Pub Date : 2025-02-01DOI: 10.1016/j.pbb.2024.173942
Luke Manietta
{"title":"Reconsidering OCD pharmacotherapy: The case for levomilnacipran as a safer alternative to clomipramine","authors":"Luke Manietta","doi":"10.1016/j.pbb.2024.173942","DOIUrl":"10.1016/j.pbb.2024.173942","url":null,"abstract":"","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173942"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786393","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 : 2025-02-01DOI: 10.1016/j.pbb.2024.173918
Rebecca L. Chalmé, Eric Rubin , Suzette M. Evans, Margaret Haney, Richard W. Foltin
Individuals seeking treatment for their cocaine use often report depressive systems and nearly half meet criteria for major depressive disorder (MDD). This descriptive study aimed to assess the effects of the antidepressant venlafaxine alone and in combination with gabapentin on depressive symptoms, subjective effects of cocaine, and cocaine self-administration in depressed and non-depressed people who use cocaine. The effects of medication condition on mood and on the effects of smoked cocaine were compared between a group of clinically depressed people who use cocaine (n = 5) and a control group of non-depressed people who use cocaine (n = 5) using laboratory-based measures. In the MDD group, venlafaxine (300 mg/day) was associated with reduced mean Beck Depression Inventory (BDI) scores (35 to <5) and marginally lower ratings of “good drug effect” without affecting cocaine “wanting” or cocaine (0–50 mg) self-administration. In both groups, venlafaxine treatment increased resting heart rate, systolic pressure, and diastolic pressure. The addition of gabapentin (2400 mg/day) had no effect relative to venlafaxine alone for either group. Conclusions regarding venlafaxine's effectiveness in treating depression in the MDD group are tempered by the lack of a venlafaxine placebo condition and by reductions in BDI scores associated with abstinence prior to venlafaxine administration. Further research is necessary to identify effective treatments for depressed people who use cocaine.
{"title":"Venlafaxine treatment is associated with improved mood, but not decreased cocaine self-administration, in depressed people who use cocaine","authors":"Rebecca L. Chalmé, Eric Rubin , Suzette M. Evans, Margaret Haney, Richard W. Foltin","doi":"10.1016/j.pbb.2024.173918","DOIUrl":"10.1016/j.pbb.2024.173918","url":null,"abstract":"<div><div>Individuals seeking treatment for their cocaine use often report depressive systems and nearly half meet criteria for major depressive disorder (MDD). This descriptive study aimed to assess the effects of the antidepressant venlafaxine alone and in combination with gabapentin on depressive symptoms, subjective effects of cocaine, and cocaine self-administration in depressed and non-depressed people who use cocaine. The effects of medication condition on mood and on the effects of smoked cocaine were compared between a group of clinically depressed people who use cocaine (<em>n</em> = 5) and a control group of non-depressed people who use cocaine (n = 5) using laboratory-based measures. In the MDD group, venlafaxine (300 mg/day) was associated with reduced mean Beck Depression Inventory (BDI) scores (35 to <5) and marginally lower ratings of “good drug effect” without affecting cocaine “wanting” or cocaine (0–50 mg) self-administration. In both groups, venlafaxine treatment increased resting heart rate, systolic pressure, and diastolic pressure. The addition of gabapentin (2400 mg/day) had no effect relative to venlafaxine alone for either group. Conclusions regarding venlafaxine's effectiveness in treating depression in the MDD group are tempered by the lack of a venlafaxine placebo condition and by reductions in BDI scores associated with abstinence prior to venlafaxine administration. Further research is necessary to identify effective treatments for depressed people who use cocaine.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173918"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770991","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 : 2025-02-01DOI: 10.1016/j.pbb.2024.173945
Beatriz Godínez-Chaparro , Maria Cristina Rodríguez-Ramos , María Guadalupe Martínez-Lorenzana , Estefanía González-Morales , Karen Pamela Pérez-Ruíz , Antonio Espinosa de los Monteros-Zuñiga , Felipe Mendoza-Pérez , Miguel Condes-Lara
