Pharmacology Biochemistry and Behavior最新文献

{"title":"Ligands of the trace amine-associated receptors (TAARs): A new class of anxiolytics","authors":"Yazen Alnefeesi ,&nbsp;Ilya Sukhanov ,&nbsp;Raul R. Gainetdinov","doi":"10.1016/j.pbb.2024.173817","DOIUrl":"10.1016/j.pbb.2024.173817","url":null,"abstract":"<div><p>Most cases of anxiety are currently treated with either benzodiazepines or serotonin reuptake inhibitors. These drugs carry with them risks for a multitude of side effects, and patient compliance suffers for this reason. There is thus a need for novel anxiolytics, and among the most compelling prospects in this vein is the study of the TAARs. The anxiolytic potential of ulotaront, a full agonist at the human TAAR1, is currently being investigated in patients with generalized anxiety disorder. Irrespective of whether this compound succeeds in clinical trials, a growing body of preclinical literature underscores the relevance of modulating the TAARs in anxiety. Multiple behavioral paradigms show anxiolytic-like effects in rodents, possibly due to increased neurogenesis and plasticity, in addition to a panoply of interactions between the TAARs and other systems. Crucially, multiple lines of evidence suggest that the TAARs, particularly TAAR1, TAAR2, and TAAR5, are expressed in the extended amygdala and hippocampus. These regions are central in the actuation of anxiety, and are particularly susceptible to neurogenic and neuroplastic effects which the TAARs are now known to regulate. The TAARs also regulate the dopamine and serotonin systems, both of which are implicated in anxiety. Ligands of the TAARs may thus constitute a new class of anxiolytics.</p></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"242 ","pages":"Article 173817"},"PeriodicalIF":3.3,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2,5-Dimethoxy-4-iodoamphetamine and altanserin induce region-specific shifts in dopamine and serotonin metabolization pathways in the rat brain","authors":"Susanne Nikolaus ,&nbsp;Benedetta Fazari ,&nbsp;Owen Y. Chao ,&nbsp;Filipe Rodrigues Almeida ,&nbsp;Laila Abdel-Hafiz ,&nbsp;Markus Beu ,&nbsp;Jan Henke ,&nbsp;Christina Antke ,&nbsp;Hubertus Hautzel ,&nbsp;Eduards Mamlins ,&nbsp;Hans-Wilhelm Müller ,&nbsp;Joseph P. Huston ,&nbsp;Charlotte von Gall ,&nbsp;Frederik L. Giesel","doi":"10.1016/j.pbb.2024.173823","DOIUrl":"10.1016/j.pbb.2024.173823","url":null,"abstract":"<div><h3>Purpose</h3><p>For understanding the neurochemical mechanism of neuropsychiatric conditions associated with cognitive deficits it is of major relevance to elucidate the influence of serotonin (5-HT) agonists and antagonists on memory function as well dopamine (DA) and 5-HT release and metabolism. In the present study, we assessed the effects of the 5-HT_2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and the 5-HT_2A receptor altanserin (ALT) on object and place recognition memory and cerebral neurotransmitters and metabolites in the rat.</p></div><div><h3>Methods</h3><p>Rats underwent a 5-min exploration trial in an open field with two identical objects. After systemic injection of a single dose of either DOI (0.1 mg/kg), ALT (1 mg/kg) or the respectice vehicle (0.9 % NaCl, 50 % DMSO), rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Upon the assessment of object exploration and motor/exploratory behaviors, rats were sacrificed. DA, 5-HT and metabolite levels were analyzed in cingulate (CING), caudateputamen (CP), nucleus accumbens (NAC), thalamus (THAL), dorsal (dHIPP) and ventral hippocampus (vHIPP), brainstem and cerebellum with high performance liquid chromatography.</p></div><div><h3>Results</h3><p>DOI decreased rearing but increased head-shoulder motility relative to vehicle. Memory for object and place after both DOI and ALT was not different from vehicle. Network analyses indicated that DOI inhibited DA metabolization in CING, CP, NAC, and THAL, but facilitated it in dHIPP. Likewise, DOI inhibited 5-HT metabolization in CING, NAC, and THAL. ALT facilitated DA metabolization in the CING, NAC, dHIPP, vHIPP, and CER, but inhibited it in the THAL. Additionally, ALT facilitated 5-HT metabolization in NAC and dHIPP.