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 avoidance in female rats. Further, assessments were made on both the aversive and rewarding effects of these drugs, given the importance of these for abuse vulnerability. In the present study, adult female Sprague-Dawley rats were exposed to eutylone or saline prior to concurrent taste aversion/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":"https://doi.org/10.1016/j.pbb.2026.174152","url":null,"abstract":"<p><p>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 avoidance in female rats. Further, assessments were made on both the aversive and rewarding effects of these drugs, given the importance of these for abuse vulnerability. In the present study, adult female Sprague-Dawley rats were exposed to eutylone or saline prior to concurrent taste aversion/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.</p>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":" ","pages":"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}
Pain-depression morbidity affects millions, but there are no effective treatments available. Dezocine is a clinically used opioid analgesic with complicated pharmacological mechanisms. Given this unique pharmacological profile and the crucial involvement of noradrenergic/serotonergic systems in the pathophysiology of depression, dezocine might be able to relieve pain-depression comorbidity. This possibility has not been tested and is the focus of this study. However, this potential has not yet been empirically validated, and investigating it constitutes the primary aim of this study.
Methods
Animal models of depression (Lipopolysaccharides [LPS] and chronic unpredictable mild stress models [CUMS]) were established, and two neuropathic pain models (chronic constriction injury [CCI] and spared nerve injury [SNI]) were used to establish chronic pain-induced depressive-like behaviors and the antidepressive-like effects of dezocine were then examined. Tail suspension test (TST) and force swimming test (FST) were used as behavioral readouts of antidepressant effects. For receptor mechanisms studies, 5-HT1A receptor antagonist WAY-100635, nonselective opioid receptor antagonist naltrexone [NTX]), and three selective opioid receptor antagonists (μ: CTAP; δ: naltrindole [NAL]; k: nor-binaltorphimine [nor-BNI]) were used as pretreatment to antagonize the effects of dezocine.
Results
Dezocine (5 and 10 mg/kg, i.p.) significantly reduced immobility time, suggesting its robust antidepressive-like effects in stand-alone depression models and in neuropathic pain-induced depression models. WAY-100635, NTX, and CTAP but not NAL or nBNI blocked the antidepressive-like effects of dezocine, suggesting the involvement of 5-HT1A and μ-opioid receptors in mediating the antidepressive-like effects of dezocine.
Conclusion
This study demonstrates that dezocine alleviates pain-depression comorbidity by activating both 5-HT1A and μ-opioid receptor.
{"title":"Dual activation of 5-HT1A and μ-opioid receptors mediates dezocine's antidepressant effects in mice with comorbid pain and depression","authors":"Qian-Qian Wei , Kun-Hong Zhong , Xiao-Ke Zhang , Liangxue Zhou , Qing Zhu , Junxu Li","doi":"10.1016/j.pbb.2025.174136","DOIUrl":"10.1016/j.pbb.2025.174136","url":null,"abstract":"<div><h3>Background</h3><div>Pain-depression morbidity affects millions, but there are no effective treatments available. Dezocine is a clinically used opioid analgesic with complicated pharmacological mechanisms. Given this unique pharmacological profile and the crucial involvement of noradrenergic/serotonergic systems in the pathophysiology of depression, dezocine might be able to relieve pain-depression comorbidity. This possibility has not been tested and is the focus of this study. However, this potential has not yet been empirically validated, and investigating it constitutes the primary aim of this study.</div></div><div><h3>Methods</h3><div>Animal models of depression (Lipopolysaccharides [LPS] and chronic unpredictable mild stress models [CUMS]) were established, and two neuropathic pain models (chronic constriction injury [CCI] and spared nerve injury [SNI]) were used to establish chronic pain-induced depressive-like behaviors and the antidepressive-like effects of dezocine were then examined. Tail suspension test (TST) and force swimming test (FST) were used as behavioral readouts of antidepressant effects. For receptor mechanisms studies, 5-HT<sub>1A</sub> receptor antagonist WAY-100635, nonselective opioid receptor antagonist naltrexone [NTX]), and three selective opioid receptor antagonists (μ: CTAP; δ: naltrindole [NAL]; k: nor-binaltorphimine [nor-BNI]) were used as pretreatment to antagonize the effects of dezocine.</div></div><div><h3>Results</h3><div>Dezocine (5 and 10 mg/kg, i.p.) significantly reduced immobility time, suggesting its robust antidepressive-like effects in stand-alone depression models and in neuropathic pain-induced depression models. WAY-100635, NTX, and CTAP but not NAL or nBNI blocked the antidepressive-like effects of dezocine, suggesting the involvement of 5-HT<sub>1A</sub> and μ-opioid receptors in mediating the antidepressive-like effects of dezocine.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that dezocine alleviates pain-depression comorbidity by activating both 5-HT<sub>1A</sub> and μ-opioid receptor.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"259 ","pages":"Article 174136"},"PeriodicalIF":2.5,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715290","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 : 2025-12-05DOI: 10.1016/j.pbb.2025.174135
Daniel A. Palacios-Lagunas , Juan C. Hernández-Mondragón , Kjell Fuxe , Dasiel O. Borroto-Escuela , Minerva Crespo-Ramírez , Francisco Pérez-Eugenio , Miguel Pérez de la Mora
The promotion of prosocial behavior is a remarkable MDMA property. Such an effect is rather uncommon among other psychoactive substances and has been proposed to be of relevance for the potential therapeutic utility of MDMA. We aim to expand our knowledge of the prosocial effects of MDMA, considering sex and housing conditions as extra variables. To this end, housed individually or collectively, male and female Wistar rats were tested using the Social Preference paradigm.
