Psychopharmacology最新文献

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.

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 & 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.

Rationale: Alzheimer's disease (AD), an age-dependent devastating neuropsychiatric disorder, is a leading cause of learning, memory and intellectual disabilities. Current therapeutic approaches for the amelioration of the anomalies of AD are not effective.

Objective: In the present study, the molecular mechanisms underlying sporadic AD (sAD), the memory related behavioral analysis and neuroprotective effects of Ellagic acid (EA) were investigated.

Method: sAD mouse model was developed by intracerebroventricular (ICV) injection of Streptozotocin (STZ). The efficacy of EA, a naturally occurring polyphenol, in amelioration of anomalies associated with sAD was assessed. EA was administered once daily for 28 days at a dose of 75 mg/kg body weight followed by neurobehavioral, biochemical, molecular and neuronal count analysis to delineate the mode of action of EA.

Result: The ICV injection of STZ in mice significantly increased the expression of AD biomarkers in addition to enhanced oxidative stress. A decline in the discrimination index in Novel Object Recognition Test was observed indicating the compromise of recognition memory in AD. Studies on the expression of genes involved in synaptic plasticity reveal the dysregulation of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) of the glutamate and its scaffolding proteins in the postsynaptic density and thereby synaptic plasticity in AD. ICV-STZ led to significant upregulation of apoptotic markers which led to decrease in neuronal density of the cerebral cortex. EA significantly reversed the above and improved anomalies of sAD.

Conclusion: EA was observed to profoundly modulate the genes involved in AD pathophysiology, restored antioxidant enzymes activity, reduced lipid peroxidation and neuronal loss in the sAD brain. Further, EA was observed to effectively modulate the genes involved in apoptosis and synaptic plasticity. Therefore, EA possesses promising anti-AD properties, which may improve AD-associated anomalies by modulating synaptic plasticity via AMPAR signaling.

Rationale: Stress during childhood or adolescence increases vulnerability to psychiatric disorders in adults. In adult rodents, the delayed effects of stress can increase anxiety-like behavior. These effects, however, can be prevented with post-stress administration of corticosterone (CORT). The effectiveness of CORT in preventing adolescent stress-induced emotional behavior alterations in adulthood has yet to be investigated.

Objectives: Here, we investigated the interactions between early adolescent stress and exogenous corticosterone on adult social, aversive, and drug-seeking behavior in mice, which are translationally related to symptoms associated with psychiatric and substance abuse disorders.

Methods and results: A single administration of CORT in drinking water (400ug/mL) for 24 h after social defeat or context fear conditioning prevents defeat-induced social avoidance, alters fear processing, prevents adolescent stress-induced anhedonia, and prevents stress-potentiated morphine place preference in adulthood. Exogenous CORT did not immediately prevent stress-induced potentiation of morphine conditioned-place preference in adolescents but did so in adult mice. However, when administered to adolescent mice, CORT also prevented the incubation of morphine-conditioned place preference into adulthood. Lastly, exogenous CORT administration blunted endogenous corticosterone but was unrelated to freezing behavior during a fear test.

Conclusions: This is the first demonstration of adolescent post-stress CORT promoting socio-emotional resilience and preventing drug-seeking behavior. Our data suggest elevated corticosterone after a stress experience promotes resilience for at least 40 days across the developmental transition from adolescence to adulthood and is effective for socio-emotional and drug-seeking behavior. These results are critical for understanding how adolescent stress impacts emotional and drug-seeking behavior into adulthood.

Rationale: Motivational dysfunctions related to effort exertion are common in psychiatric disorders. Dopamine systems regulate exertion of effort and effort-based choice in humans and rodents.

Objectives: Previous rodent studies mainly employed male rats, and it is imperative to conduct studies in male and female rats.

Methods: The present studies compared the effort-related effects of IP injections of the dopamine antagonists ecopipam and haloperidol, and the vesicular monoamine transport-2 inhibitor tetrabenazine (TBZ), in male and female rats using the fixed ratio 5/chow feeding choice task.