</p></div><div><h3>Conclusions</h3><p>DOI and ALT differentially altered the quantitative relations between the neurotransmitter/metabolite levels in the individual brain regions, by inducing region-specific shifts in the metabolization pathways. Findings are relevant for understanding the neurochemistry underlying DAergic and/or 5-HTergic dysfunction in neurological and psychiatric conditions.</p></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"242 ","pages":"Article 173823"},"PeriodicalIF":3.3,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0091305724001175/pdfft?md5=391c635a379ee00471e0425513cdda90&pid=1-s2.0-S0091305724001175-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clemastine improves emotional and social deficits in adolescent social isolation mice by reversing demyelination","authors":"Dan Guo ,&nbsp;Yuan Yao ,&nbsp;Xiumin Liu ,&nbsp;Ying Han","doi":"10.1016/j.pbb.2024.173824","DOIUrl":"10.1016/j.pbb.2024.173824","url":null,"abstract":"<div><p>Adolescence is a critical period for social experience-dependent oligodendrocyte maturation and myelination. Adolescent stress predisposes to cause irreversible changes in brain structure and function with lasting effects on adulthood or beyond. However, the molecular mechanisms linking adolescent social isolation stress with emotional and social competence remain largely unknown. In our study, we found that social isolation during adolescence leads to anxiety-like behaviors, depression-like behaviors, impaired social memory and altered patterns of social ultrasonic vocalizations in mice. In addition, adolescent social isolation stress induces demyelination in the prefrontal cortex and hippocampus of mice, with decreased myelin-related gene expression and disrupted myelin structure. More importantly, clemastine was sufficient to rescue the impairment of emotional and social memory by promoting remyelination. These findings reveal the demyelination mechanism of emotional and social deficits caused by social isolation stress in adolescence, and provides potential therapeutic targets for treating stress-related mental disorders.</p></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"242 ","pages":"Article 173824"},"PeriodicalIF":3.3,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adjunctive clozapine with bright light mitigates cognitive deficits by synaptic plasticity and neurogenesis in sub-chronic MK-801 treated mice","authors":"Lizhi Zhang ,&nbsp;Yiying Zhou ,&nbsp;Yanhong Xie ,&nbsp;Yudong Ying ,&nbsp;Yan Li ,&nbsp;Sen Ye ,&nbsp;Zhengchun Wang","doi":"10.1016/j.pbb.2024.173821","DOIUrl":"10.1016/j.pbb.2024.173821","url":null,"abstract":"<div><p>Schizophrenia impacts about 1 % of the global population, with clozapine (CLZ) being a critical treatment for refractory cases despite its limitations in effectiveness and adverse effects. Therefore, the search for more effective treatments remains urgent. Light treatment (LT) recognized for enhancing cognition and mood, presents a promising complementary approach. This study investigated the effects of CLZ and LT on cognitive impairments in a sub-chronic MK-801 induced schizophrenia mouse model. Results showed that both CLZ and CLZ + LT treatment elevate cognitive performance of sub-chronic MK-801 treated mice in serial behavioral tests over two months. Histological analysis revealed increased dendritic spine density and branching, and synaptic repair in the hippocampus with CLZ and CLZ + LT interventions. Furthermore, both treatments increased brain-derived neurotrophic factor (BDNF) expression in the hippocampus, likely contributing to cognitive amelioration in MK-801 treated mice. Additionally, BrdU labeling revealed that CLZ + LT further enhances neurogenesis in the dentate gyrus (DG) and lateral ventricle (LV) of sub-chronic MK-801 treated mice. These findings may have implications for the development of noninvasive and adjunctive treatment strategies aimed at alleviating cognitive impairments and improving functional outcomes in individuals with schizophrenia.