Pub Date : 2026-01-28DOI: 10.1016/j.pbb.2026.174158
Xin-Mu Li , Ning-Ning Zhang , Xiao-Ling Zhang , Nuo Liu , Cong-Yuan Xia , Xiong Yang , Hui-Qin Wang , Xu Yan , Shi-Feng Chu , Nai-Hong Chen , Zhen-Zhen Wang
Depression is a debilitating disorder influenced by individual variation in stress susceptibility. The identification of stress-sensitive and stress-resistant phenotypes is critical for understanding its pathogenesis. We previously identified several proteins associated with these phenotypes, yet their functional roles remain unclear. Here, we investigated whether protocadherin 10 (PCDH10), a brain-enriched non-clustered protocadherin, underlies individual differences in stress susceptibility. Rats were subjected to chronic unpredictable stress and classified as stress-sensitive or stress-resistant individuals based on sucrose preference. We found that PCDH10 mRNA and protein levels were significantly downregulated in the medial prefrontal cortex of stress-sensitive rats but upregulated in stress-resistant rats compared to controls. Conversely, opposing expression patterns were observed in the hippocampus. Functional studies demonstrated that PCDH10 overexpression in the hippocampus promoted depression-like behaviors, whereas its knockdown exerted a protective, antidepressant-like effect. Our findings reveal PCDH10 as a key region-specific regulator of stress susceptibility. Targeted inhibition of PCDH10 in the hippocampus represents a promising new therapeutic strategy for depression.
{"title":"Protocadherin 10, a member of cadherin superfamily, increases stress-susceptibility in chronic unpredictable stress-treated rats","authors":"Xin-Mu Li , Ning-Ning Zhang , Xiao-Ling Zhang , Nuo Liu , Cong-Yuan Xia , Xiong Yang , Hui-Qin Wang , Xu Yan , Shi-Feng Chu , Nai-Hong Chen , Zhen-Zhen Wang","doi":"10.1016/j.pbb.2026.174158","DOIUrl":"10.1016/j.pbb.2026.174158","url":null,"abstract":"<div><div>Depression is a debilitating disorder influenced by individual variation in stress susceptibility. The identification of stress-sensitive and stress-resistant phenotypes is critical for understanding its pathogenesis. We previously identified several proteins associated with these phenotypes, yet their functional roles remain unclear. Here, we investigated whether protocadherin 10 (PCDH10), a brain-enriched non-clustered protocadherin, underlies individual differences in stress susceptibility. Rats were subjected to chronic unpredictable stress and classified as stress-sensitive or stress-resistant individuals based on sucrose preference. We found that PCDH10 mRNA and protein levels were significantly downregulated in the medial prefrontal cortex of stress-sensitive rats but upregulated in stress-resistant rats compared to controls. Conversely, opposing expression patterns were observed in the hippocampus. Functional studies demonstrated that PCDH10 overexpression in the hippocampus promoted depression-like behaviors, whereas its knockdown exerted a protective, antidepressant-like effect. Our findings reveal PCDH10 as a key region-specific regulator of stress susceptibility. Targeted inhibition of PCDH10 in the hippocampus represents a promising new therapeutic strategy for depression.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"261 ","pages":"Article 174158"},"PeriodicalIF":2.5,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070984","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}
Pub Date : 2026-01-23DOI: 10.1016/j.pbb.2026.174157
Qian-Zhong Song , Bing-Yao Liu , Si-Wei Wang , Hai-Yan Wang , Hui Cheng , Jun-Hua Chen , Qi-Feng Li , Sen Li , Xiu-Min Lu , Yong-Tang Wang
Exposure to severe psychological trauma is a recognized etiological precursor to post-traumatic stress disorder (PTSD), a potentially debilitating psychiatric condition. Increasing evidence indicates a strong connection between mental disorders and the metabolic system, in which the gut microbiota, as a key component, exerts significant influence on psychiatric health. The gut is often referred to as the “second brain”, the gut engages in bidirectional communication with the central nervous system to maintain physiological homeostasis. Trauma affecting the nervous system and cognitive functions such as learning and memory can disrupt the gut microbial community and even trigger inflammatory responses. Conversely, changes in the gut microbiota can adversely affect neurocognitive function. This review systematically summarizes the bidirectional relationship between PTSD and gut microbiota, the pathways through which microbial dysbiosis influences PTSD symptoms, and the underlying mechanisms involving immune regulation, microbial metabolites, and vagus nerve signaling. It also discusses microbiota-based intervention strategies for PTSD, aiming to provide a theoretical foundation for microbial-targeted therapeutic approaches.
