Psilocybin has emerged as a promising therapeutic agent, with clinical benefits attributed to enhanced neuroplasticity rather than acute pharmacological effects. However, the fundamental mechanisms underlying these effects remain poorly understood. Using planarians as a model system, we investigated whether psilocybin enhances associative learning using a conditioned place preference paradigm. Following a single exposure to 5 µM psilocybin, planarians underwent 5 days of conditioning in which light was paired with sucrose. Psilocybin-treated planarians showed a significantly greater shift in light preference compared to controls (time × group × drug interaction: F(2,38) = 3.3, P < 0.05), with effects persisting at least 6 days post-administration. These findings demonstrate that psilocybin enhances appetitive associative learning in an invertebrate model, supporting the hypothesis that psychedelic-induced neuroplasticity operates through evolutionarily conserved serotonergic mechanisms.

Sweetened alcoholic beverages are thought to contribute to developing alcohol use disorder by increasing palatability. One monosaccharide, glucose, readily enters the brain more than fructose and directly impacts the activity of central neurons. The objective of this study is to determine the impact of glucose versus fructose on alcohol drinking patterns in female and male rats. Rats drank alcohol cocktails (1.25-10%) containing either glucose or fructose (10%) in 4-h sessions. We sought to parse orosensory effects from post-ingestive central effects by analyzing drinking microstructure. We compared measures of palatability and post-ingestive feedback between early and later in the session when brain levels of alcohol and glucose are different. We found that rats of both sexes drank more low alcohol glucose cocktails than cocktails containing fructose by volume and by overall calories. When considering the estimated dose of alcohol, glucose potentiated alcohol intake by shifting the estimated dose-response curve leftward compared to similar fructose cocktails. We found that drinking patterns associated with palatability remained stable for both types of cocktails over the entire session. In contrast, post-ingestive behavior related to brain mediated satiety or positive feedback showed a greater influence of session time, as well as a greater interaction with sex. Overall, our results suggest that glucose and alcohol interact to impact central regulation of cocktail drinking. This highlights that the type of sugar within cocktails interacts and ultimately may have different effects on brain regulated alcohol drinking.

The delayed nonmatch to position (DNMTP) task is an instrumental learning paradigm applied to assess higher executive functions including attention and working memory in rats. In this study, the effect of systemic challenge with the acute inflammatory stimulus [lipopolysaccharide (LPS) 0.25 mg/kg, intraperitoneally] was assessed in Wistar rats on performance in the DNMTP task. By means of validation, the effect of treatment with the muscarinic receptor antagonist scopolamine [0.02 mg/kg, subcutaneously (s.c.)], known to disrupt performance in the task, and its reversal by coadministration of the cognitive-enhancing agent and acetylcholinesterase inhibitor donepezil (0.3 mg/kg, s.c.) were confirmed. Sex differences emerged between males' and females' mnemonic response to LPS 24-h postadministration with males showing reduced performance in the DNMTP task at higher working memory loads compared with females. Noradrenaline is an endogenous neurotransmitter with innate anti-inflammatory properties. The impact of targeting the noradrenergic system with the β2-adrenoceptor agonist Formoterol was further assessed on LPS-induced cognitive impairment in the DNMTP task. Coadministration of Formoterol (0.5 mg/kg, s.c.) attenuated LPS-driven mnemonic impairments in males but not females. Overall, the results show the DNMTP task is a paradigm sensitive to acute systemic inflammation and indicate that Formoterol may have useful anti-inflammatory properties in mitigating inflammatory-associated cognitive impairment.

This bibliometric synthesis maps the global research landscape on aspartame (ASP) and neurobehavioral symptoms over a 40-year period (1985-2025). Working from 30 included records, we quantified temporal trends, authorship, journal distribution, study designs, and recurring thematic emphases. Interest in the topic has revived, with most records (approximately 60%, 18/30) published from 2015 onwards. The literature is dispersed across many outlets, and animal/in-vivo studies (56.7%, 17/30) outnumber human/clinical studies (30.0%, 9/30). Recurring domains were behavioral, cognitive, and memory-related outcomes, with proposed mechanisms including neurotransmitter disruption and oxidative imbalance. Despite this activity, a critical evidence gap persists, driven chiefly by the scarcity of adequately powered human data and by methodological heterogeneity. Larger human studies and methodological harmonization are needed to reduce uncertainty and to inform public-health policy. To our knowledge, this is among the first bibliometric syntheses focused specifically on the ASP neurobehavior literature; it is intended to complement, rather than replace, existing narrative and toxicological reviews of the field.