</p></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"243 ","pages":"Article 173821"},"PeriodicalIF":3.3,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A single exposure to the predator odor 2,4,5-trimethylthiazoline causes long-lasting affective behavioral changes in female mice: Modulation by kappa opioid receptor signaling","authors":"","doi":"10.1016/j.pbb.2024.173822","DOIUrl":"10.1016/j.pbb.2024.173822","url":null,"abstract":"<div><p>Abstract</p><p>The volatile compound <em>2,4,5-trimethylthiazoline</em> (TMT, a synthetic predator scent) triggers fear, anxiety, and defensive responses in rodents that can outlast the encounter. The receptor systems underlying the development and persistence of TMT-induced behavioral changes remain poorly characterized, especially in females. Kappa opioid receptors regulate threat generalization and fear conditioning and alter basal anxiety, but their role in unconditioned fear responses in females has not been examined. Here, we investigated the effects of the long-lasting kappa opioid receptor antagonist, nor-binalthorphinmine dihydrochloride (nor-BNI; 10 mg/kg), on TMT-induced freezing and conditioned place aversion in female mice. We also measured anxiety-like behavior in the elevated plus maze three days after TMT and freezing behavior when returned to the TMT-paired context ten days after the single exposure. We found that 35<span><math><mi>μl</mi></math></span> of 10 % TMT elicited a robust freezing response during a five-minute exposure in female mice. TMT evoked persistent fear as measured by conditioned place aversion, reduced entries into the open arm of the elevated plus maze, and increased general freezing behavior long after TMT exposure. In line with the known role of kappa-opioid receptors in threat generalization, we found that kappa-opioid receptor antagonism increased basal freezing but reduced freezing during TMT presentation. Together, these findings indicate that a single exposure to TMT causes long-lasting changes in fear-related behavioral responses in female mice and highlights the modulatory role of kappa-opioid receptor signaling on fear-related behavioral patterns in females.</p></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"242 ","pages":"Article 173822"},"PeriodicalIF":3.3,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0091305724001163/pdfft?md5=e754fff4948e1d0d61d38492e4d37725&pid=1-s2.0-S0091305724001163-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippocampal SorCS2 overexpression represses chronic stress-induced depressive-like behaviors by promoting the BDNF-TrkB system","authors":"","doi":"10.1016/j.pbb.2024.173820","DOIUrl":"10.1016/j.pbb.2024.173820","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;Emerging data has demonstrated that in mature neurons, SorCS2 localizes to the postsynaptic density of dendritic spines and facilitates plasma membrane sorting of TrkB by interacting with it, transmitting positive signaling from BDNF on neurons. Thus, it is possible that SorCS2 plays a role in the pathophysiology of depression by regulating the BDNF-TrkB system.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;In the present study, SorCS2 expression in different brain regions [hippocampus, medial prefrontal cortex (mPFC), hypothalamus, amygdala, ventral tegmental area (VTA), and nucleus accumbens (NAc)] was thoroughly investigated in the chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression. The changes in depressive-like behaviors, the hippocampal BDNF signaling cascade, and amounts of hippocampal immature neurons were further investigated after SorCS2 overexpression by microinjection of the adenovirus associated virus vector containing the coding sequence of mouse SorCS2 (AAV-SorCS2) into the hippocampus of mice exposed to CSDS or CUMS.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;It was found that both CSDS and CUMS significantly decreased the protein and mRNA expression of SorCS2 in the hippocampus but not in other brain regions. Chronic stress also notably downregulated the level of hippocampal SorCS2-TrkB binding in mice. In contrast, AAV-based genetic overexpression of hippocampal SorCS2 fully reversed the chronic stress-induced not only depressive-like behaviors but also decreased SorCS2-TrkB binding, BDNF signaling pathway, and amounts of immature neurons in the hippocampus of mice.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;All these results suggest that enhancing the hippocampal SorCS2 expression protects against chronic stress, producing antidepressant-like actions. Hippocampal SorCS2 may participate in depression neurobiology and be a potential antidepressant target.