Results: Ecopipam (0.05-0.2 mg/kg) and haloperidol (0.05-0.15 mg/kg) induced a low-effort bias, decreasing lever pressing and increasing chow intake in males and females in the same dose range. With lever pressing, there was a modest but significant dose x sex interaction after ecopipam injection, but there was no significant interaction after administration of haloperidol. In the first study with TBZ (0.25-1.0 mg/kg), there was a robust sex difference. TBZ shifted choice from lever pressing to chow intake in male rats, but was ineffective in females. In a second experiment, 2.0 mg/kg affected choice behavior in both males and females. TBZ increased accumbens c-Fos immunoreactivity in a sex-dependent manner, with males significantly increasing at 1.0 mg/kg, while females showed augmented immunoreactivity at 2.0 mg/kg.

Conclusions: The neural and behavioral effects of TBZ differed across sexes, emphasizing the importance of conducting studies in male and female rats. This research has implications for understanding the effort-related motivational dysfunctions seen in psychopathology.

Rationale: Muscarinic receptor activity in the basolateral amygdala (BLA) is known to be involved in plasticity mechanisms that underlie emotional learning. The BLA is involved in the Attenuation of Neophobia, an incidental taste learning task in which a novel taste becomes familiar and recognized as safe.

Objective: Here we assessed the role of muscarinic receptor activity in the BLA in incidental taste learning.

Methods: Young adult male Wistar rats were bilaterally implanted with cannulas aimed at BLA. After recovery, rats were randomly assigned to either vehicle or muscarinic antagonist group, for each experiment. We tested the effect of specific and non-specific muscarinic antagonists administered either 1) 20 min before novel taste presentation; 2) immediately after novel taste presentation; 3) immediately after retrieval (the second taste presentation on Day 5 -S2-) or immediately after the fifth taste presentation on Day 8 (S5).

Results: Non-specific muscarinic receptor antagonist scopolamine infused prior to novel taste, while not affecting novel taste preference, abolished AN, i.e., the increased preference observed in control animals on the second presentation. When administered after taste consumption, intra-BLA scopolamine not only prevented AN but caused a steep decrease in the taste preference on the second presentation. This scopolamine-induced taste avoidance was not dependent on taste novelty, nor did it generalize to another novel taste. Targeting putative postsynaptic muscarinic receptors with specific M1 or M3 antagonists appeared to produce a partial taste avoidance, while M2 antagonism had no effect.

Conclusion: These data suggest that if a salient gustatory experience is followed by muscarinic receptors antagonism in the BLA, it will be strongly and persistently avoided in the future. The study also shows that scopolamine is not just an amnesic drug, and its cognitive effects may be highly dependent on the task and the structure involved.

Rationale: Recent reports have shown increased cannabis use among women, leading to growing concerns about cannabis use disorder (CUD). While there is preclinical evidence suggesting biological sex influences cannabinoid effects, human research remains scant. We investigated sex differences in the acute response to oral tetrahydrocannabinol (THC) in humans.

Methods: 56 healthy men and women with prior exposure to cannabis but no history of CUD participated in a randomized, placebo-controlled, human laboratory study where they received a single 10 mg dose of oral THC (dronabinol). Subjective psychoactive effects were assessed by the visual analog scale of "high", psychotomimetic effects by the Clinician-Administered Dissociative Symptoms Scale and Psychotomimetic States Inventory, verbal learning and memory by Rey Auditory Verbal Learning Test (RAVLT), and physiological effects by heart rate. Outcomes were regularly measured on the test day, except for the RAVLT, which was assessed once. Peak differences from baseline were analyzed using a nonparametric method for repeated measures.

