Psychopharmacology最新文献

Rationale: Prenatal exposure to infection is a risk factor for neuropsychiatric disorders that often co-occur with alcohol misuse. However, the mechanisms by which early exposure to infection might increase the risk of such disorders remains unclear. One hypothesis is that prenatal stressors interact with adolescent stressors (i.e., "two-hits") to promote alcohol misuse development.

Objectives: The current project tested whether maternal immune activation (MIA) combined with adolescent alcohol exposure (AA) increases the motivation to work for alcohol and negative affect in adulthood, and whether prenatal antioxidant treatment prevents these effects.

Methods: Pregnant Sprague-Dawley rats were exposed to poly(I: C) (4 mg/kg) or saline on gestational day 15, and the antioxidant n-acetylcysteine (NAC; 100 mg/kg) or saline 24 h before and after poly(I: C). Offspring had 24-hour access to 10% ethanol and water during adolescence. In adulthood, offspring were trained to self-administer 10% ethanol and tested on escalating schedules of reinforcement. Elevated plus maze (EPM) behavior was assessed on non-self-administration days.

Results: Poly(I: C) and NAC treatment independently led to an increased willingness to work for alcohol in males, but not females, relative to same-sex controls. NAC treatment suppressed the MIA-induced increase in alcohol-seeking. Poly(I: C) increased locomotor activity in the EPM in both sexes, independent of NAC, without altering open or closed arm time.

Conclusions: These data support the hypothesis that MIA-induced oxidative stress negatively influences development, leaving the brain more susceptible to the negative effects of AA, and increasing the risk of alcohol misuse in adulthood, particularly in males.

Rationale: Stimulant drugs increase objective indices of reward-related behavior, including willingness to expend effort for reward, and also produce feelings of well-being and positive mood. However, it is not known to what extent these different measures are related to each other.

Objectives: The present study was designed to assess the relationship between the behavioral measure of effort expenditure and positive subjective responses to methamphetamine (MA).

Methods: 96 healthy adults completed the Effort Expenditure for Rewards Task (EEfRT) during two laboratory sessions after receiving 20 mg MA or placebo (PL) under double blind conditions. They also self-reported their mood states and drug effects.

Results: MA (vs. PL) increased willingness to complete a high effort/high reward option vs. a low effort/low reward option during the EEfRT (N = 96), and this effect was greater in participants with low effort at baseline. A subjective value modeling analysis (N = 91) showed that MA decreased sensitivity to the perceived cost of effort for the low baseline performance group only. MA also increased self-reported positive affect (euphoria; N = 94, liking the drug; N = 92) in the full sample, but this increase was unrelated to either baseline EEfRT performance or MA-induced EEfRT performance changes (N = 91).

Conclusions: As reported previously, MA increased choice of the high effort/high reward option, particularly in participants with low effort at baseline, who also showed drug-induced changes in effort sensitivity. These behavioral effects were not related to drug liking and drug-induced euphoria. These findings suggest that the effects of stimulants on reward-related behavior and mood are dissociable.

Aims: Depression is associated with numerous metabolic pathway abnormalities, and several studies have suggested a link between depression and branched chain amino acids (BCAAs) metabolic disorders. However, the precise causality and direction remain inconclusive. Consequently, this study aims to ascertain the relationship between the risk of depression and BCAAs levels using two-sample Mendelian randomization (MR) analysis.

Materials and methods: Single nucleotide polymorphisms associated with the BCAAs were extracted from the IEU OpenGWAS. Pooled level data for major depressive disorder (MDD) was obtained from the Psychiatric Genomics Consortium. We performed genome-wide linkage disequilibrium score regression, MR analyses, and colocalization analyses using summary genome-wide association study data across European population to probe genetic causality between BCAAs and MDD.

