Pub Date : 2025-07-24DOI: 10.1016/j.pbb.2025.174072
Madeline K. Elsey , Nina M. Beltran , Katherine M. Serafine
High fat diets are linked to several negative health consequences in humans including disrupted insulin signaling, and research with rodents has demonstrated that these diets can also increase individual sensitivity to drugs that act on dopamine systems. Since ketogenic diets have different effects on weight and insulin signaling than traditional high fat diets, it was hypothesized that a ketogenic diet (high in fat but very low in carbohydrates) might not increase sensitivity of rats to dopaminergic drugs. To test this hypothesis rats eating standard chow (17 % kcal from fat), high fat chow (60 % kcal from fat), or ketogenic chow (90.5 % kal from fat) were tested once weekly with quinpirole [0.0032–0.32 mg/kg, intraperitoneally (i.p.)] or methamphetamine (0.1–3.2 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and methamphetamine. While eating a ketogenic chow did not impact sensitivity to quinpirole, rats eating ketogenic chow were more sensitive than rats eating standard chow to methamphetamine-induced locomotion, but only at the largest cumulative dose tested. These results suggest that traditional high fat diets and ketogenic diets might produce similar, but non-identical effects on sensitivity to the behavioral effects of dopaminergic drugs.
{"title":"Eating a ketogenic diet enhances sensitivity of rats to the effects of methamphetamine, but not dopamine D2/D3 receptor agonist quinpirole","authors":"Madeline K. Elsey , Nina M. Beltran , Katherine M. Serafine","doi":"10.1016/j.pbb.2025.174072","DOIUrl":"10.1016/j.pbb.2025.174072","url":null,"abstract":"<div><div>High fat diets are linked to several negative health consequences in humans including disrupted insulin signaling, and research with rodents has demonstrated that these diets can also increase individual sensitivity to drugs that act on dopamine systems. Since ketogenic diets have different effects on weight and insulin signaling than traditional high fat diets, it was hypothesized that a ketogenic diet (high in fat but very low in carbohydrates) might not increase sensitivity of rats to dopaminergic drugs. To test this hypothesis rats eating standard chow (17 % kcal from fat), high fat chow (60 % kcal from fat), or ketogenic chow (90.5 % kal from fat) were tested once weekly with quinpirole [0.0032–0.32 mg/kg, intraperitoneally (i.p.)] or methamphetamine (0.1–3.2 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and methamphetamine. While eating a ketogenic chow did not impact sensitivity to quinpirole, rats eating ketogenic chow were more sensitive than rats eating standard chow to methamphetamine-induced locomotion, but only at the largest cumulative dose tested. These results suggest that traditional high fat diets and ketogenic diets might produce similar, but non-identical effects on sensitivity to the behavioral effects of dopaminergic drugs.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174072"},"PeriodicalIF":2.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718303","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 : 2025-07-15DOI: 10.1016/j.pbb.2025.174071
Gauri Vishen Singh , Chetna , Amarjot Kaur Grewal , Ojashvi Sharma , Amit Kumar , Heena Khan , Varinder Singh , Pragati Silakari , Thakur Gurjeet Singh , Tanveer Singh , Sheikh F. Ahmad , Haneen A. Al-Mazroua
Chronic unpredictable stress (CUS) is a significant contributor to neurobehavioral changes, via disrupted cellular homeostasis, corticosterone and altered neurotransmitter dynamics. The PERK (Protein Kinase RNA-like Endoplasmic Reticulum Kinase)-TFEB (Transcription factor EB) pathway integrates stress responses with autophagy and lysosomal biogenesis to maintain cellular resilience, influencing oxidative stress, neuroinflammation and neurodegeneration. Hence, this study was intended to explore the possible involvement of PERK-TFEB pathway in mediating the neuroprotective effects of SB202190 (a PERK activator) in mitigating neurobehavioral changes induced by CUS. For evaluating the impact pharmacological interventions on neurobehavioral alterations, the Swiss albino either sex mice were subjected to different stressors