Results: Oral THC (10 mg) demonstrated significant dose-related effects in psychotomimetic and physiological domains, but not in RAVLT outcomes. A notable interaction between THC dose and sex emerged concerning the subjective "high" scores, with women reporting heightened sensations (p = 0.05). No other significant effects of sex and THC dose interaction were observed.

Conclusion: Oral THC (10 mg) yields similar acute psychotomimetic and physiological effects across sexes, but women may experience a pronounced subjective psychoactive effect. Further research is needed to identify individual vulnerabilities and facilitate tailored interventions addressing CUD.

Clinicaltrials: GOV REGISTRATION: https://clinicaltrials.gov/study/NCT02781519?term=Ranganathan&intr=THC&rank=3 .

Rationale: Alcohol can disrupt conditioned sexual inhibition (CSI) established by first-order conditioning in male rats. CSI can also be induced using second-order conditioning, during which male rats are trained to associate a neutral odor with a nonreceptive female. As a result, when given access to two receptive females (one scented and one unscented) during a copulatory preference test, they display CSI toward the scented female.

Objective: The present study examined the effect of low-to-moderate doses of alcohol on CSI and brain activation following exposure to alcohol and the olfactory cue alone.

Methods: Sexually-naïve Long-Evans rats received alternate conditioning sessions with unscented receptive or scented (almond extract) non-receptive females. Following the conditioning phase, males were injected with saline, alcohol 0.5 g/kg or 1 g/kg, 45 min before a copulatory test with two receptive females, with one bearing the olfactory cue. Fos activation was later assessed, following exposure to alcohol and the olfactory cue alone, in several brain regions involved in the expression and regulation of male sexual behavior.

Results: While males in the saline group displayed sexual avoidance towards the scented female, those injected with alcohol before the copulatory test, regardless of the dose, copulated indiscriminately with both females. Subsequent exposure to alcohol and the olfactory cue alone induced different Fos expression between groups in several brain regions.

Conclusions: Low to moderate doses of alcohol disrupt conditioned sexual inhibition in male rats and induce a differential pattern of neural activation, particularly in regions involved in the expression and regulation of sexual behavior.

Rationale: Evidence of the effects of chronic caffeine (CAFF)-containing beverages, alone or in combination with agomelatine (AGO) or quetiapine (QUET), on electroencephalography (EEG), which is relevant to cognition, epileptogenesis, and ovarian function, remains lacking. Estrogenic, adenosinergic, and melatonergic signaling is possibly linked to the dynamics of these substances.

Objectives: The brain and ovarian effects of CAFF were compared with those of AGO + CAFF and QUET + CAFF. The implications of estrogenic, adenosinergic, and melatonergic signaling and the brain-ovarian crosstalk were investigated.

Methods: Adult female rats were administered AGO (10 mg/kg), QUET (10 mg/kg), CAFF, AGO + CAFF, or QUET + CAFF, once daily for 8 weeks. EEG, estrous cycle progression, and microstructure of the brain and ovaries were examined. Brain and ovarian 17β-estradiol (E2), antimullerian hormone (AMH), estrogen receptor alpha (E2Rα), adenosine receptor 2A (A2AR), and melatonin receptor 2 (MT2R) were assessed.

Results: CAFF, alone or combined with AGO or QUET, reduced the maximum EEG peak, which was positively linked to ovarian E2Rα, negatively correlated to cortical neurodegeneration and ovarian MT2R, and associated with cystic ovaries. A large corpus luteum emerged with AGO + CAFF and QUET + CAFF, antagonizing the CAFF-mediated increased ovarian A2AR and reduced cortical E2Rα. AGO + CAFF provoked TTP delay and increased ovarian AMH, while QUET + CAFF slowed source EEG frequency to δ range and increased brain E2.

Conclusions: CAFF treatment triggered brain and ovarian derangements partially antagonized with concurrent AGO or QUET administration but with no overt affection of estrus cycle progression. Estrogenic, adenosinergic, and melatonergic signaling and brain-ovarian crosstalk may explain these effects.