Pain is one of the principal non-motor symptoms of Parkinson's disease (PD), negatively impacting the patient's quality of life. This study aimed to demonstrate whether an effective dose of pramipexole (PPX) can modulate the NF-κB/p-p65 activation in glial cells (astrocytes and microglia) and diminish the hypersensitivity (allodynia and hyperalgesia) in male Wistar rats with PD. For this, 2 μl of 6-hydroxydopamine (6-OHDA, 8 μg/μL/0.2 μl/min) was administered unilaterally in the Substantia Nigra of the Pars Compacta (SNpc) to establish a PD model rat. Motor behavioral tests were used to validate the PD model, and von Frey filaments were used to evaluate allodynia and hyperalgesia. Immunohistochemical and immunofluorescence were used to analyze the level of tyrosine hydroxylase in SNpc and striatum as well as the expression of GFAP, Iba-1, NF-κB/p-65 in the L4-L6 spinal cord dorsal horn. Unilateral 6-OHDA-lesion reduces motor capacity and produces long-term allodynia and hyperalgesia in both hind paws. L4-L6 spinal cord dorsal horn astrocytes and microglia were active in these 6-OHDA-lesioned rats. Moreover, PPX (1 and 3 mg/Kg, i.p./10 days, n = 10 per group) inhibited the bilateral mechanical hypersensitivity, and PPX (3 mg/Kg/i.p./10 days) reduced 6-OHDA-induced astrocyte and microglia activation, as well as reduced NF-κB/p-p65 expression only in astrocytes of dorsal horn spinal cord in the L5-L6. These findings suggest that PPX could alleviate pain by decreasing the activation of microglia and astrocytes through the NF-κB/p-p65 pathway in the dorsal horn spinal cord. Therefore, PPX could be considered an optional tool for improving pain hypersensitivity in PD patients.
{"title":"Pramipexole decreases allodynia and hyperalgesia via NF-κB in astrocytes in rats with Parkinson's disease","authors":"Beatriz Godínez-Chaparro , Maria Cristina Rodríguez-Ramos , María Guadalupe Martínez-Lorenzana , Estefanía González-Morales , Karen Pamela Pérez-Ruíz , Antonio Espinosa de los Monteros-Zuñiga , Felipe Mendoza-Pérez , Miguel Condes-Lara","doi":"10.1016/j.pbb.2024.173945","DOIUrl":"10.1016/j.pbb.2024.173945","url":null,"abstract":"<div><div>Pain is one of the principal non-motor symptoms of Parkinson's disease (PD), negatively impacting the patient's quality of life. This study aimed to demonstrate whether an effective dose of pramipexole (PPX) can modulate the NF-κB/p-p65 activation in glial cells (astrocytes and microglia) and diminish the hypersensitivity (allodynia and hyperalgesia) in male Wistar rats with PD. For this, 2 μl of 6-hydroxydopamine (6-OHDA, 8 μg/μL/0.2 μl/min) was administered unilaterally in the Substantia Nigra of the Pars Compacta (SNpc) to establish a PD model rat. Motor behavioral tests were used to validate the PD model, and von Frey filaments were used to evaluate allodynia and hyperalgesia. Immunohistochemical and immunofluorescence were used to analyze the level of tyrosine hydroxylase in SNpc and striatum as well as the expression of GFAP, Iba-1, NF-κB/p-65 in the L4-L6 spinal cord dorsal horn. Unilateral 6-OHDA-lesion reduces motor capacity and produces long-term allodynia and hyperalgesia in both hind paws. L4-L6 spinal cord dorsal horn astrocytes and microglia were active in these 6-OHDA-lesioned rats. Moreover, PPX (1 and 3 mg/Kg, i.p./10 days, <em>n</em> = 10 per group) inhibited the bilateral mechanical hypersensitivity, and PPX (3 mg/Kg/i.p./10 days) reduced 6-OHDA-induced astrocyte and microglia activation, as well as reduced NF-κB/p-p65 expression only in astrocytes of dorsal horn spinal cord in the L5-L6. These findings suggest that PPX could alleviate pain by decreasing the activation of microglia and astrocytes through the NF-κB/p-p65 pathway in the dorsal horn spinal cord. Therefore, PPX could be considered an optional tool for improving pain hypersensitivity in PD patients.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173945"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829663","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}
Pub Date : 2025-02-01DOI: 10.1016/j.pbb.2024.173932
Harrison M. Carvour, Charlotte A.E.G. Roemer, D'Erick P. Underwood, Edith S. Padilla, Oscar Sandoval, Megan Robertson, Mallory Miller, Natella Parsadanyan, Thomas W. Perry, Anna K. Radke
Mu-opioid receptors (MORs) in the amygdala and striatum are important in addictive and rewarding behaviors. The transcription factor Foxp2 is a genetic marker of intercalated (ITC) cells in the amygdala and a subset of striatal medium spiny neurons (MSNs), both of which express MORs in wild-type mice and are neuronal subpopulations of potential relevance to alcohol-drinking behaviors. For the current series of studies, we characterized the behavior of mice with genetic deletion of the MOR gene Oprm1 in Foxp2-expressing neurons (Foxp2-Cre/Oprm1fl/fl). Male and female Foxp2-Cre/Oprm1fl/fl mice were generated and heterozygous Cre+ (knockout) and homozygous Cre− (control) animals were tested for aversion-resistant alcohol consumption using an intermittent access (IA) task, operant responding for a sucrose reward, conditioned place aversion (CPA) to morphine withdrawal, and