{"title":"The role of short-chain fatty acids and neuroinflammation in PTSD pathogenesis: A gut microbial perspective","authors":"Qian-Zhong Song , Bing-Yao Liu , Si-Wei Wang , Hai-Yan Wang , Hui Cheng , Jun-Hua Chen , Qi-Feng Li , Sen Li , Xiu-Min Lu , Yong-Tang Wang","doi":"10.1016/j.pbb.2026.174157","DOIUrl":"10.1016/j.pbb.2026.174157","url":null,"abstract":"<div><div>Exposure to severe psychological trauma is a recognized etiological precursor to post-traumatic stress disorder (PTSD), a potentially debilitating psychiatric condition. Increasing evidence indicates a strong connection between mental disorders and the metabolic system, in which the gut microbiota, as a key component, exerts significant influence on psychiatric health. The gut is often referred to as the “second brain”, the gut engages in bidirectional communication with the central nervous system to maintain physiological homeostasis. Trauma affecting the nervous system and cognitive functions such as learning and memory can disrupt the gut microbial community and even trigger inflammatory responses. Conversely, changes in the gut microbiota can adversely affect neurocognitive function. This review systematically summarizes the bidirectional relationship between PTSD and gut microbiota, the pathways through which microbial dysbiosis influences PTSD symptoms, and the underlying mechanisms involving immune regulation, microbial metabolites, and vagus nerve signaling. It also discusses microbiota-based intervention strategies for PTSD, aiming to provide a theoretical foundation for microbial-targeted therapeutic approaches.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"260 ","pages":"Article 174157"},"PeriodicalIF":2.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046909","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}
Pub Date : 2026-01-22DOI: 10.1016/j.pbb.2026.174156
María Ángeles Martínez-Caballero , Claudia Calpe-López , María Pilar García-Pardo , María Carmen Arenas , Carmen Manzanedo , María Asunción Aguilar
Several studies have demonstrated that exposure to different protocols of social defeat induces anxiety- and depression-like symptoms in male and female mice. Moreover, male mice exposed to an intermittent social defeat (ISD) show increased vulnerability to the rewarding effects of cocaine, although several behavioural traits have been found to confer resilience against this effect. However, the effects of ISD on the vulnerability to drugs of abuse in female mice have not been studied. Thus, our aim was to evaluate the short-term behavioural effects of ISD and its long-term influence on the rewarding effects of cocaine in female mice. Intruder female mice were exposed to an ISD protocol and performed the elevated plus maze, hole-board, social interaction, splash, object recognition and tail suspension tests 24 or 48 h after the last episode of defeat. Three weeks later, female mice underwent the conditioned place preference procedure with cocaine. ISD exposure induced a slight anxiogenic effect, decreased novelty-seeking behaviour and enhanced sensitivity to the conditioned rewarding effects of cocaine. However, defeated female mice characterized by an active coping response during episodes of defeat and an avoidance of potential dangers in unknown environments did not develop cocaine preference. Our results show that defeat in an inter-female aggression protocol is a useful way to study the long-term consequences of social stress on cocaine reward and the behavioural traits associated with resilience.