Given that previous studies have provided mixed results on cathinone neurotoxicity, we compared the effects of 'functionally equivalent' dosing regimens of methamphetamine (METH), methcathinone, and α-pyrrolidinopropiophenone (α-PPP) on behavioral and neurochemical markers associated with dopaminergic alterations and cognitive function. Male Swiss Webster mice received METH (5 mg/kg), methcathinone (80 mg/kg), or α-PPP (80 mg/kg), using a 'binge'-like dosing regimen (q2h × 4, intraperitoneal). Body weight and temperature were recorded during dosing. Behavior was assessed 2-4 days later, followed by brain extraction. Motor function was evaluated by open-field testing and stride length analysis. Cognitive function was assessed with the passive avoidance test. Striatal levels of dopamine and its major metabolites were measured using ultra-HPLC. All three drug treatments induced weight loss. METH treatment produced a small, transient increase in rectal temperature (~1 °C); methcathinone and α-PPP did not. All three drug treatments impaired passive avoidance performance (P < 0.05 to P < 0.01), but none produced persistent motor deficits. METH and methcathinone treatment significantly reduced striatal dopamine levels (P < 0.001), whereas α-PPP did not, and only METH treatment increased homovanillic acid/dopamine turnover (P < 0.01). Only METH exposure triggered measurable changes in dopamine metabolism and a small, transient increase in temperature, highlighting its distinct neurochemical profile compared with methcathinone and α-PPP under these conditions. All three drug treatments impaired passive avoidance performance, but none caused lasting motor deficits, demonstrating that behavioral deficits can occur without persistent motor changes.

To investigate the association between preoperative anxiety and opioid tolerance in patients undergoing primary hip arthroplasty, focusing on heterogeneity across opioid types and the mechanisms underlying this association, this retrospective cohort study identified 1763 such patients from the Medical Information Mart for Intensive Care IV database. Of these, 198 patients were identified as anxious based on an anxiety diagnosis at admission. Opioid tolerance was assessed by evaluating dosage patterns of morphine, oxycodone, and tramadol. Multivariable logistic regression, Johnson-Neyman, and restricted cubic spline analysis were employed to evaluate the associations and interactions. Transcriptomic data from a rat neuropathic pain model (GSE53897) were used to analyze differential pathways between morphine and oxycodone treatments. Preoperative anxiety was significantly associated with high-dose oxycodone use across model 1 [odds ratio (OR) = 2.025], model 3 (OR = 1.786), and model 4 (OR = 1.679), but not with high-dose morphine or tramadol. Exploratory age analyses revealed that this association exhibited marked age specificity: it persisted only in patients aged less than or equal to 75 years (P < 0.05) and was nonsignificant in those more than 75 years, with effect strength diminishing with increasing age. Mechanistic analysis revealed different gene profiles and enriched biological pathways between morphine and oxycodone treatment groups, suggesting a molecular basis for treatment heterogeneity. In hip arthroplasty patients, preoperative anxiety was an independent risk factor for oxycodone tolerance, and this effect was age-modulated, significant only in patients aged less than or equal to 75 years. Integrating psychological status and age into pain management strategies deserves consideration in clinical practice.

Major depressive disorder represents a critical global health burden with limited rapid-acting therapeutic options. This study investigated the natural triterpenoid saponin polygalic acid for rapid antidepressant efficacy and its mechanistic relationship with neuroinflammation. In male C57BL/6 mice subjected to chronic unpredictable mild stress, acute intraperitoneal administration of polygalic acid (30 mg/kg) produced robust behavioral improvements 2 h postinjection (n = 8-10 per group), as evidenced by reduced immobility in the tail suspension and forced swimming tests (indicative of enhanced stress coping), restored sucrose preference (reversal of anhedonia), and decreased latency to feed in the novelty-suppressed feeding test (improved motivation) - all without altering locomotor activity or anxiety-like behavior in the open field test. Mechanistically, polygalic acid concurrently suppressed hippocampal nuclear factor-kappa B activation and elevated antiinflammatory cytokines (tumor necrosis factor-beta and interleukin-10) and brain-derived neurotrophic factor (BDNF). To causally examine whether inflammatory status gates polygalic acid's efficacy, coadministration of lipopolysaccharide, which induces acute systemic inflammation, completely abolished polygalic acid's behavioral and molecular effects. These findings demonstrate that polygalic acid produces ketamine-like rapid antidepressant effects specifically through the resolution of chronic neuroinflammatory dysregulation and BDNF restoration. However, the presence of acute inflammatory activation nullifies its therapeutic efficacy, establishing neuroinflammatory context as a critical determinant of treatment response. While limited to male subjects and acute (2-h) assessment, this work identifies polygalic acid as a promising rapid-acting antidepressant candidate and underscores the therapeutic importance of patient stratification based on inflammatory biomarkers when targeting the nuclear factor-kappa B-BDNF axis.

