Behavioural Pharmacology最新文献

Depression, a major psychiatric disorder with profound societal impact, remains incompletely understood in its etiology. Identifying novel pathogenic pathways is therefore essential. The gut microbiota ('second brain') critically regulates bidirectional gut-brain axis (GBA) communication with the central nervous system. Dysbiosis correlates strongly with depression, positioning microbiota restoration as a promising therapeutic strategy. Critically, gut microbial metabolic processes - particularly involving amino acids and short-chain fatty acids (SCFAs) - have emerged as key contributors to depression pathogenesis; however, depression-specific alterations in gut microbiota and their metabolic signatures are inadequately characterized, and the molecular mechanisms linking microbial metabolites to depression require further elucidation. This review synthesizes recent advances on GBA-mediated depression pathogenesis, with emphasis on gut dysbiosis-induced disruptions in amino acid and SCFA metabolism, and delineates their mechanistic links to depressive pathophysiology.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in social interaction, communication, restricted interests, and repetitive behaviors. Its higher prevalence in males underscores the importance of understanding potential sex-specific differences. Prenatal exposure to valproic acid (VPA) is a widely used preclinical model to induce ASD-like traits in rodents; however, few studies have systematically compared neurobehavioral outcomes in both sexes. Here, we aimed to investigate sex-specific variations in developmental, behavioral, and physiological parameters in Wistar rat offspring prenatally exposed to VPA. Pregnant rats received a single intraperitoneal injection of VPA (600 mg/kg) or saline on gestational day (GD) 12.5, and offspring were assigned to four groups: control males, control females, VPA males, and females (n = 9 per group). VPA-exposed rats of both sexes exhibited autism-like behaviors, including heightened anxiety, increased exploratory activity, repetitive behaviors, social deficits, spatial and recognition memory impairments, and depressive-like traits. Physiological assessments revealed altered gastrointestinal (GIT) motility, increased brain edema, impaired blood-brain barrier (BBB) function, and neuronal injury with no sex-based difference in estrogen β (ERβ/ESR2) mRNA expression. These findings demonstrate that in utero exposure to VPA induces autism-like behaviors, developmental abnormalities, and neurodegenerative changes in both rat sexes, emphasizing the importance of including females in preclinical ASD research.

Memory impairment is a core feature of neurodegenerative diseases such as Alzheimer's disease, often modeled using scopolamine-induced cognitive dysfunction in animals. While Alcea aucheri (Boiss.) Alef has demonstrated anxiolytic properties, but its potential impact on cognitive function, particularly memory, remains unexplored. This study investigates the effects of extract of flower of Alcea aucheri (EFA) on cognitive performance in scopolamine-free rats and in a scopolamine-induced memory impairment model. Male Wistar rats were administered EFA [17.5-700 mg/kg, intraperitoneally (i.p.)] across various experimental groups. Cognitive function was assessed using the passive avoidance test for long-term memory and two-trial Y-maze for spatial reference memory. Scopolamine (2 mg/kg, i.p.) was administered to induce memory impairment. The efficacy of EFA in mitigating scopolamine-induced cognitive deficits was evaluated, and memory maintenance was assessed over 6 weeks following treatment. Except for the EFA dose of 700 mg/kg which adversly affected passive avoidance test, its other doses had no significant impact on memory performance in scopolamine-free rats, as observed in both the passive avoidance test and the two-trial Y-maze; however, in rats with scopolamine-induced cognitive deficits, EFA (particularly at 70 mg/kg) significantly improved step-through latency in the passive avoidance test ( P  < 0.001). This suggests a dose-dependent reversal of memory impairment. In addition, EFA demonstrated sustained cognitive enhancement over a 6-week period without affecting body weight. The findings suggest that EFA has a protective effect against scopolamine-induced memory impairment and could serve as a potential therapeutic agent for neurodegenerative conditions associated with cognitive decline. Further research is required to elucidate the underlying mechanisms responsible for these effects.

Previous studies have shown that resveratrol has antidepressant effects in a variety of depression models, but the effect and mechanism of resveratrol on menopausal depression are unclear. In this study, transgenic mice were ovariectomized combined with chronic restraint stress to establish a model of menopausal depression. The antidepressant effect of resveratrol was evaluated by tail suspension test (TST), forced swimming test, sucrose preference test (SPT), and novel inhibition feeding test (NSFT). Using the characteristic expression of yellow fluorescent protein in excitatory neurons of transgenic mice, the effects of resveratrol on the density of dendrites and dendritic spines were evaluated by a three-dimensional imaging technique. Brain-derived neurotrophic factor (BDNF), cofilin1, and p-cofilin1 were quantitatively analyzed by quantitative PCR and immunofluorescence quantification to explore the effects of resveratrol on synaptic plasticity in the hippocampus and medial prefrontal cortex (mPFC) and its mechanism. The results revealed that resveratrol significantly decreased the immobility time in TST, shortened the feeding latency and increased the food intake in NSFT, and enhanced the sucrose consumption in SPT. Consistent with these changes, resveratrol treatment significantly increased the density of p-cofilin1 immunoreactive dendritic spines and the mRNA level of BDNF in these brain regions. The results suggest that resveratrol can improve the synaptic plasticity in the corresponding brain regions by upregulating BDNF levels, enhancing the phosphorylation of cofilin 1, increasing the density of dendrites and dendritic spines in the hippocampus and mPFC, and ultimately improving menopausal depression-like behaviors.