{"title":"Behaviour of female mice defeated in an inter-female aggression protocol predicts resilience to cocaine-induced conditioned place preference","authors":"María Ángeles Martínez-Caballero , Claudia Calpe-López , María Pilar García-Pardo , María Carmen Arenas , Carmen Manzanedo , María Asunción Aguilar","doi":"10.1016/j.pbb.2026.174156","DOIUrl":"10.1016/j.pbb.2026.174156","url":null,"abstract":"<div><div>Several studies have demonstrated that exposure to different protocols of social defeat induces anxiety- and depression-like symptoms in male and female mice. Moreover, male mice exposed to an intermittent social defeat (ISD) show increased vulnerability to the rewarding effects of cocaine, although several behavioural traits have been found to confer resilience against this effect. However, the effects of ISD on the vulnerability to drugs of abuse in female mice have not been studied. Thus, our aim was to evaluate the short-term behavioural effects of ISD and its long-term influence on the rewarding effects of cocaine in female mice. Intruder female mice were exposed to an ISD protocol and performed the elevated plus maze, hole-board, social interaction, splash, object recognition and tail suspension tests 24 or 48 h after the last episode of defeat. Three weeks later, female mice underwent the conditioned place preference procedure with cocaine. ISD exposure induced a slight anxiogenic effect, decreased novelty-seeking behaviour and enhanced sensitivity to the conditioned rewarding effects of cocaine. However, defeated female mice characterized by an active coping response during episodes of defeat and an avoidance of potential dangers in unknown environments did not develop cocaine preference. Our results show that defeat in an inter-female aggression protocol is a useful way to study the long-term consequences of social stress on cocaine reward and the behavioural traits associated with resilience.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"260 ","pages":"Article 174156"},"PeriodicalIF":2.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039145","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}
Pub Date : 2026-01-21DOI: 10.1016/j.pbb.2026.174155
Chunlu Li , Yujie Wei , Dan Yin , Chuanrui Zhao , Guangkun Chen , Qian Wang , Mingjuan Shi , Yan Hong , Yixin Li , Baijuan Xia
Recent studies have found that microglia-mediated hippocampal damage may be involved in cognitive impairment induced by chronic heroin treatment. However, its specific molecular mechanism remains unclear. This study explored the possible role of the SIRT1-HMGB1 pathway in this phenomenon. We found that 30 days, but not 15 days, of chronic heroin treatment could impair the learning and memory of mice in the water maze task; compared with 15 days of heroin treatment, 30 days of chronic heroin treatment induced more hippocampal SIRT1 and HMGB1 expression, especially the number of SIRT1-positive and HMGB1-positive microglia, and promoted the polarization of microglia to proinflammatory types. Selective knockdown of SIRT1 expression in hippocampal microglia exacerbated the learning and memory impairment induced by 30 days of heroin treatment; reduced the number of HMGB1-positive microglia, reversed the polarization of microglia to proinflammatory types, and exacerbated the apoptosis of cells in the hippocampus. These results suggest that chronic heroin treatment may be involved in the cognitive impairment process by activating the SIRT1-HMGB1 pathway in microglia.
{"title":"The SIRT1-HMGB1 pathway in hippocampal microglia is involved in chronic heroin-induced cognitive impairment","authors":"Chunlu Li , Yujie Wei , Dan Yin , Chuanrui Zhao , Guangkun Chen , Qian Wang , Mingjuan Shi , Yan Hong , Yixin Li , Baijuan Xia","doi":"10.1016/j.pbb.2026.174155","DOIUrl":"10.1016/j.pbb.2026.174155","url":null,"abstract":"<div><div>Recent studies have found that microglia-mediated hippocampal damage may be involved in cognitive impairment induced by chronic heroin treatment. However, its specific molecular mechanism remains unclear. This study explored the possible role of the SIRT1-HMGB1 pathway in this phenomenon. We found that 30 days, but not 15 days, of chronic heroin treatment could impair the learning and memory of mice in the water maze task; compared with 15 days of heroin treatment, 30 days of chronic heroin treatment induced more hippocampal SIRT1 and HMGB1 expression, especially the number of SIRT1-positive and HMGB1-positive microglia, and promoted the polarization of microglia to proinflammatory types. Selective knockdown of SIRT1 expression in hippocampal microglia exacerbated the learning and memory impairment induced by 30 days of heroin treatment; reduced the number of HMGB1-positive microglia, reversed the polarization of microglia to proinflammatory types, and exacerbated the apoptosis of cells in the hippocampus. These results suggest that chronic heroin treatment may be involved in the cognitive impairment process by activating the SIRT1-HMGB1 pathway in microglia.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"260 ","pages":"Article 174155"},"PeriodicalIF":2.5,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039146","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}