locomotor sensitization to morphine. The results demonstrate that deletion of MOR on Foxp2-expressing neurons renders mice more sensitive to quinine-adulterated alcohol. Mice with the deletion (vs. Cre− controls) also consumed less alcohol during the final sessions of the IA task, were less active at baseline and following morphine injection, and there was a trend toward less responding for sucrose under an FR3 schedule. Foxp2-MOR deletion did not impair the ability to learn to respond for reward or develop a conditioned aversion to morphine withdrawal. Together, these investigations demonstrate that Foxp2-expressing neurons may be involved in escalation of alcohol consumption and the development of compulsive-like alcohol drinking.
{"title":"Mu-opioid receptor knockout on Foxp2-expressing neurons reduces aversion-resistant alcohol drinking","authors":"Harrison M. Carvour, Charlotte A.E.G. Roemer, D'Erick P. Underwood, Edith S. Padilla, Oscar Sandoval, Megan Robertson, Mallory Miller, Natella Parsadanyan, Thomas W. Perry, Anna K. Radke","doi":"10.1016/j.pbb.2024.173932","DOIUrl":"10.1016/j.pbb.2024.173932","url":null,"abstract":"<div><div>Mu-opioid receptors (MORs) in the amygdala and striatum are important in addictive and rewarding behaviors. The transcription factor <em>Foxp2</em> is a genetic marker of intercalated (ITC) cells in the amygdala and a subset of striatal medium spiny neurons (MSNs), both of which express MORs in wild-type mice and are neuronal subpopulations of potential relevance to alcohol-drinking behaviors. For the current series of studies, we characterized the behavior of mice with genetic deletion of the MOR gene <em>Oprm1</em> in <em>Foxp2</em>-expressing neurons (Foxp2-Cre/Oprm1<sup>fl/fl</sup>). Male and female Foxp2-Cre/Oprm1<sup>fl/fl</sup> mice were generated and heterozygous Cre+ (knockout) and homozygous Cre− (control) animals were tested for aversion-resistant alcohol consumption using an intermittent access (IA) task, operant responding for a sucrose reward, conditioned place aversion (CPA) to morphine withdrawal, and locomotor sensitization to morphine. The results demonstrate that deletion of MOR on <em>Foxp2</em>-expressing neurons renders mice more sensitive to quinine-adulterated alcohol. Mice with the deletion (vs. Cre− controls) also consumed less alcohol during the final sessions of the IA task, were less active at baseline and following morphine injection, and there was a trend toward less responding for sucrose under an FR3 schedule. <em>Foxp2</em>-MOR deletion did not impair the ability to learn to respond for reward or develop a conditioned aversion to morphine withdrawal. Together, these investigations demonstrate that <em>Foxp2</em>-expressing neurons may be involved in escalation of alcohol consumption and the development of compulsive-like alcohol drinking.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173932"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795012","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 : 2025-02-01DOI: 10.1016/j.pbb.2024.173929
Taena Hanson , Dustin J. Stairs
Impulsivity and behavioral inhibition are measures commonly associated with substance misuse, particularly cocaine use disorder. However, patterns of impulsive behaviors have been shown to differ based on cocaine use history and level of cocaine dependence. Extended cocaine access, which more closely models neural and behavioral changes that take place during the development of problematic cocaine use, has been shown to decrease behavioral inhibition in comparison to limited cocaine access. However, previous preclinical studies investigating these relationships have been mostly correlational and only utilize non-drug rewards. This study aims to utilize a differential rates of low reinforcement (DRL) schedule to investigate the impact of extended access to cocaine on behavioral inhibition toward a cocaine reinforcer. Male Sprague Dawley rats first self-administered intravenous cocaine infusions on a DRL schedule of reinforcement before being split into two groups: one given 6-h extended cocaine access (LgA) and one given 1-h short cocaine access (ShA) for 10 daily sessions. Following a washout period, the rats were placed back on DRL cocaine self-administration sessions. Results revealed that LgA rats showed impaired performance on the behavioral inhibition measure during the DRL self-administration sessions compared to baseline DRL performance and compared to ShA post-access behavioral inhibition measures. These results indicate that extended cocaine access impairs an organism's behavioral inhibition toward future cocaine use, indicating that those individuals with a history of heavy cocaine use will have impaired behavioral inhibition toward future cocaine use.