Results: Our results showed a causal effect of MDD risk on the increasing valine levels (IVW OR = 1.043, 95% CI = 1.006-1.082, P = 0.024) and a genetic correlation between MDD and valine. However, leucine, isoleucine, and total BCAAs were not causally associated with the risk of MDD (P > 0.05). The sensitivity analyses indicated that there was no heterogeneity or horizontal pleiotropy in our findings. The linkage disequilibrium score regression demonstrated significant evidence of shared genetic architecture between MDD and valine, with the genetic correlation estimated to be 0.112 (P = 0.002). Colocalization analysis did not provide any evidence of a shared causal variant between MDD and valine.

Conclusions: It was revealed that valine metabolism may be significantly affected by depression through a two-sample MR analysis, while no significant connection was identified between other branched-chain amino acids and depression. This result provided new insights into the metabolic processes involved in depression.

Rationale: Widespread methamphetamine (meth) misuse remains a worldwide public health issue that lacks effective clinical treatment. Besides the high relapse and overdose rates, chronic meth use produces a spectrum of cognitive deficits that further complicate treatment and recovery. Activation of metabotropic glutamate receptor 3 (mGlu3) attenuates drug-seeking behavior and/or improves cognition in several animal models, though its ability to improve meth-associated behavioral deficits has not been explored.

Objectives: Here, we evaluated working memory and meth-seeking following abstinence and the effects of mGlu3 activation on such behaviors.

Methods: Adult male and female Sprague-Dawley rats were first trained and tested on the operant delayed match-to-sample (DMS) working memory task. Rats then underwent 7 days of short-access (1 h/day) and 14 days of long-access (6 h/day) self-administration or served as drug-naïve controls. During the first 3 weeks of abstinence, rats were re-tested on the DMS task and underwent relapse tests to evaluate meth-seeking behavior. Additionally, the effects of indirect mGlu3 activator 2-PMPA (30 mg/kg, i.p.) on both behavioral measures were assessed.

Results: Meth self-administration produced working memory impairment in both sexes. Significantly, the decline in DMS task performance predicted the magnitude of subsequent meth-seeking. 2-PMPA treatment improved DMS task performance in a cognitively impaired subgroup of rats but had no immediate effects on meth-seeking.

Conclusions: The current study shows that chronic meth self-administration in rats produces co-occurring working memory deficits and robust meth-seeking, akin to meth use disorder (MUD), and that mGlu3 manipulation holds promise in the treatment of meth-associated cognitive deficits.

Objective: Neurodegenerative diseases are a leading cause of disability worldwide, and recent evidence highlights the role of angiogenesis in their pathophysiology. This review aimed to explore molecular and metabolic links between neurodegeneration and angiogenesis, and to assess the potential of antiangiogenic drugs as therapeutic agents.

Methods: A targeted literature search of experimental and clinical studies was performed, focusing on angiogenesis-related mechanisms in neurodegeneration and the effects of antiangiogenic compounds on neuronal and vascular function.

Results: Antiangiogenic agents have been shown to promote synaptic plasticity, enhance neurotransmission, and exert anti-inflammatory effects. They also modulate vascular remodeling, which supports optimal cerebral blood flow and nutrient delivery to neurons. These actions may counteract key pathological processes in neurodegenerative diseases and help preserve cognitive and motor function.

Conclusions: Modulation of angiogenesis represents a promising therapeutic approach in neurodegenerative disorders. Antiangiogenic drugs may address both vascular and neuronal dysfunction, offering a potential avenue for disease-modifying treatments. Further preclinical and clinical research is needed to validate their safety, efficacy, and long-term benefits.

Rationale: Major depressive disorder (MDD) is a significant global health issue, yet its pathophysiology remains unclear. One-third of patients achieve complete remission with monotherapy, highlighting the need for effective add-on therapies.

Objectives: This study explores the antidepressant potential of galantamine (GAL) as an add-on to escitalopram (ESC), focusing on the neurotrophic system, kynurenine pathway, neuroinflammation, and oxidative stress in MDD.