Pub Date : 2026-01-12DOI: 10.1016/j.pbb.2026.174154
Catherine F. Moore , Cecilia L. Bergeria , Cristina Sempio , Jost Klawitter , Uwe Christians , Elise M. Weerts
Cannabigerol (CBG) is a phytocannabinoid found in cannabis that is increasingly being sold and used as an isolate product or as the dominant cannabinoid in cannabis products for purported cognitive enhancement (attention, focus, and memory). The purpose of this study was to evaluate the effects of orally administered CBG on sustained attention, motivation, and memory. In a series of experiments, separate groups of male and female adult Sprague Dawley rats received oral CBG (30–600 mg/kg, per os [p.o.]) or sesame oil vehicle prior to testing in 1) the rodent psychomotor vigilance test; 2) progressive ratio responding for food; 3) spontaneous alternation test of working memory (selected doses: 300–600 mg/kg, p.o.). Blood plasma was collected 60 min following oral administration for assessments of circulating CBG levels. CBG produced deficits in sustained attention at the highest doses (300–600 mg/kg) in female, but not male, rats. CBG did not affect motivation to respond for a food reward nor working memory, indicating an effect specific to attention in females. Finally, females showed significantly higher circulating CBG in plasma compared with males following oral CBG. In sum, these data suggest a sex-specific effect of CBG on sustained attention in females.
{"title":"High doses of orally administered cannabigerol produce deficits in sustained attention in female rats","authors":"Catherine F. Moore , Cecilia L. Bergeria , Cristina Sempio , Jost Klawitter , Uwe Christians , Elise M. Weerts","doi":"10.1016/j.pbb.2026.174154","DOIUrl":"10.1016/j.pbb.2026.174154","url":null,"abstract":"<div><div>Cannabigerol (CBG) is a phytocannabinoid found in cannabis that is increasingly being sold and used as an isolate product or as the dominant cannabinoid in cannabis products for purported cognitive enhancement (attention, focus, and memory). The purpose of this study was to evaluate the effects of orally administered CBG on sustained attention, motivation, and memory. In a series of experiments, separate groups of male and female adult Sprague Dawley rats received oral CBG (30–600 mg/kg, per os [p.o.]) or sesame oil vehicle prior to testing in 1) the rodent psychomotor vigilance test; 2) progressive ratio responding for food; 3) spontaneous alternation test of working memory (selected doses: 300–600 mg/kg, p.o.). Blood plasma was collected 60 min following oral administration for assessments of circulating CBG levels. CBG produced deficits in sustained attention at the highest doses (300–600 mg/kg) in female, but not male, rats. CBG did not affect motivation to respond for a food reward nor working memory, indicating an effect specific to attention in females. Finally, females showed significantly higher circulating CBG in plasma compared with males following oral CBG. In sum, these data suggest a sex-specific effect of CBG on sustained attention in females.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"260 ","pages":"Article 174154"},"PeriodicalIF":2.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145963366","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}
Pub Date : 2026-01-09DOI: 10.1016/j.pbb.2026.174153
Suky Martinez , Jermaine D. Jones , Kelly E. Dunn , Andrew Huhn , Joshua A. Lile , Thomas P. Shellenberg , Laura Brandt
Aims
This study characterized the heterogeneity of opioid withdrawal by comparing naturally occurring withdrawal during opioid abstinence (spontaneous withdrawal) with abrupt, pharmacologically induced naloxone-precipitated withdrawal in adults with Opioid Use Disorder (OUD).
Methods
A secondary analysis was conducted on de-identified data from 86 adults meeting DSM-5 criteria for moderate-to-severe OUD. Participants either presented in spontaneous withdrawal (n = 28) or underwent naloxone challenge to precipitate withdrawal (n = 58). Withdrawal symptoms were rated using the Wang procedure. Principal Component Analysis (PCA) of binary symptom data was performed to identify dominant patterns of symptom co-occurrence. Separate PCAs were then conducted for the withdrawal syndrome types to delineate group-specific symptom clusters.