{"title":"Long- vs short-access cocaine alters behavioral inhibition for cocaine in male rats","authors":"Taena Hanson , Dustin J. Stairs","doi":"10.1016/j.pbb.2024.173929","DOIUrl":"10.1016/j.pbb.2024.173929","url":null,"abstract":"<div><div>Impulsivity and behavioral inhibition are measures commonly associated with substance misuse, particularly cocaine use disorder. However, patterns of impulsive behaviors have been shown to differ based on cocaine use history and level of cocaine dependence. Extended cocaine access, which more closely models neural and behavioral changes that take place during the development of problematic cocaine use, has been shown to decrease behavioral inhibition in comparison to limited cocaine access. However, previous preclinical studies investigating these relationships have been mostly correlational and only utilize non-drug rewards. This study aims to utilize a differential rates of low reinforcement (DRL) schedule to investigate the impact of extended access to cocaine on behavioral inhibition toward a cocaine reinforcer. Male Sprague Dawley rats first self-administered intravenous cocaine infusions on a DRL schedule of reinforcement before being split into two groups: one given 6-h extended cocaine access (LgA) and one given 1-h short cocaine access (ShA) for 10 daily sessions. Following a washout period, the rats were placed back on DRL cocaine self-administration sessions. Results revealed that LgA rats showed impaired performance on the behavioral inhibition measure during the DRL self-administration sessions compared to baseline DRL performance and compared to ShA post-access behavioral inhibition measures. These results indicate that extended cocaine access impairs an organism's behavioral inhibition toward future cocaine use, indicating that those individuals with a history of heavy cocaine use will have impaired behavioral inhibition toward future cocaine use.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173929"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792210","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 : 2025-02-01DOI: 10.1016/j.pbb.2024.173928
Catherine F. Moore , William W. Stoops
{"title":"The role of reward in substance use disorders: Introduction to the special issue","authors":"Catherine F. Moore , William W. Stoops","doi":"10.1016/j.pbb.2024.173928","DOIUrl":"10.1016/j.pbb.2024.173928","url":null,"abstract":"","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173928"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755470","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 : 2025-02-01DOI: 10.1016/j.pbb.2024.173902
Martina Krakora Compagno , Claudia Rose Silver , Alexis Cox-Holmes , Kari B. Basso , Caroline Bishop , Amber Michal Bernstein , Aidan Carley , Joshua Cazorla , Jenna Claydon , Ashleigh Crane , Chloe Crespi , Emma Curley , Tyla Dolezel , Ezabelle Franck , Katie Heiden , Carley Marie Huffstetler , Ashley M. Loeven , Camilla Ann May , Nicholas Maykut , Alejandro Narvarez , Debra Ann Fadool
Rationale
The consequences of perinatal cannabidiol (CBD) exposure are severely understudied, but are important, given its widespread use and believed safety as a natural supplement.
Objective
The objective of this study was to test the health, metabolic, and behavioral consequences of perinatal CBD exposure on dams and their offspring raised to adult.