Methods: We employed corticosterone (CORT)-induced toxicity in Neuro-2a cells and an unpredictable chronic mild stress (UCMS) model in mice to simulate depressive conditions. Neuro-2a cells were treated with GAL (39 µM) and ESC (107 µM) in CORT pretreated cells to better understand the protective potential of the drug combination. In vivo treatment with GAL (3 and 5 mg/kg) and ESC (5 and 10 mg/kg) for four weeks in UCMS mice was evaluated for behavioural, biochemical, and histopathological changes.

Results: The combination therapy enhanced cell viability, reduced apoptosis, and lowered intracellular ROS levels in Neuro-2a cells. In vivo, treatment with the GAL + ESC combination significantly alleviated UCMS-induced depressive symptoms and improved working memory. The combined therapy modulated the brain-derived neurotrophic factor (BDNF), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), TNF-α, and IL-6 levels, reversing oxidative stress markers in the hippocampus. Moreover, the combined therapy preserved hippocampal structure and modulated α7 nicotinic acetylcholine receptor (α7nAChR) density in the CA1 region of the hippocampus.

Conclusions: This study signifies the potential of GAL as an add-on therapy to ESC, enhancing antidepressant effects and cognitive function, warranting further clinical investigation for treating depressive disorders.

Rationale: The efficacy of hypnotic drugs for sleep-wake state discrepancy remains unclear.

Objective: This study evaluated the efficacy of lemborexant in improving sleep-wake state discrepancy in insomnia disorder and its associations with sleep quality and daytime functioning.

Methods: Twenty-nine participants diagnosed with insomnia disorder were treated with lemborexant for 12 weeks. Objective sleep parameters were measured using a home electroencephalography device, and subjective parameters were obtained from electronic sleep diaries. Sleep-wake state discrepancy indices, including discrepancies of sleep onset latency (disSOL), wake after sleep onset (disWASO), total sleep time (disTST), and sleep efficiency (disSE), were calculated as objective minus subjective sleep parameters. The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were used to assess sleep quality and daytime sleepiness. Linear mixed-effects models were used for data analysis.

Results: Both subjective and objective sleep parameters were improved at 12 weeks after lemborexant administration. The disTST decreased significantly at 4 and 12 weeks. The disSOL increased and disSE decreased significantly by 12 weeks. Participants with defined sleep-wake state discrepancy (disTST > 0 min) showed greater decreases in these indices, whereas minimal changes were observed in those without. The disWASO did not change significantly among baseline and 4 and 12 weeks. The improvement in disTST demonstrated a significant association with the reduction of ESS scores (p = 0.008), whereas there was no substantial effect on PSQI scores.

Conclusions: The present findings suggest that lemborexant treatment reduces sleep-wake state discrepancy, which may be associated with improved daytime functioning in patients with insomnia disorder.

Introduction: Tamoxifen (TAM) is an off-label treatment option for men with breast cancer, infertility, and gynecomastia. Unfortunately, one of the undesirable effects of TAM is sexual dysfunction. Therefore, this study was designed to investigate the possible associated mechanisms with TAM-induced sexual dysfunction and the possible ameliorative effect of omega-3 fatty acids (O3FA).

Methodology: Animals were randomly divided into control, O3FA, TAM, and TAM + O3FA. All treatment lasted for 28 days.

Results: TAM exposure impaired sperm qualities (count, motility, viability, and normal morphology) and led to a decline in serum testosterone and an increase in luteinizing hormone, follicle-stimulating hormone, prolactin, and estradiol. Furthermore, TAM led to an increase in mount, intromission, and ejaculation latencies and a decrease in their corresponding frequencies. It also led to a decrease in motivation to mate and an increase in post-ejaculatory interval. These events were associated with impaired pregnancy outcomes, hormonal imbalance, a decrease in nitric oxide/cyclic cyclic guanosine monophosphate and dopamine and an increase in acetylcholine esterase and serotonin activities. These observed TAM-induced sexual dysfunction markers were ameliorated in animals that received O3FA and TAM co-treatment.

Conclusions: O3FA ameliorates TAM-induced sexual dysfunction.