Results
In the combined sample, four principal components together accounted for 55.6% of the variance in withdrawal symptoms, with the highest loadings observed on autonomic (e.g., temperature change, sweating) and somatic (e.g., restlessness, yawning) domains. Subgroup analyses revealed distinct symptom-loading patterns: the spontaneous withdrawal group displayed a more pronounced autonomic profile dominated by temperature dysregulation and muscle aching, whereas the precipitated withdrawal group exhibited greater variability, with notable gastrointestinal (vomiting, stomach pain) and somatic features. Across analyses, inter-individual variability was substantial, underscoring the multidimensional nature of opioid withdrawal.
Conclusion
These findings suggest spontaneous and precipitated withdrawal are distinct clinical phenomena: the former emerges gradually, the latter produces diverse, acute symptoms, though both display heterogeneity. Moreover, relying solely on naloxone-challenge paradigms for treatment development may overlook key aspects of “real-world” spontaneous withdrawal, reinforcing the importance of broader experimental models and individualized care.
{"title":"Evidence of heterogeneity in the opioid withdrawal syndrome: Spontaneous and precipitated withdrawal","authors":"Suky Martinez , Jermaine D. Jones , Kelly E. Dunn , Andrew Huhn , Joshua A. Lile , Thomas P. Shellenberg , Laura Brandt","doi":"10.1016/j.pbb.2026.174153","DOIUrl":"10.1016/j.pbb.2026.174153","url":null,"abstract":"<div><h3>Aims</h3><div>This study characterized the heterogeneity of opioid withdrawal by comparing naturally occurring withdrawal during opioid abstinence (spontaneous withdrawal) with abrupt, pharmacologically induced naloxone-precipitated withdrawal in adults with Opioid Use Disorder (OUD).</div></div><div><h3>Methods</h3><div>A secondary analysis was conducted on de-identified data from 86 adults meeting DSM-5 criteria for moderate-to-severe OUD. Participants either presented in spontaneous withdrawal (<em>n</em> = 28) or underwent naloxone challenge to precipitate withdrawal (<em>n</em> = 58). Withdrawal symptoms were rated using the Wang procedure. Principal Component Analysis (PCA) of binary symptom data was performed to identify dominant patterns of symptom co-occurrence. Separate PCAs were then conducted for the withdrawal syndrome types to delineate group-specific symptom clusters.</div></div><div><h3>Results</h3><div>In the combined sample, four principal components together accounted for 55.6% of the variance in withdrawal symptoms, with the highest loadings observed on autonomic (e.g., temperature change, sweating) and somatic (e.g., restlessness, yawning) domains. Subgroup analyses revealed distinct symptom-loading patterns: the spontaneous withdrawal group displayed a more pronounced autonomic profile dominated by temperature dysregulation and muscle aching, whereas the precipitated withdrawal group exhibited greater variability, with notable gastrointestinal (vomiting, stomach pain) and somatic features. Across analyses, inter-individual variability was substantial, underscoring the multidimensional nature of opioid withdrawal.</div></div><div><h3>Conclusion</h3><div>These findings suggest spontaneous and precipitated withdrawal are distinct clinical phenomena: the former emerges gradually, the latter produces diverse, acute symptoms, though both display heterogeneity. Moreover, relying solely on naloxone-challenge paradigms for treatment development may overlook key aspects of “real-world” spontaneous withdrawal, reinforcing the importance of broader experimental models and individualized care.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"260 ","pages":"Article 174153"},"PeriodicalIF":2.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145952733","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}
Pub Date : 2026-01-07DOI: 10.1016/j.pbb.2026.174152
Negar G. Ardabili, Shira Tan, María Elisa Márquez de Prado Arrarás, Honeyeh Younesie, Anthony L. Riley
Both the rewarding and aversive effects of a drug contribute to its abuse potential. One factor known to impact the balance of these effects is concurrent and serial polydrug use. A drug class for which such interactions are common is synthetic cathinones. In prior work, history with the synthetic cathinone eutylone had no effect on cocaine- or MDMA-induced taste avoidance in male rats, possibly as a function of the insufficient overlap between the pharmacological activity of eutylone and the other compounds. To investigate the broader scope of this effect, this study assessed how a history of eutylone influenced drug-induced taste avoidance in female rats. Assessments were also made on the rewarding effects of these drugs, given their importance for abuse vulnerability. In the present study, adult female Sprague-Dawley rats were exposed to eutylone or saline prior to concurrent taste avoidance/place preference conditioning in which saccharin and a distinct compartment were repeatedly paired with cocaine, MDMA, or eutylone. All drugs induced taste avoidance. Avoidance induced by eutylone was attenuated by eutylone history, but those induced by MDMA and cocaine were unaffected. Eutylone history had no effect on place preferences induced by MDMA or eutylone (but increased place preferences induced by cocaine). The failure of eutylone to impact the aversive effects of cocaine and MDMA despite sharing neurochemical actions suggests that eutylone's pharmacological activity may produce subjective effects that differ from those of either MDMA or cocaine. The differential effects of eutylone history on drug reward (increasing cocaine reward but having no impact on eutylone or MDMA) remain unknown but suggests that the basis for the aversive and rewarding effects of these drugs are dissociable.