Contrary to expectations, MDMA treatment reduced the prosocial behavior in male rats, irrespective of the housing conditions. Similar effects are observed in female rats, but only in those individually housed. Intriguingly, no MDMA social effects were observed on those female rats, which are collectively housed. Also interesting was the apparent existence of two subgroups of rats that responded differentially to the MDMA administration, suggesting that individual variations among rats may influence the degree of their response to the MDMA treatment. More work is needed to understand how differences across individuals are relevant to the behavioral effects of MDMA.
{"title":"The 3,4-methylenedioxymethamphetamine (MDMA) reduces prosocial behavior in the social preference test in male and female rats","authors":"Daniel A. Palacios-Lagunas , Juan C. Hernández-Mondragón , Kjell Fuxe , Dasiel O. Borroto-Escuela , Minerva Crespo-Ramírez , Francisco Pérez-Eugenio , Miguel Pérez de la Mora","doi":"10.1016/j.pbb.2025.174135","DOIUrl":"10.1016/j.pbb.2025.174135","url":null,"abstract":"<div><div>The promotion of prosocial behavior is a remarkable MDMA property. Such an effect is rather uncommon among other psychoactive substances and has been proposed to be of relevance for the potential therapeutic utility of MDMA. We aim to expand our knowledge of the prosocial effects of MDMA, considering sex and housing conditions as extra variables. To this end, housed individually or collectively, male and female Wistar rats were tested using the Social Preference paradigm.</div><div>Contrary to expectations, MDMA treatment reduced the prosocial behavior in male rats, irrespective of the housing conditions. Similar effects are observed in female rats, but only in those individually housed. Intriguingly, no MDMA social effects were observed on those female rats, which are collectively housed. Also interesting was the apparent existence of two subgroups of rats that responded differentially to the MDMA administration, suggesting that individual variations among rats may influence the degree of their response to the MDMA treatment. More work is needed to understand how differences across individuals are relevant to the behavioral effects of MDMA.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"259 ","pages":"Article 174135"},"PeriodicalIF":2.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701244","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 : 2025-11-29DOI: 10.1016/j.pbb.2025.174134
Yonca Cam , Carlos A. Sardina , Sanya K. Suri , Elizabeth C. Pickering , Felicia M. Padilla , Matthew J. Will
Melanin-concentrating hormone (MCH) system within the nucleus accumbens (Acb) has been shown to regulate feeding behavior; however, the interaction between MCH and opioid-driven hedonic eating remains unclear. This study investigated the effects of intra-Acb administration of the MCHR1 antagonist SNAP-94847 on opioid-driven sucrose pellet intake in male and female rats. Subjects received MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/0.5 μl/side) immediately prior to intra-Acb administration of the μ-opioid receptor agonist, D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO; 0 μg and 0.025 μg/0.5 μl/side) before completing free-feeding tests. Results showed that DAMGO significantly increased sucrose pellet intake in both sexes, while SNAP-94847 alone had no effect, nor did it block the DAMGO-induced increase in either males or females. This finding suggests that MCHR1 within the Acb does not play a significant role in low-effort palatability-driven motivation for food consumption, contrasting with its role in effort-based motivation tasks.