Depression remains a leading cause of disability worldwide, yet the predictive validity of many preclinical behavioral assays for antidepressant efficacy remains limited. The differential reinforcement of low-rate behavior (DRL) task has classically been used in rodents to identify antidepressant-like effects, but its utility in non-human primates (NHPs) has not been established. Here, we adapted the DRL task for use in adult male cynomolgus macaques (Macaca fascicularis) and evaluated its pharmacological sensitivity and translational relevance across 19 compounds spanning multiple drug classes. Antidepressants, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and phosphodiesterase-4 (PDE4) inhibitors, generally shifted DRL performance in an antidepressant-like direction, increasing reinforcers earned and inter-response times while decreasing response output. In contrast, benzodiazepine and antipsychotic control compounds did not produce a consistent antidepressant-like profile, whereas stimulant effects were mixed, with nicotine and cocaine also producing overlapping antidepressant-like behavioral effects. Importantly, the primate DRL task identified antidepressant-like effects of PDE4 inhibitors while also capturing emesis, a dose-limiting side effect not observable in rodent models. These findings support the primate DRL task as a translationally relevant platform for screening antidepressant-like efficacy, while also highlighting important design considerations for interpreting pharmacological sensitivity in the NHP setting. By modeling behavioral processes implicated in depression, including response inhibition and temporal regulation, this assay offers a unique opportunity to bridge preclinical and clinical antidepressant development with improved sensitivity to both efficacy and tolerability.

Chronic pain is a common complication of many diseases, often leading to severe hyperalgesia and allodynia with limited therapeutic options. Opioids are restricted in widespread clinical use due to side effects such as addiction and tolerance. Therefore, identifying novel pain-modulating targets is of great significance for the comprehensive and long-term treatment of chronic pain. This study reports that an endogenous polypeptide, phoenixin-14 (PNX-14), exhibits sexually dimorphic regulatory effects in various pain models. Briefly, intrathecally administered PNX-14 produces a more potent, dose-dependent elevation of pain thresholds in female mice than in male mice under physiological conditions. In models of spared nerve injury-induced neuropathic pain and complete Freund's adjuvant-induced inflammatory pain, intrathecal injection of PNX-14 elicited antinociceptive responses in both sexes, yet the magnitude observed in females was significantly greater than that in males. Further investigation revealed that this sexually dimorphic effect is not attributable to differential pharmacokinetics, as the plasma half-life of PNX-14 shows no difference between male and female mice both in vivo and in vitro . Notably, surgical and pharmacological manipulations revealed that PNX-14-regulated pain is promoted by estrogen but suppressed by androgen, suggesting an involvement of sex hormones. These results collectively position PNX-14 as a novel, nonopioid, and female-specific target for chronic pain management.

Some drugs possess reinforcing properties, which are commonly studied using the conditioned place preference (CPP) paradigm. CPP has been applied across a wide range of taxa, including nonmammalian vertebrates and invertebrates. In the present study, goldfish were used as an experimental model to examine CPP induced by nicotine, a substance that remains a major public health concern. Nicotine produced CPP at lower doses and conditioned place aversion (CPA) at higher doses. One advantage of fish models is the feasibility of drug administration by immersion, an animal-friendly alternative to injection. However, because intraperitoneal injection is the standard method in rodent studies, quantitative comparisons of dose-response relationships across taxa are difficult. To address this issue, I compared the dose-response relationship of general activity following nicotine administration by immersion with that following intraperitoneal injection in goldfish. Based on this comparison, a conversion factor between the two administration procedures was estimated. Using this conversion, nicotine-induced CPP and CPA in goldfish were quantitatively compared with findings from rodent studies. These results contribute to cross-species evaluation of drug reinforcement and support the utility of fish models in behavioral pharmacology.