{"title":"Eutylone history selectively impacts the rewarding and aversive effects of cocaine, MDMA, and eutylone in female Sprague-Dawley rats","authors":"Negar G. Ardabili, Shira Tan, María Elisa Márquez de Prado Arrarás, Honeyeh Younesie, Anthony L. Riley","doi":"10.1016/j.pbb.2026.174152","DOIUrl":"10.1016/j.pbb.2026.174152","url":null,"abstract":"<div><div>Both the rewarding and aversive effects of a drug contribute to its abuse potential. One factor known to impact the balance of these effects is concurrent and serial polydrug use. A drug class for which such interactions are common is synthetic cathinones. In prior work, history with the synthetic cathinone eutylone had no effect on cocaine- or MDMA-induced taste avoidance in male rats, possibly as a function of the insufficient overlap between the pharmacological activity of eutylone and the other compounds. To investigate the broader scope of this effect, this study assessed how a history of eutylone influenced drug-induced taste avoidance in female rats. Assessments were also made on the rewarding effects of these drugs, given their importance for abuse vulnerability. In the present study, adult female Sprague-Dawley rats were exposed to eutylone or saline prior to concurrent taste avoidance/place preference conditioning in which saccharin and a distinct compartment were repeatedly paired with cocaine, MDMA, or eutylone. All drugs induced taste avoidance. Avoidance induced by eutylone was attenuated by eutylone history, but those induced by MDMA and cocaine were unaffected. Eutylone history had no effect on place preferences induced by MDMA or eutylone (but increased place preferences induced by cocaine). The failure of eutylone to impact the aversive effects of cocaine and MDMA despite sharing neurochemical actions suggests that eutylone's pharmacological activity may produce subjective effects that differ from those of either MDMA or cocaine. The differential effects of eutylone history on drug reward (increasing cocaine reward but having no impact on eutylone or MDMA) remain unknown but suggests that the basis for the aversive and rewarding effects of these drugs are dissociable.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"260 ","pages":"Article 174152"},"PeriodicalIF":2.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145945548","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}
Pub Date : 2025-12-29DOI: 10.1016/j.pbb.2025.174145
Yikai Chen , Wen Ye , Wenxin Wang , Nan Miao , Yongqiang Sha , Tao Sun
Major depressive disorder (MDD) is characterized by anhedonia and cognitive deficits. In this study, we investigated the therapeutic effects of nicotinic acid (NA), a nicotinamide adenine dinucleotide+ (NAD+) precursor, in a mouse chronic restraint stress (CRS) model. Behavioral assessments revealed that NA ameliorated depressive-like behaviors, evidenced by restored sucrose preference and reduced immobility in forced swim and tail suspension tests, without affecting motor coordination in the rotarod test. Hippocampal transcriptomic analysis indicated that NA reversed stress-induced gene dysregulation, activated neuroprotective Wnt/β-catenin, cGMP–PKG, and cAMP pathways, and rescued lipid and porphyrin metabolism. In conclusion, NA likely exerts antidepressant effects by remodeling hippocampal gene networks to enhance synaptic plasticity and restore metabolic homeostasis. These findings highlight NA as a promising metabolic antidepressant and support the development of NAD+ precursor–based potential therapies for mood disorders.