Methods
Primiparous female C57BL/6J mice were orally administered 100 mg/kg CBD in strawberry jam to expose offspring during gestation, lactation, or both using a cross-fostering design. Adult offspring were metabolically profiled using indirect calorimetry and intraperitoneal glucose tolerance testing. Adults were behaviorally phenotyped, video recorded, and mouse position tracked using DeepLabCut.
Results
CBD was detected in maternal plasma using LC-MS 10-min post consumption (34.2 ± 1.7 ng/μl) and peaked within 30 min (371.0 ± 34.0 ng/μl). Fetal exposure to CBD significantly decreased survival of the pups, and decreased male postnatal development, but did not alter litter size, maternal body weight or pup birth weight. We observed many sex-dependent effects of perinatal CBD exposure. Exposure to CBD during gestation and lactation increased meal size, caloric intake, and respiratory exchange ratio for adult male offspring, while exposure during lactation decreased fasting glucose, but had no effect on clearance. Adult female offspring exposed to CBD during lactation showed increased drink size. Perinatal CBD exposure increased obsessive compulsive- and decreased anxiety-like behaviors (marble burying, light-dark box, elevated-plus maze) in female mice, decreased long-term object memory in male mice, and had no effect on attention tasks for either sex.
Conclusions
We conclude that orally-administered CBD during pregnancy affects behavior and metabolism in a sex-dependent manner, and mice are differentially sensitive to exposure during gestation vs. lactation, or both. Because long-term changes are observed following perinatal exposure to the drug, and exposure significantly decreases survival to weaning, more research during development is warranted.
{"title":"Maternal ingestion of cannabidiol (CBD) in mice leads to sex-dependent changes in memory, anxiety, and metabolism in the adult offspring, and causes a decrease in survival to weaning age","authors":"Martina Krakora Compagno , Claudia Rose Silver , Alexis Cox-Holmes , Kari B. Basso , Caroline Bishop , Amber Michal Bernstein , Aidan Carley , Joshua Cazorla , Jenna Claydon , Ashleigh Crane , Chloe Crespi , Emma Curley , Tyla Dolezel , Ezabelle Franck , Katie Heiden , Carley Marie Huffstetler , Ashley M. Loeven , Camilla Ann May , Nicholas Maykut , Alejandro Narvarez , Debra Ann Fadool","doi":"10.1016/j.pbb.2024.173902","DOIUrl":"10.1016/j.pbb.2024.173902","url":null,"abstract":"<div><h3>Rationale</h3><div>The consequences of perinatal cannabidiol (CBD) exposure are severely understudied, but are important, given its widespread use and believed safety as a natural supplement.</div></div><div><h3>Objective</h3><div>The objective of this study was to test the health, metabolic, and behavioral consequences of perinatal CBD exposure on dams and their offspring raised to adult.</div></div><div><h3>Methods</h3><div>Primiparous female C57BL/6J mice were orally administered 100 mg/kg CBD in strawberry jam to expose offspring during gestation, lactation, or both using a cross-fostering design. Adult offspring were metabolically profiled using indirect calorimetry and intraperitoneal glucose tolerance testing. Adults were behaviorally phenotyped, video recorded, and mouse position tracked using DeepLabCut.</div></div><div><h3>Results</h3><div>CBD was detected in maternal plasma using LC-MS 10-min post consumption (34.2 ± 1.7 ng/μl) and peaked within 30 min (371.0 ± 34.0 ng/μl). Fetal exposure to CBD significantly decreased survival of the pups, and decreased male postnatal development, but did not alter litter size, maternal body weight or pup birth weight. We observed many sex-dependent effects of perinatal CBD exposure. Exposure to CBD during gestation and lactation increased meal size, caloric intake, and respiratory exchange ratio for adult male offspring, while exposure during lactation decreased fasting glucose, but had no effect on clearance. Adult female offspring exposed to CBD during lactation showed increased drink size. Perinatal CBD exposure increased obsessive compulsive- and decreased anxiety-like behaviors (marble burying, light-dark box, elevated-plus maze) in female mice, decreased long-term object memory in male mice, and had no effect on attention tasks for either sex.</div></div><div><h3>Conclusions</h3><div>We conclude that orally-administered CBD during pregnancy affects behavior and metabolism in a sex-dependent manner, and mice are differentially sensitive to exposure during gestation vs. lactation, or both. Because long-term changes are observed following perinatal exposure to the drug, and exposure significantly decreases survival to weaning, more research during development is warranted.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173902"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558458","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}
To identify some novel fatty acid hydrolase (FAAH) inhibitors that may contribute to the treatment of Alzheimer's disease (AD).