Behavioural analysis with small aquatic model organisms is increasingly applied across diverse areas of biosciences and biomedicine, including ecology, pharmacology, and experimental neurobiology. High-throughput behavioural phenotyping workflows frequently employ organisms such as larval zebrafish (Danio rerio) in multiwell laboratory plates, yet the considerable cost of commercial imaging platforms often limits access for smaller laboratories, early career investigators and researchers in low- and middle-income countries. Here, we describe a rapid and practical approach for constructing an inexpensive, flexible and fully customisable behavioural data acquisition system suitable for use with a broad range of aquatic model species. We also examine an important but frequently overlooked methodological issue in quantitative behavioural research: how video acquisition parameters, particularly resolution and bitrate, influence the reliability of automated animal tracking. Using Artemia franciscana nauplii, adult Daphnia carinata , and 7 days postfertilisation larval Danio rerio , we show that video resolution is a major determinant of detection reliability, particularly for very small test organisms. Artemia franciscana could not be reliably tracked in multiarena configurations at resolutions below full high definition, whereas ultra high definition (3840 × 2160 pixels) provided robust detection across all tested species. We also show that concerns regarding ultra high definition file size can be mitigated by optimising bitrate settings. Moderate compression produced major reductions in file size while preserving detection reliability at practical compression levels. Together, these findings provide a practical framework for designing affordable and custom animal tracking systems and selecting video acquisition settings that support reliable high-throughput behavioural phenotyping across diverse aquatic species.

Choosing a relatively large reward with a lower chance of payoff compared with a relatively small reward with a higher chance of payoff can be operationalized as a risky choice. Risky choices are often observed in humans through gambling. Gambling disorder is characterized by excessive gambling that results in detrimental personal, social, and financial outcomes. Clarifying mechanisms that contribute to perseverative gambling could help clarify why problem gambling may occur. The presentation of win-paired cues is suggested to contribute to excessive gambling because of a conditioned-reinforcing function. Stimulant drugs have been shown to enhance conditioned reinforcers and to increase risky choice under certain experimental conditions. The present study was designed to examine how the combined administration of d -amphetamine, a commonly prescribed psychomotor stimulant, and the presentation of win-paired cues on winning and losing trials would impact risky choice patterns in a probability-discounting procedure in Sprague-Dawley rats. d -Amphetamine produced dose-dependent increases in risky choice with or without win-paired cues. Win-paired cues alone did not alter absolute levels of risky choice, but the combination of d -amphetamine and win-paired cues promoted perseveration for the risk-associated response option. This effect was particularly evident following losing trials where the win-paired cue was presented. Results are discussed in the context of electronic gambling machine use, and suggestions for research with more commonly used stimulants are offered.

Maternal deprivation in the postnatal period triggers complex conditions along with impairment in brain development. Research indicates that N-acetyl-L-cysteine (NAC), a nootropic agent, restores glutathione levels for antioxidant protection in neurons. It also balances neurotransmitters and alleviates irritability and anxiety symptoms by reducing oxidative damage. Micro-RNA-146a plays a significant role in neuroinflammation in individuals with autism spectrum disorder, and its expression is upregulated in brain regions involved in cognitive function. This study assessed the effects of NAC on autistic-like behaviors and miRNA146a gene expression in an animal model of maternal deprivation. Rats were divided into four groups: control, NAC-treated, maternal deprivation model, and maternal deprivation model treated with NAC. Rats in the maternal deprivation model groups were deprived of their mothers for 10 consecutive days (3 h/day), starting at postnatal day 1 (PND1) or 24 h after birth. From PND30, the treated groups received gastric gavage of NAC at 150 mg/kg body weight for 30 days. Behavioral tests were performed at PND61, and brain tissue samples were collected to assess miRNA146a gene expression levels using real time PCR. This study indicates that NAC treatment alleviated repetitive and anxiety-like behaviors and improved exploration and sociability in the maternal deprivation model group. It also significantly reduced the overexpression of miRNA146a gene. These findings suggest that NAC may be a promising dietary supplement or therapeutic candidate for behavioral disorders caused by maternal deprivation. The protective effect of NAC likely occurred through the downregulation of miRNA146a gene expression.