{"title":"Nicotinic acid (NA) facilitates antidepressant effects through promoting neuro-protective transcriptome in the hippocampus","authors":"Yikai Chen , Wen Ye , Wenxin Wang , Nan Miao , Yongqiang Sha , Tao Sun","doi":"10.1016/j.pbb.2025.174145","DOIUrl":"10.1016/j.pbb.2025.174145","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is characterized by anhedonia and cognitive deficits. In this study, we investigated the therapeutic effects of nicotinic acid (NA), a nicotinamide adenine dinucleotide<sup>+</sup> (NAD<sup>+</sup>) precursor, in a mouse chronic restraint stress (CRS) model. Behavioral assessments revealed that NA ameliorated depressive-like behaviors, evidenced by restored sucrose preference and reduced immobility in forced swim and tail suspension tests, without affecting motor coordination in the rotarod test. Hippocampal transcriptomic analysis indicated that NA reversed stress-induced gene dysregulation, activated neuroprotective Wnt/β-catenin, cGMP–PKG, and cAMP pathways, and rescued lipid and porphyrin metabolism. In conclusion, NA likely exerts antidepressant effects by remodeling hippocampal gene networks to enhance synaptic plasticity and restore metabolic homeostasis. These findings highlight NA as a promising metabolic antidepressant and support the development of NAD<sup>+</sup> precursor–based potential therapies for mood disorders.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"259 ","pages":"Article 174145"},"PeriodicalIF":2.5,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878801","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}
Pub Date : 2025-12-12DOI: 10.1016/j.pbb.2025.174144
Alena Lemeshova , Kaya A. Patel , Alexander J. Bloom, Lindsay Golan, Haney Haidari, Aiman Limbada, Cherish Zhao, Jennifer A. Honeycutt
Background
Ketamine, a nonselective NMDA-receptor antagonist, is an emerging therapeutic for treatment-resistant depression and could also be a promising treatment for anxiety and post-traumatic stress disorders. However, preclinical studies in these areas lack methodological standardization, limiting clinical translatability. This review evaluates ketamine's anxiolytic potential in rodents by examining outcomes among different animal models, dosages, and treatment timing.
Methods & Results
A PubMed search of studies published up to July 21, 2025, identified 562 articles assessing ketamine's effects on anxiety and PTSD in rodent models. After applying inclusion and exclusion criteria, 35 studies were analyzed. Key methodological variables, model type, dosage, and timing were summarized to assess consistency and effectiveness across studies.
Conclusion
Current research on ketamine's anxiolytic potential in rodents is limited by inconsistent methods and inadequate sex inclusion. Evidence suggests that administering 10 to 30 mg/kg intraperitoneally and waiting ≥24 h before behavioral testing procedures produces anxiolytic effects, in deficit models. Future studies should include female subjects and standardized designs to enhance clinical translatability and relevance.
{"title":"A systematic review of ketamine's anxiolytic potential in rodent behavioral models of anxiety and PTSD","authors":"Alena Lemeshova , Kaya A. Patel , Alexander J. Bloom, Lindsay Golan, Haney Haidari, Aiman Limbada, Cherish Zhao, Jennifer A. Honeycutt","doi":"10.1016/j.pbb.2025.174144","DOIUrl":"10.1016/j.pbb.2025.174144","url":null,"abstract":"<div><h3>Background</h3><div>Ketamine, a nonselective NMDA-receptor antagonist, is an emerging therapeutic for treatment-resistant depression and could also be a promising treatment for anxiety and post-traumatic stress disorders. However, preclinical studies in these areas lack methodological standardization, limiting clinical translatability. This review evaluates ketamine's anxiolytic potential in rodents by examining outcomes among different animal models, dosages, and treatment timing.</div></div><div><h3>Methods & Results</h3><div>A PubMed search of studies published up to July 21, 2025, identified 562 articles assessing ketamine's effects on anxiety and PTSD in rodent models. After applying inclusion and exclusion criteria, 35 studies were analyzed. Key methodological variables, model type, dosage, and timing were summarized to assess consistency and effectiveness across studies.</div></div><div><h3>Conclusion</h3><div>Current research on ketamine's anxiolytic potential in rodents is limited by inconsistent methods and inadequate sex inclusion. Evidence suggests that administering 10 to 30 mg/kg intraperitoneally and waiting ≥24 h before behavioral testing procedures produces anxiolytic effects, in deficit models. Future studies should include female subjects and standardized designs to enhance clinical translatability and relevance.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"259 ","pages":"Article 174144"},"PeriodicalIF":2.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757177","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}
