Behavioural Pharmacology最新文献

{"title":"Presence of itch qualities in mice.","authors":"Tsugunobu Andoh, Mami Suzuki, Jung-Bum Lee","doi":"10.1097/FBP.0000000000000855","DOIUrl":"https://doi.org/10.1097/FBP.0000000000000855","url":null,"abstract":"<p><p>In our clinical study, we found that itching had many different expressions (or qualities), including 'muzumuzu' (creepy-crawly itching, somewhat like tickling) and 'itch like mosquito bites'. Therefore, we investigated whether there were behavioral differences in response to different pruritogens in mice. In addition, we compared the behavioral characteristics of spontaneous scratching in mice with atopic-like dermatitis. In this study, we used six pruritogens [histamine, 5-hydroxytryptamine (5-HT), substance P, α-melanocyte-stimulating hormone (α-MSH), protease-activated receptor 2 agonist Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SLIGRL), and chloroquine]. Pruritogen was intradermally injected into the rostral back skin of institute of cancer research (ICR) mice. Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) mice infected with mites were used as animal model of atopic dermatitis (dermatitis NC/Nga mice). Their behavior was recorded using a digital video camera. The number of scratching behaviors was divided according to the presence or absence of precursor behaviors, such as shivering and body grooming-like behavior with the forelimbs, to scratching behaviors. Intradermal injection of histamine and substance P induced scratching without precursor behavior. On the other hand, intradermal injection of 5-HT and α-MSH-induced scratching after precursor behaviors. SLIGRL elicited scratching both with and without precursor behavior. In dermatitis NC/Nga mice, spontaneous scratching was induced mainly following precursor behaviors. These results suggest that itch-related behavior in mice is also characterized by the type of itching. Itching in atopic dermatitis is resistant to antihistamines. In this study, we demonstrated that the characteristics of histamine-induced scratching and dermatitis-induced spontaneous itching are different. This suggests that behavioral analyses may be useful for developing drugs to treat itching caused by diseases.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of the hot-plate pain effect between three inhalation methods and subcutaneous injection of heroin.","authors":"Yawen Xu, Qinghua Liu, Yuanyuan Chen, Simeng Zhang, Dan Wang, Bin Di, Peng Xu, Cheng Jiang, Xiangyu Li","doi":"10.1097/FBP.0000000000000854","DOIUrl":"10.1097/FBP.0000000000000854","url":null,"abstract":"<p><p>Heroin, a widely abused opioid, is frequently consumed via inhalation; however, the majority of existing studies have focused on traditional administrations. This study aimed to compare the analgesic effects of heroin across different deliveries to elucidate the unique characteristics of inhalation. Two distinct inhalation exposure systems (nasal and systemic) were established and validated for stability. Liquid chromatography-tandem mass spectrometry was used to quantify blood concentrations of heroin and its metabolite 6-monoacetylmorphine following subcutaneous injection and three intratracheal/inhalation administrations, establishing dose-concentration linearity for cross-comparison at equivalent blood concentration levels. The analgesic of heroin across four different administrations were assessed by the hot plate pain test while comparing outcomes based on both blood and intracerebral drug concentrations. The findings indicated that both inhalation systems exhibited stable drug delivery, with linear correlations between exposure chamber concentration, administered dose, and resultant blood concentration. A logarithmic correlation was identified between the administration duration and blood concentration levels. Analgesic assessments revealed that significantly enhanced effects in both inhalation groups compared to subcutaneous injection, despite lower delivered doses. At the median effective dose (ED 50 ), olfactory bulb drug concentrations in inhalation were approximately eight-fold higher than in subcutaneous and intratracheal groups, while blood concentrations showed no statistical difference. This study validated that inhaled heroin produces stronger analgesic effects than subcutaneous injection, likely attributed to the mechanism of direct brain entry via the olfactory pathway, which enhances psychoactive potency. These findings highlight the distinct pharmacological properties of inhaled heroin, providing critical insights into its abuse potential.