Methods
In-silico pharmacophore modelling including ligand-based pharmacophore modelling, virtual screening, molecular docking, molecular dynamics modelling, density functional theory and in-silico pharmacokinetics and toxicological studies were employed for the retrieving of novel FAAH inhibitors. Further, these compounds were evaluated for FAAH inhibitory activity using an in vitro enzymatic assay, and later, an in vivo streptozotocin (STZ)-induced AD model was examined in mice.
Results
Using an in-silico pharmacophore modelling process with molecular docking, molecular dynamic modelling, density functional theory and in-silico pharmacokinetics and toxicological analysis, three compounds (NCI1697, NCI1001and NCI1041) were retrieved. The in vitro FAAH activity assay kit (Fluorometric) was employed to examine the FAAH inhibitory activity of identified compounds. Further, in in-vivo studies, treatment with these compounds at 2.5 and 5 mg/kg doses orally for 10 days restored the STZ-induced memory deficits in mice, as evident in the radial arm and Morris's water maze assays. Also, these compounds ameliorated oxidative stress profiles and neuroinflammatory biomarkers in mice. Interestingly, STZ-induced disturbance in gene expressions related to AD pathophysiology including endocannabinoid signalling neuroinflammation and neuroimmune signalling were also restored after the treatment. Histopathological findings also confirmed the improvement in the organization of cells and reduction in vacuolation in mice hippocampal tissue in treated mice.
Conclusion
The in-silico, in vitro and in-vivo findings collectively indicated that these compounds have impressive FAAH inhibitory activity and may be developed as therapeutic agents in the management of AD.
{"title":"Discovery of novel fatty acid amide hydrolase (FAAH) inhibitors as anti-alzheimer agents via in-silico-based drug design, virtual screening, molecular docking, molecular dynamics simulation, DFT, and non-clinical studies","authors":"Smita Jain , Ritu Singh , Tripti Paliwal , Kanika Verma , Jaya Dwivedi , Sarvesh Paliwal , Swapnil Sharma","doi":"10.1016/j.pbb.2024.173943","DOIUrl":"10.1016/j.pbb.2024.173943","url":null,"abstract":"<div><h3>Aim</h3><div>To identify some novel fatty acid hydrolase (FAAH) inhibitors that may contribute to the treatment of Alzheimer's disease (AD).</div></div><div><h3>Methods</h3><div>In-silico pharmacophore modelling including ligand-based pharmacophore modelling, virtual screening, molecular docking, molecular dynamics modelling, density functional theory and in-silico pharmacokinetics and toxicological studies were employed for the retrieving of novel FAAH inhibitors. Further, these compounds were evaluated for FAAH inhibitory activity using an in vitro enzymatic assay, and later, an in vivo streptozotocin (STZ)-induced AD model was examined in mice.</div></div><div><h3>Results</h3><div>Using an in-silico pharmacophore modelling process with molecular docking, molecular dynamic modelling, density functional theory and in-silico pharmacokinetics and toxicological analysis, three compounds (NCI1697, NCI1001and NCI1041) were retrieved. The in vitro FAAH activity assay kit (Fluorometric) was employed to examine the FAAH inhibitory activity of identified compounds. Further, in in-vivo studies, treatment with these compounds at 2.5 and 5 mg/kg doses orally for 10 days restored the STZ-induced memory deficits in mice, as evident in the radial arm and Morris's water maze assays. Also, these compounds ameliorated oxidative stress profiles and neuroinflammatory biomarkers in mice. Interestingly, STZ-induced disturbance in gene expressions related to AD pathophysiology including endocannabinoid signalling neuroinflammation and neuroimmune signalling were also restored after the treatment. Histopathological findings also confirmed the improvement in the organization of cells and reduction in vacuolation in mice hippocampal tissue in treated mice.</div></div><div><h3>Conclusion</h3><div>The in-silico, in vitro and in-vivo findings collectively indicated that these compounds have impressive FAAH inhibitory activity and may be developed as therapeutic agents in the management of AD.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173943"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818863","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 : 2025-02-01DOI: 10.1016/j.pbb.2024.173950
Talita Rodrigues , Getulio Nicola Bressan , Patrícia Zorzi Juliani , Maria Eduarda Brandli da Silva , Roselei Fachinetto
