg polyinosinic-polycytidylic acid. Male mouse offspring (age 2.5 months, n = 12) were treated by clozapine (15 mg/kg/day) or fed 0.5% NA for 6 weeks. Cytokine and dopamine (DA) concentrations, and glial phenotypes and myelin markers were measured in both human plasma and mouse brain samples.

Results: In patient plasma, increased proinflammatory cytokines were associated with reactive microglia (Iba-1) up-regulation, while decreased anti-inflammatory cytokines were related to microglia (CD206) downregulation. Decreased astrocyte marker (p11) concentrations were accompanied by reduced concentrations of oligodendrocyte and synaptic markers. However, NA and DA contents were increased. Compared with control mice, SZ-like behaviors appeared in MIA male mice. Changes in microglia and astrocytes markers, and cytokine concentrations in the frontal cortex were consistent with those observed in patients' plasma. Hippocampal oligodendrocyte and synaptic marker expression were also decreased. DA content and DA/metabolite (DAPOC) were increased in MIA mouse brains. Most of these changes were normalized by both clozapine and NA. Even though some NA effects were more pronounced than clozapine, only clozapine restored cytokine function.

Conclusion: The data suggest a possible therapeutic route for schizophrenia patients.

Rationale: Cocaine use disorder (CUD) is a brain disorder for which there is no Food and Drug Administration-approved pharmacological treatment. Evidence suggests that glutamate and metabotropic glutamate receptor subtype 5 (mGlu5) play critical roles in synaptic plasticity, neuronal development, and psychiatric disorders.

Objective: In the present study, we tested the hypothesis that the mGlu5 receptor is functionally involved in intravenous cocaine self-administration and assessed the effects of sex and cocaine exposure history.

Methods: We used a preclinical model of CUD in rats that were allowed long access (LgA; 6 h/day) or short access (ShA; 1 h/day) to intravenous cocaine (750 µg/kg/infusion [0.1 ml]) self-administration. Rats received acute intraperitoneal or oral administration of the mGlu5 receptor negative allosteric modulator mavoglurant (1, 3, and 10 mg/kg) or vehicle.

Results: Both intraperitoneal and oral mavoglurant administration dose-dependently reduced intravenous cocaine self-administration in the first hour and in the entire 6 h session in rats in the LgA group, with no effect on locomotion. In the ShA group, mavoglurant decreased locomotion but had no effects on cocaine self-administration. We did not observe significant sex × treatment interactions.

Conclusions: These findings suggest that the mGlu5 receptor is involved in escalated cocaine self-administration. These findings support the development of clinical trials of mavoglurant to evaluate its potential therapeutic benefits for CUD.

Rationale: Early-life maternal separation can lead to anxiety-like and depression-like behaviors in mice reared under maternal separation conditions. Scopoletin, a compound with anti-inflammatory and antidepressant properties, may offer therapeutic benefits, but its effectiveness against behaviors induced by maternal separation during adulthood remains unexplored.

Objectives: This study investigates scopoletin's efficacy in alleviating anxiety-like and depression-like phenotypes in male mice subjected to early-life maternal separation.

Methods: Male C57BL/6J mice experienced daily maternal separation for 4 h from postnatal day (PND) 2 to 21. From postnatal day 61(PND 61), scopoletin was administered intraperitoneally at 20 mg/kg/day for four weeks. Behavioral and biochemical assessments were conducted at postnatal day 95 (PND 95).

Results: Maternally separated mice displayed marked anxiety-like and depression-like behaviors, evident in behavioral tests like the open field and elevated plus maze. These mice also showed increased immobility in the forced swimming and tail suspension tests. Biochemically, there were elevated levels of IL-1β, IL-6, and TNF-α in the hippocampus, with a decrease in Sirt1 and upregulation in NF-κB p65 expression. Scopoletin treatment significantly mitigated these behavioral abnormalities, normalizing both anxiety-like and depression-like behaviors. Correspondingly, it reduced the levels of pro-inflammatory cytokines and reinstated the expression of Sirt1 and NF-κB p65.

Conclusions: Scopoletin effectively reverses the adverse behavioral and biochemical effects induced by early-life maternal separation in male mice, suggesting its potential as a therapeutic agent for treating anxiety-like and depression-like behaviors. Modulation of neuroinflammatory pathways and the Sirt1/NF-κB signaling axis is one possible mechanism.