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Significance statement&lt;/h3&gt;&lt;p&gt;Targeting of proteins to distinct subcellular compartments is essential for neuronal activity and modulated by VPS10P domain receptors which include SorCS2. In mature neurons, SorCS2 localizes to the postsynaptic density of dendritic spines and facilitates plasma membrane sorting of TrkB by interacting with it, transmitting positive signaling from BDNF on neurons. Our study is the first direct evidence preliminarily showing that SorCS2 plays a role in depression neurobiology. It was found that chronic stress induced not only depressive-like behaviors but also decreased SorCS2 expression in the hippocampus. Chronic stress did not affect SorCS2 expression in the mPFC, hypothalamus, amygdala, VTA, or NAc. In contrast, genetic overexpression of hippocampal SorCS2 prevented against chronic stress, producing antidepressant-like actions in mice. Thus, hippocampal SorCS2 is a potential participant underlying depression neurobiology and may be a novel antidepressant target. Our study may also ","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"242 ","pages":"Article 173820"},"PeriodicalIF":3.3,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chlordiazepoxide reduces anxiety-like behavior in the adolescent mouse elevated plus maze: A pharmacological validation study","authors":"Anapaula Themann,&nbsp;Minerva Rodriguez,&nbsp;Joselynn Reyes-Arce,&nbsp;Sergio D. Iñiguez","doi":"10.1016/j.pbb.2024.173819","DOIUrl":"10.1016/j.pbb.2024.173819","url":null,"abstract":"<div><p>This report evaluates the effects of chlordiazepoxide, a benzodiazepine commonly prescribed to manage anxiety-related disorders in adolescent/pediatric populations, on elevated plus maze (EPM) performance in juvenile mice. This approach was taken because chlordiazepoxide produces anxiolytic-like effects in multiple models in adult rodents, however, less is known about the behavioral effects of this benzodiazepine in juveniles. Thus, we administered a single intraperitoneal injection of chlordiazepoxide (0, 5, or 10 mg/kg) to postnatal day 35 male C57BL/6 mice. Thirty minutes later, mice were allowed to explore the EPM for 5-min. We found that chlordiazepoxide-treated mice (5 and 10 mg/kg) spent more time exploring the open arms of the EPM. No differences in velocity (cm/s) or distance traveled (cm) were observed between the groups. These results indicate that chlordiazepoxide induces anxiolytic-related behavior in adolescent male mice.</p></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"242 ","pages":"Article 173819"},"PeriodicalIF":3.3,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of NOS-cGMP pathways promotes stress-induced sensitization of behavioral responses in zebrafish","authors":"","doi":"10.1016/j.pbb.2024.173816","DOIUrl":"10.1016/j.pbb.2024.173816","url":null,"abstract":"<div><p>Nitric oxide (NO) is a molecule involved in plasticity across levels and systems. The role of NOergic pathways in stress-induced sensitization (SIS) of behavioral responses, in which a particular stressor triggers a state of hyper-responsiveness to other stressors after an incubation period, was assessed in adult zebrafish. In this model, adult zebrafish acutely exposed to a fear-inducing conspecific alarm substance (CAS) and left undisturbed for an incubation period show increased anxiety-like behavior 24 h after exposure. CAS increased forebrain glutamate immediately after stress and 30 min after stress, an effect that was accompanied by increased nitrite levels immediately after stress, 30 min after stress, 90 min after stress, and 24 h after stress. CAS also increased nitrite levels in the head kidney, where cortisol is produced in zebrafish. CAS-elicited nitrite responses in the forebrain 90 min (but not 30 min) after stress were prevented by a NOS-2 blocker. Blocking NOS-1 30 min after stress prevents SIS; blocking NOS-2 90 min after stress also prevents stress-induced sensitization, as does blocking calcium-activated potassium channels in this latter time window. Stress-induced sensitization is also prevented by blocking guanylate cyclase activation in both time windows, and cGMP-dependent channel activation in the second time window. These results suggest that different NO-related pathways converge at different time windows of the incubation period to induce stress-induced sensitization.