Schizophrenia is a mental disorder characterized by positive, negative, and cognitive symptoms which is treated with antipsychotics. However, these drugs present several side effects and, some schizophrenia symptoms, like cognitive, are difficult to treat. The peroxisome proliferator-activated receptors-gamma (PPAR-γ) are expressed in dopaminergic neurons of the midbrain participating in the modulation of dopamine-mediated behavior . We investigated the effects of pioglitazone, an agonist of PPAR-γ, on the behavioral alterations induced by ketamine and, whether alterations in monoamine oxidase (MAO) activity, glutamic acid decarboxylase (GAD67), PPAR-γ or tyrosine hydroxylase (TH) immunoreactivity in brain tissues are involved in these effects. Male mice received ketamine (30 mg/kg), intraperitoneally, for 14 consecutive days, and pioglitazone (3 or 9 mg/kg), by gavage (day 8 up to day 14). Ketamine decreased nail-biting increasing the time exploring the center of the open field on day 8 and the number of rearing evaluated 30 min after its administration on day 14. Furthermore, ketamine decreased the percentage of investigation in the NOR test and the immunoreactivity of GAD67 in the hippocampus. No significant changes were found in other behavioral and biochemical tests. Pioglitazone attenuated the effects of ketamine on rearing and GAD67 immunoreactivity in the hippocampus, recovering the ketamine effects on NOR test. At a dose of 9 mg/kg, pioglitazone alone reduced the immunoreactivity of GAD67 in the hippocampus. Pioglitazone at both doses recovered the cognitive symptoms induced by ketamine an effect that seems to involve the modulation of GAD67 immunoreactivity in the hippocampus. In conclusion, pioglitazone improved the effects of ketamine on the NOR test which was, at least in part, associated with the modulation of GAD67 immunoreactivity in the hippocampus suggesting its beneficial role in cognitive symptoms.
{"title":"Ketamine impairs the performance of male mice in novel recognition object test and reduces the immunoreactivity of GAD67 in the hippocampus: Role of pioglitazone","authors":"Talita Rodrigues , Getulio Nicola Bressan , Patrícia Zorzi Juliani , Maria Eduarda Brandli da Silva , Roselei Fachinetto","doi":"10.1016/j.pbb.2024.173950","DOIUrl":"10.1016/j.pbb.2024.173950","url":null,"abstract":"<div><div>Schizophrenia is a mental disorder characterized by positive, negative, and cognitive symptoms which is treated with antipsychotics. However, these drugs present several side effects and, some schizophrenia symptoms, like cognitive, are difficult to treat. The peroxisome proliferator-activated receptors-gamma (PPAR-γ) are expressed in dopaminergic neurons of the midbrain participating in the modulation of dopamine-mediated behavior . We investigated the effects of pioglitazone, an agonist of PPAR-γ, on the behavioral alterations induced by ketamine and, whether alterations in monoamine oxidase (MAO) activity, glutamic acid decarboxylase (GAD<sub>67</sub>), PPAR-γ or tyrosine hydroxylase (TH) immunoreactivity in brain tissues are involved in these effects. Male mice received ketamine (30 mg/kg), intraperitoneally, for 14 consecutive days, and pioglitazone (3 or 9 mg/kg), by gavage (day 8 up to day 14). Ketamine decreased nail-biting increasing the time exploring the center of the open field on day 8 and the number of rearing evaluated 30 min after its administration on day 14. Furthermore, ketamine decreased the percentage of investigation in the NOR test and the immunoreactivity of GAD<sub>67</sub> in the hippocampus. No significant changes were found in other behavioral and biochemical tests. Pioglitazone attenuated the effects of ketamine on rearing and GAD<sub>67</sub> immunoreactivity in the hippocampus, recovering the ketamine effects on NOR test. At a dose of 9 mg/kg, pioglitazone alone reduced the immunoreactivity of GAD<sub>67</sub> in the hippocampus. Pioglitazone at both doses recovered the cognitive symptoms induced by ketamine an effect that seems to involve the modulation of GAD<sub>67</sub> immunoreactivity in the hippocampus. In conclusion, pioglitazone improved the effects of ketamine on the NOR test which was, at least in part, associated with the modulation of GAD<sub>67</sub> immunoreactivity in the hippocampus suggesting its beneficial role in cognitive symptoms.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173950"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896629","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 : 2025-02-01DOI: 10.1016/j.pbb.2024.173944
Johanna E.L. Möller , Franziska W. Schmitt , Daniel Günther , Alicia Stöver , Yvonne Bouter
Background
Alzheimer's disease (AD) is characterized by cognitive decline, with pathological features including amyloid β (Aβ) plaques and inflammation. Despite recent approvals of anti-amyloid antibodies, there remains a need for disease-modifying and easily accessible therapies. The endocannabinoid system presents a promising target for AD treatment, as it regulates various processes implicated in AD pathogenesis.