Pain and inflammation are critical and complex biological responses to tissue damage or disease, which significantly impair life quality. The complex pathophysiological mechanisms highlight the necessity for multitarget therapeutic interventions. Limonene, a monoterpene, has shown promising antioxidant and anti-inflammatory properties. This study aimed to elucidate the anti-inflammatory and antinociceptive role of limonene and related mechanisms of action in two animal models. Two models of carrageenan-induced inflammation in rats and formalin-induced pain in mice were employed. In the carrageenan model of inflammation, 30 male Wistar rats were used, including control, diclofenac, and three doses of limonene (5, 10, and 15 mg/kg). The groups followed for 4 h, and paw edema was evaluated using a plethysmometer. In the formalin model of pain, 114 male mice were divided into 19 groups including control, and diclofenac, limonene (5, 10, and 15 mg/kg), l -arginine, N(gamma)-nitro-l-arginine methyl ester (L-NAME), S-nitroso- N -acetylpenicillamine (SNAP), sildenafil, glibenclamide, naloxone, and flumazenil, individually and before the most effective doses of limonene, all intraperitoneal. After the limonene administration, a formalin test was conducted to evaluate pain responses in the mice during both the early neurogenic and late inflammatory phases. The findings indicated that a 10 mg/kg dose of limonene produced the most significant antinociceptive and anti-inflammatory effects. Furthermore, while L-NAME, glibenclamide, naloxone, and flumazenil diminished the antinociceptive properties of limonene, l -arginine, SNAP, and sildenafil increased its effectiveness. This study demonstrated that limonene exhibited antinociceptive and anti-inflammatory properties, mediated through the l -arginine/nitric oxide (NO)/cyclic GMP (cGMP)/ATP-sensitive potassium channel (K ATP ) signaling pathways, opioidergic, and benzodiazepine receptors.

Methamphetamine (METH) use disorder is a serious public health problem with no Food and Drug Administration-approved therapeutic drugs to aid recovery. METH's primary mechanism of action increases dopaminergic neurotransmission in brain regions implicated in reward. However, the serotonergic system is also involved in reward processing and dopamine modulation, thus drugs affecting the serotonin system may have therapeutic potential for treating METH use disorder. To use male and female UAS-Gal4 flies expressing designer receptors exclusively activated by designer drugs to investigate the contributions of nondopaminergic neurons on locomotor response to METH over multiple days, as measured by the Drosophila activity monitoring system. While METH increased locomotor activity in most flies, sex and strain also contribute to METH response, with males of most fly strains displaying significantly greater METH-induced locomotor activity than females. We found METH-induced locomotor activity to be highly modulated by serotonergic signaling and circadian regulators. The mushroom body, serotonin availability, 5-HT 1A neurons, 5-HT 7 neurons, drosophila insulin-like protein neurons, and pigment dispersing factor neurons modulate locomotor activity independent of METH response. The mushroom body, 5-HT 7 neurons, and drosophila insulin-like protein neurons also modulate METH response. While all the neuron types investigated were shown to modulate locomotor activity in some way, 5-HT 7 neurons appear to mediate METH-induced locomotor response most directly.

Alpha-methyltryptamine (AMT), 5-methoxy-alpha-methyltryptamine (5-MeO-AMT), and 5-methoxy- N , N -diisopropyltryptamine (5-MeO-DiPT) are synthetic tryptamines with hallucinogenic-like properties that are widely abused worldwide. There, however, has been a paucity of research and a lack of available data on their pharmacological properties. The objective of this study was to investigate the safety of AMT and 5-MeO-DiPT and to compare the effects of AMT, 5-MeO-AMT, and 5-MeO-DiPT under identical conditions in terms of locomotor performance and hallucinogenic-like behavior, and the role of 5-hydroxytryptamine-2A receptor antagonists (M100907) on hallucinogenic-like behavior. The results showed that both AMT and 5-MeO-DiPT exhibited some acute toxic effects. AMT, 5-MeO-AMT, and 5-MeO-DiPT inhibited locomotor activity and induced head-twitch response (HTR) in mice. Pretreatment with M100907 (0.01 mg/kg) blocked AMT, 5-MeO-AMT, and 5-MeO-DiPT induced HTR in mice. The findings of this study demonstrated that the three tryptamines are toxic, inhibit locomotor activity, and have hallucinogenic effects. These results provide experimental data that can provide fundamental support for future control strategies and in-depth mechanistic studies of these substances.