</p></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"243 ","pages":"Article 173816"},"PeriodicalIF":3.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melanin-concentrating hormone receptor: A therapeutic target for novel anxiolytics","authors":"Shigeyuki Chaki","doi":"10.1016/j.pbb.2024.173818","DOIUrl":"10.1016/j.pbb.2024.173818","url":null,"abstract":"<div><p>Anxiety disorders are chronic, disabling psychiatric disorders, and there is a growing medical need for the development of novel pharmacotherapeutic agents showing improved efficacy and an improved side effect profile as compared with the currently prescribed anxiolytic drugs. In the course of the search for next-generation anxiolytics, neuropeptide receptors have garnered interest as potential therapeutic targets, underscored by pivotal roles in modulating stress responses and findings from animal studies using pharmacological tools.</p><p>Among these neuropeptide receptors, the type 1 receptor for melanin-concentrating hormone (MCH1), which has been demonstrated to be involved in an array of physiological processes, including the regulation of stress responses and affective states, has gained attraction as a therapeutic target for drugs used in the treatment of psychiatric disorders, including anxiety disorders. To date, a plethora of MCH1 antagonists have been synthesized, and studies using MCH1 antagonists and genetically manipulated mice lacking MCH1 have revealed that the blockade of MCH1 produces anxiolytic-like effects across diverse rodent paradigms. In addition, MCH1 antagonists have been demonstrated to show a rapid onset of antidepressant-like effects; therefore, they may be effective for conditions commonly encountered in patients with anxiety disorders, which is an advantage for anxiolytic drugs. Notably, MCH1 antagonists have not manifested the undesirable side effects observed with the currently prescribed anxiolytics. All these preclinical findings testify to the potential of MCH1 antagonists as novel anxiolytics.</p><p>Although there are still issues that need to be resolved prior to the initiation of clinical trials, such as elucidating the precise neuronal mechanisms underlying their anxiolytic effects and exploring pertinent biomarkers that can be used in clinical trials, MCH1 blockade appears to be an attractive way to tackle anxiety disorders.</p></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"242 ","pages":"Article 173818"},"PeriodicalIF":3.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The antidepressant-like effect and proposed mechanism of action of TPN672MA, a novel serotonin-dopamine receptor modulator for the treatment of schizophrenia","authors":"Jiaxin Cheng ,&nbsp;Chunhui Wu ,&nbsp;Yu Wang ,&nbsp;Zhen Wang ,&nbsp;Yang He ,&nbsp;Jingshan Shen","doi":"10.1016/j.pbb.2024.173809","DOIUrl":"10.1016/j.pbb.2024.173809","url":null,"abstract":"<div><p>TPN672MA, an innovative antipsychotic drug candidate currently in clinical trials, acts as a dopamine D₂/D₃ receptor partial agonist, serotonin 5-HT_1A receptor agonist, and serotonin 5-HT_2A receptor antagonist. Preclinical investigations have demonstrated its potential in treating the core symptoms of schizophrenia. The present study highlights TPN672MA’s significant antidepressant-like effects in classical behavioral models, such as the chronic social defeat stress paradigm. The pronounced 5-HT_1A receptor agonism and D₂/D₃ receptor partial agonism of TPN672MA likely contribute to its therapeutic effects in depression. Additionally, TPN672MA’s antidepressant-like efficacy may be linked to its ability to enhance the expression levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein-95 (PSD95) in the hippocampus. Furthermore, TPN672MA displayed a more rapid onset of antidepressant-like action. In conclusion, TPN672MA represents a promising new drug candidate for the treatment of symptoms of schizophrenia and depression.</p></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"242 ","pages":"Article 173809"},"PeriodicalIF":3.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}