Aims
This study assesses the effects of the synthetic cannabinoid WIN 55,212-2 on AD pathology and behavior deficits in aged 5XFAD mice, a well-established AD model.
Methods
Male 9-month-old 5XFAD mice received either 0.2 mg/kg WIN 55,212-2 or a vehicle solution for 42 days. Memory, anxiety, and motor tests were conducted at 10 months to identify potential changes in behavior and cognition following WIN 55,212-2 treatment. Additionally, the effects of prolonged WIN 55,212-2 treatment on Aβ pathology and neuroinflammation in the brain were quantified immunohistochemically.
Results
Therapeutic WIN 55,212-2 treatment improved the motor performance of 5XFAD mice on the rotarod and rescued memory deficits in the water maze. However, WIN 55,212-2 treatment did not significantly affect anxiety-like behavior in 5XFAD mice. Additionally, prolonged treatment with WIN 55,212-2 reduced Aβ plaque pathology and astrogliosis in the cortex and hippocampus.
Conclusions
This study highlights the therapeutic potential of WIN 55,212-2 in AD by ameliorating cognitive and motor deficits and reducing neuropathology. These findings support a cannabinoid-based therapy as a promising strategy for AD treatment, with WIN 55,212-2 emerging as a potential candidate.
{"title":"The synthetic cannabinoid WIN 55,212-2 attenuates cognitive and motor deficits and reduces amyloid load in 5XFAD Alzheimer mice","authors":"Johanna E.L. Möller , Franziska W. Schmitt , Daniel Günther , Alicia Stöver , Yvonne Bouter","doi":"10.1016/j.pbb.2024.173944","DOIUrl":"10.1016/j.pbb.2024.173944","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD) is characterized by cognitive decline, with pathological features including amyloid β (Aβ) plaques and inflammation. Despite recent approvals of anti-amyloid antibodies, there remains a need for disease-modifying and easily accessible therapies. The endocannabinoid system presents a promising target for AD treatment, as it regulates various processes implicated in AD pathogenesis.</div></div><div><h3>Aims</h3><div>This study assesses the effects of the synthetic cannabinoid WIN 55,212-2 on AD pathology and behavior deficits in aged 5XFAD mice, a well-established AD model.</div></div><div><h3>Methods</h3><div>Male 9-month-old 5XFAD mice received either 0.2 mg/kg WIN 55,212-2 or a vehicle solution for 42 days. Memory, anxiety, and motor tests were conducted at 10 months to identify potential changes in behavior and cognition following WIN 55,212-2 treatment. Additionally, the effects of prolonged WIN 55,212-2 treatment on Aβ pathology and neuroinflammation in the brain were quantified immunohistochemically.</div></div><div><h3>Results</h3><div>Therapeutic WIN 55,212-2 treatment improved the motor performance of 5XFAD mice on the rotarod and rescued memory deficits in the water maze. However, WIN 55,212-2 treatment did not significantly affect anxiety-like behavior in 5XFAD mice. Additionally, prolonged treatment with WIN 55,212-2 reduced Aβ plaque pathology and astrogliosis in the cortex and hippocampus.</div></div><div><h3>Conclusions</h3><div>This study highlights the therapeutic potential of WIN 55,212-2 in AD by ameliorating cognitive and motor deficits and reducing neuropathology. These findings support a cannabinoid-based therapy as a promising strategy for AD treatment, with WIN 55,212-2 emerging as a potential candidate.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173944"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828694","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}
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