The forced swim test (FST) assesses antidepressant activity in rodents by measuring suppression of immobility. This study reviewed the literature to evaluate how experimental conditions, study quality, and bias influence antidepressant efficacy in the FST (PROSPERO: CRD42020200604). Systematic searches in Embase and MEDLINE (PubMed) identified 8247 relevant records. After being screened by two independent reviewers, 2588 records were included in the library. A random sample ( k  = 200) yielded 561 studies for meta-analysis. One reviewer extracted data, double-checked by a second; discrepancies were resolved by a third. Meta-analyses were conducted using a random-effects model (metafor R package) to estimate combined effect size (CES), 95% confidence intervals (CI), heterogeneity, and publication bias. Risk of bias was assessed via SYRCLE's tool and the CAMARADES checklist. Despite high inconsistency ( I ² = 81.5%), the global CES was large and significant [Hedges' g  = 1.66, 95% CI (1.53; 1.79), k  = 561, power > 80%], consistent across most subgroups. Small study effects and publication bias inflated CES estimates, especially in mice, while results in rats were more variable. Nonetheless, antidepressants consistently reduced immobility in mice across diverse conditions. In rats, findings were less consistent, though the most robust data showed a significant, dose-dependent antidepressant-like effect of imipramine in both species. However, publication bias and incomplete reporting compromise the accuracy of CES estimates and raise concerns about the validity of the FST literature. These findings highlight the need for more transparent reporting practices in FST-based antidepressant research.

Multifunctional drug treatment is currently the most promising approach in neuropsychopharmacology to overcome complex disorders, such as schizophrenia. We previously showed that the natural protoalkaloid, methyl 2-amino-3-methoxybenzoate [or daopine (DAO)] has procognitive effects in animal models of schizophrenia. Because DAO is a metabolite of the anthranilic acid biosynthesis pathway in Nigella damascena plant seeds, we sought to find out if DAO exerts its procognitive effects via the 'anthranilic acid-brain-pathway-twin' and mutimetabolite-multitarget pharmacology. We explored the procognitive effects of DAO using the operant set shift task in a rat model of attentional flexibility deficits induced by L-kynurenine, the precursor of both kynurenic acid and anthranilic acid. HPLC and liquid chromatography-mass spectrometry was used to identify brain and plasma DAO metabolites and the effects of DAO on dorsal striatal anthranilic acid. DAO attenuated kynurenine-induced cognitive deficits. We identified for the first time the brain (DAO-1 and DAO-3) and plasma (DAO-1 and DAO-2) metabolites of DAO, which remarkably are all methylated derivatives of 3-hydroxyanthranilic acid (3-OHAA), an endogenous brain astrocytic metabolite of anthranilic acid playing a crucial role in cognition. In vitro , DAO-2 and DAO-3 significantly reduced oxidative activity, lipid peroxidation, inflammation, and amyloid β-42-aggregation, all of which represent processes that play an important protective role against cognitive dysfunction. The results strengthen our hypothesis that administering small molecules structurally related to anthranilic acid/3-OHAA, such as DAO, may provide a multitarget strategy for the prevention and treatment of cognitive deficits in schizophrenia, and more broadly, in other cognitive disorders, such as Alzheimer's disease.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in social interaction, communication, restricted interests, and repetitive behaviors. Its higher prevalence in males underscores the importance of understanding potential sex-specific differences. Prenatal exposure to valproic acid (VPA) is a widely used preclinical model to induce ASD-like traits in rodents; however, few studies have systematically compared neurobehavioral outcomes in both sexes. Here, we aimed to investigate sex-specific variations in developmental, behavioral, and physiological parameters in Wistar rat offspring prenatally exposed to VPA. Pregnant rats received a single intraperitoneal injection of VPA (600 mg/kg) or saline on gestational day (GD) 12.5, and offspring were assigned to four groups: control males, control females, VPA males, and females (n = 9 per group). VPA-exposed rats of both sexes exhibited autism-like behaviors, including heightened anxiety, increased exploratory activity, repetitive behaviors, social deficits, spatial and recognition memory impairments, and depressive-like traits. Physiological assessments revealed altered gastrointestinal (GIT) motility, increased brain edema, impaired blood-brain barrier (BBB) function, and neuronal injury with no sex-based difference in estrogen β (ERβ/ESR2) mRNA expression. These findings demonstrate that in utero exposure to VPA induces autism-like behaviors, developmental abnormalities, and neurodegenerative changes in both rat sexes, emphasizing the importance of including females in preclinical ASD research.