Pub Date : 2025-12-08DOI: 10.1016/j.pbb.2025.174143
Larysa Bondarenko , Tetiana Karatsuba , Alla Voronina , Maksim Munko , Valentina Kovalenko , Ganna Shayakhmetova
Post-traumatic stress disorder (PTSD) is increasingly recognized as a systemic disorder, with neuroendocrine, metabolic, and immune alterations accompanying its behavioral symptoms. While selective serotonin reuptake inhibitors such as fluoxetine are widely used to treat PTSD, their systemic effects during critical developmental periods remain poorly understood. Using a peripubertal rat model of PTSD-like stress, we evaluated the effects of fluoxetine administered during puberty on behavior (passive avoidance), serum biochemistry, hematology, and IL-6 levels. Assessments were conducted in two phases: shortly following the end of fluoxetine treatment and in a delayed post-treatment period. PTSD-like stress enhanced aversive memory retention, an effect attenuated by fluoxetine in the short post-treatment phase but not in the delayed period. Uric acid content in serum was increased in both PTSD and PTSD+fluoxetine groups shortly post-treatment, while LDL elevation was observed only in the delayed phase. The long-term effect of fluoxetine on serum creatinine was observed. Additional hematological alterations were observed in the delayed period. Serum IL-6 levels remained persistently elevated in PTSD group across both phases, indicating sustained inflammation with no clear effect of fluoxetine. Thus, peripubertal PTSD-like stress induces behavioral and metabolic alterations that persist beyond the acute stress period. Fluoxetine partially normalized behavior but failed to prevent long-term biochemical and hematological alterations. These highlight the systemic and time-dependent consequences of peripubertal PTSD and its pharmacological treatment, underscoring the need for longitudinal monitoring of physiological outcomes alongside recovery of behavioral phenotype.
{"title":"Peripubertal PTSD-like stress in rats induces transient behavioral but lasting metabolic and inflammatory alterations: Limited fluoxetine efficacy","authors":"Larysa Bondarenko , Tetiana Karatsuba , Alla Voronina , Maksim Munko , Valentina Kovalenko , Ganna Shayakhmetova","doi":"10.1016/j.pbb.2025.174143","DOIUrl":"10.1016/j.pbb.2025.174143","url":null,"abstract":"<div><div>Post-traumatic stress disorder (PTSD) is increasingly recognized as a systemic disorder, with neuroendocrine, metabolic, and immune alterations accompanying its behavioral symptoms. While selective serotonin reuptake inhibitors such as fluoxetine are widely used to treat PTSD, their systemic effects during critical developmental periods remain poorly understood. Using a peripubertal rat model of PTSD-like stress, we evaluated the effects of fluoxetine administered during puberty on behavior (passive avoidance), serum biochemistry, hematology, and IL-6 levels. Assessments were conducted in two phases: shortly following the end of fluoxetine treatment and in a delayed post-treatment period. PTSD-like stress enhanced aversive memory retention, an effect attenuated by fluoxetine in the short post-treatment phase but not in the delayed period. Uric acid content in serum was increased in both PTSD and PTSD+fluoxetine groups shortly post-treatment, while LDL elevation was observed only in the delayed phase. The long-term effect of fluoxetine on serum creatinine was observed. Additional hematological alterations were observed in the delayed period. Serum IL-6 levels remained persistently elevated in PTSD group across both phases, indicating sustained inflammation with no clear effect of fluoxetine. Thus, peripubertal PTSD-like stress induces behavioral and metabolic alterations that persist beyond the acute stress period. Fluoxetine partially normalized behavior but failed to prevent long-term biochemical and hematological alterations. These highlight the systemic and time-dependent consequences of peripubertal PTSD and its pharmacological treatment, underscoring the need for longitudinal monitoring of physiological outcomes alongside recovery of behavioral phenotype.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"259 ","pages":"Article 174143"},"PeriodicalIF":2.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145725082","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}
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