{"title":"Intra-accumbens melanin-concentrating hormone (MCH) receptor-1 antagonism on opioid-driven sucrose consumption in male and female rats","authors":"Yonca Cam , Carlos A. Sardina , Sanya K. Suri , Elizabeth C. Pickering , Felicia M. Padilla , Matthew J. Will","doi":"10.1016/j.pbb.2025.174134","DOIUrl":"10.1016/j.pbb.2025.174134","url":null,"abstract":"<div><div>Melanin-concentrating hormone (MCH) system within the nucleus accumbens (Acb) has been shown to regulate feeding behavior; however, the interaction between MCH and opioid-driven hedonic eating remains unclear. This study investigated the effects of intra-Acb administration of the MCHR1 antagonist SNAP-94847 on opioid-driven sucrose pellet intake in male and female rats. Subjects received MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/0.5 μl/side) immediately prior to intra-Acb administration of the μ-opioid receptor agonist, D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO; 0 μg and 0.025 μg/0.5 μl/side) before completing free-feeding tests. Results showed that DAMGO significantly increased sucrose pellet intake in both sexes, while SNAP-94847 alone had no effect, nor did it block the DAMGO-induced increase in either males or females. This finding suggests that MCHR1 within the Acb does not play a significant role in low-effort palatability-driven motivation for food consumption, contrasting with its role in effort-based motivation tasks.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174134"},"PeriodicalIF":2.5,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621255","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 : 2025-11-20DOI: 10.1016/j.pbb.2025.174133
Joo Hye Sim , Hye Jin Choi , Ohhyeon Kwon , Taeyeon Kim , Doheon Lee , Jeong June Choi
Depression is a chronic mental disorder characterized by alternations in emotions, thoughts, physical condition, and behavior. Using the natural product database Compound Combination-Oriented Natural Product Database with Unified Terminology (COCONUT) and the bioinformatics tool CODA (Context-Oriented Directed Associations), we screened and identified 1,4-naphthoquinone (1,4-NQ) as a promising candidate for depression treatment. Oral administration of 1,4-NQ attenuated the depressive-like behaviors in the open field test (OFT), elevated plus maze test (EPM) and forced swim test (FST) in a chronic restraint stress (CRS)-induced depressive-like mouse model. Real-time PCR analysis demonstrated that 1,4-NQ increased the mRNA levels of 5-HT1A and BDNF in the hippocampus of mouse brains. The expression level of glucocorticoid receptor (GR) in the hippocampus was increased by 1,4-NQ treatment in both CRS- and corticosterone-induced depression mouse models. We confirmed that 1,4-NQ has anti-neuroinflammatory efficacy by suppressing the levels of IL-6, TNF-α and IL-1β in LPS-stimulated BV2 microglial cell line. The western blot and real-time PCR analysis demonstrated that 1,4-NQ increased the level of GR in both the U-138 MG glial cell line and the SH-SY5Y neuronal cell line. In conclusion, 1,4-NQ is supposed to have anti-depressive efficacy by alleviating depressive-like behaviors through modulation of neuroinflammatory mediators and GR expression in the nervous system.
{"title":"1,4-Naphthoquinone improves depressive-like behaviors by modulating neuronal factors and neuroinflammatory mediators","authors":"Joo Hye Sim , Hye Jin Choi , Ohhyeon Kwon , Taeyeon Kim , Doheon Lee , Jeong June Choi","doi":"10.1016/j.pbb.2025.174133","DOIUrl":"10.1016/j.pbb.2025.174133","url":null,"abstract":"<div><div>Depression is a chronic mental disorder characterized by alternations in emotions, thoughts, physical condition, and behavior. Using the natural product database Compound Combination-Oriented Natural Product Database with Unified Terminology (COCONUT) and the bioinformatics tool CODA (Context-Oriented Directed Associations), we screened and identified 1,4-naphthoquinone (1,4-NQ) as a promising candidate for depression treatment. Oral administration of 1,4-NQ attenuated the depressive-like behaviors in the open field test (OFT), elevated plus maze test (EPM) and forced swim test (FST) in a chronic restraint stress (CRS)-induced depressive-like mouse model. Real-time PCR analysis demonstrated that 1,4-NQ increased the mRNA levels of 5-HT1A and BDNF in the hippocampus of mouse brains. The expression level of glucocorticoid receptor (GR) in the hippocampus was increased by 1,4-NQ treatment in both CRS- and corticosterone-induced depression mouse models. We confirmed that 1,4-NQ has anti-neuroinflammatory efficacy by suppressing the levels of IL-6, TNF-α and IL-1β in LPS-stimulated BV2 microglial cell line. The western blot and real-time PCR analysis demonstrated that 1,4-NQ increased the level of GR in both the U-138 MG glial cell line and the SH-SY5Y neuronal cell line. In conclusion, 1,4-NQ is supposed to have anti-depressive efficacy by alleviating depressive-like behaviors through modulation of neuroinflammatory mediators and GR expression in the nervous system.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174133"},"PeriodicalIF":2.5,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582441","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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