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pretreatment with LY2090314, a potent glycogen synthase kinase-3 inhibitor, suppresses methamphetamine-induced stereotyped behavior but not hyperlocomotion in mice.","authors":"Kentaro Matsuda, Nobue Kitanaka, Frank Scott Hall, Takahiro Hamana, Masanori Nakai, Sho Yuze, Kazuo Tomita, Kento Igarashi, Tomoaki Sato, George R Uhl, Junichi Kitanaka","doi":"10.1097/FBP.0000000000000853","DOIUrl":"https://doi.org/10.1097/FBP.0000000000000853","url":null,"abstract":"<p><p>Neuronal glycogen synthase kinase-3s (GSK-3α and the more abundant GSK-3β) are serine/threonine kinases that have been postulated to play roles in neuronal adaptations, including those that come from exposures to substances of abuse; however, there is only modest information about ways in which GSK-3 alters the effects of the widely abused psychostimulant, methamphetamine (METH). To evaluate the effects of GSK-3 inhibition on METH-induced symptoms, mice were treated with LY2090314, a potent and selective GSK-3 inhibitor, followed by METH. Horizontal locomotion, vertical rearing, and stereotyped behaviors were measured. Pretreatment with LY2090314 (2.5, 10, and 25 mg/kg) significantly inhibited stereotypic behavior induced by METH (10 mg/kg) in a dose-dependent fashion. Stereotyped biting was most robustly reduced by LY2090314. By contrast, LY2090314 had no significant effect on METH (3 mg/kg)-induced hyperlocomotion. GSK-3 signaling pathways appear to be differentially involved in acute METH effects on locomotion. GSK-3 appears essential for the expression of METH-induced stereotypy but not hyperlocomotion.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Alcea aucheri (Bioss.) Alef extract against scopolamine-induced memory impairment in rats.","authors":"Tajmah Mombeini, Hamid Gholami Pourbadie, Mohammad Kamalinejad, Ahmad Reza Dehpour, Soroush Mazloumi, Reza Hamidian","doi":"10.1097/FBP.0000000000000836","DOIUrl":"10.1097/FBP.0000000000000836","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":"387-396"},"PeriodicalIF":1.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol improves ovariectomy and chronic restraint stress-induced depression-like behaviors in mice through brain-derived neurotrophic factor associated structural synaptic remodeling.","authors":"Hui Xu, Zhen-Qiang Zhang, Geng Chen, Ming-Jun Ge, Zong-Hao Yu, Jun-Xian Shen, Chuan Pan, Fei Han, Xiu-Ling Zhu, Ya-Ping Lu","doi":"10.1097/FBP.0000000000000845","DOIUrl":"10.1097/FBP.0000000000000845","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":"364-377"},"PeriodicalIF":1.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the anti-inflammatory and antinociceptive effects of limonene in two models of carrageenan-induced inflammation and formalin-induced pain: role of l -arginine/nitric oxide/cGMP/K ATP channel signaling pathways, opioidergic, and benzodiazepine receptors.","authors":"Sajad Fakhri, Mostafa Yarmohammadi, Fatemeh Abbaszadeh, Amir Kiani, Mohammad Hosein Farzaei","doi":"10.1097/FBP.0000000000000840","DOIUrl":"10.1097/FBP.0000000000000840","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":"378-386"},"PeriodicalIF":1.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using UAS-Gal4 designer receptors exclusively activated by designer drugs to elucidate nondopaminergic modulation of methamphetamine-induced locomotion in Drosophila.","authors":"Meghan Hibicke, Charles D Nichols","doi":"10.1097/FBP.0000000000000843","DOIUrl":"10.1097/FBP.0000000000000843","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":"415-428"},"PeriodicalIF":1.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antidepressant effect or bias? Systematic review and meta-analysis of studies using the forced swimming test.","authors":"Tamires Martins, Ana B Ramos-Hryb, Marcus Antonio B da Silva, Camila Sant' Helena do Prado, Fabíola B Eckert, Fabiani F Triches, Johnny E da Costa, Juliana A Bolzan, Sarah K McCann, Cilene Lino de Oliveira","doi":"10.1097/FBP.0000000000000844","DOIUrl":"10.1097/FBP.0000000000000844","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":"347-363"},"PeriodicalIF":1.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of three tryptamines: alpha-methyltryptamine, 5-methoxy-alpha-methyltryptamine, and 5-methoxy- N , N -diisopropyltryptamine on acute toxicity, locomotor activity, and hallucinogenic behavior in mice.","authors":"Kaixi Li, Nan Li, Yuanyuan Chen, Xiangyu Li, Yanling Qiao, Dan Wang, Bin Di, Peng Xu","doi":"10.1097/FBP.0000000000000841","DOIUrl":"10.1097/FBP.0000000000000841","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":"429-437"},"PeriodicalIF":1.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Procognitive effects of methyl 2-amino-3-methoxybenzoate (or daopine) may involve the dorsal striatal anthranilic acid pathway and mutimetabolite-multitarget pharmacology.","authors":"Yami Bright, Helene I V Amatdjais-Groenen, Michel M M Verheij, Petra H H van den Broek, Marcia Spoelder, Dorien Maas, Rick Greupink, Gerard J M Martens, Judith R Homberg","doi":"10.1097/FBP.0000000000000838","DOIUrl":"10.1097/FBP.0000000000000838","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":"397-414"},"PeriodicalIF":1.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}