for 8 weeks. The parameters for anxiety-like behaviour, depressive-like behaviour and memory impairment were assessed by elevated plus maze, sucrose preference test, tail suspension test, forced swim test, Morris water maze and passive avoidance task. The levels of corticosterone, dopamine, serotonin, biochemical parameters of oxidative stress, inflammatory mediators, and acetylcholinesterase (AChE) activity along with the histological changes were also examined. Administration of SB202190 (5 and 10 mg/kg) improved anxiety-like behaviour, depression-like behaviour, spatial learning and memory retention, histological changes; restored corticosterone, dopamine levels, AChE activity, oxidative stress and inflammatory markers and serotonin levels in CUS-exposed mice compared to controls. Molecular docking studies were carried out to reveal the binding interaction of SB202190 with TFEB, suggesting that it may modulate TFEB activity. It was also observed that these neuroprotective effects of SB202190 were significantly abolished by pre-treatment with eltrombopag (50 mg/kg, p.o.), a TFEB inhibitor, which signifies the involvement of TFEB signalling in protective mechanism of SB202190 that may have resulted in enhancement of TFEB-mediated autophagy. Therefore, this study highlights the critical role of PERK- TFEB pathway in neuroprotection as well as highlights mechanism and therapeutic potential of SB202190 in alleviating neurobehavioral changes and memory dysfunction associated with chronic unpredictable stress.
{"title":"PERK activation mediates neuroprotection against chronic unpredictable stress-induced neurobehavioral changes via the TFEB pathway","authors":"Gauri Vishen Singh , Chetna , Amarjot Kaur Grewal , Ojashvi Sharma , Amit Kumar , Heena Khan , Varinder Singh , Pragati Silakari , Thakur Gurjeet Singh , Tanveer Singh , Sheikh F. Ahmad , Haneen A. Al-Mazroua","doi":"10.1016/j.pbb.2025.174071","DOIUrl":"10.1016/j.pbb.2025.174071","url":null,"abstract":"<div><div>Chronic unpredictable stress (CUS) is a significant contributor to neurobehavioral changes, <em>via</em> disrupted cellular homeostasis, corticosterone and altered neurotransmitter dynamics. The PERK (Protein Kinase RNA-like Endoplasmic Reticulum Kinase)-TFEB (Transcription factor EB) pathway integrates stress responses with autophagy and lysosomal biogenesis to maintain cellular resilience, influencing oxidative stress, neuroinflammation and neurodegeneration. Hence, this study was intended to explore the possible involvement of PERK-TFEB pathway in mediating the neuroprotective effects of SB202190 (a PERK activator) in mitigating neurobehavioral changes induced by CUS. For evaluating the impact pharmacological interventions on neurobehavioral alterations, the Swiss albino either sex mice were subjected to different stressors for 8 weeks. The parameters for anxiety-like behaviour, depressive-like behaviour and memory impairment were assessed by elevated plus maze, sucrose preference test, tail suspension test, forced swim test, Morris water maze and passive avoidance task. The levels of corticosterone, dopamine, serotonin, biochemical parameters of oxidative stress, inflammatory mediators, and acetylcholinesterase (AChE) activity along with the histological changes were also examined. Administration of SB202190 (5 and 10 mg/kg) improved anxiety-like behaviour, depression-like behaviour, spatial learning and memory retention, histological changes; restored corticosterone, dopamine levels, AChE activity, oxidative stress and inflammatory markers and serotonin levels in CUS-exposed mice compared to controls. Molecular docking studies were carried out to reveal the binding interaction of SB202190 with TFEB, suggesting that it may modulate TFEB activity. It was also observed that these neuroprotective effects of SB202190 were significantly abolished by pre-treatment with eltrombopag (50 mg/kg, p.o.), a TFEB inhibitor, which signifies the involvement of TFEB signalling in protective mechanism of SB202190 that may have resulted in enhancement of TFEB-mediated autophagy. Therefore, this study highlights the critical role of PERK- TFEB pathway in neuroprotection as well as highlights mechanism and therapeutic potential of SB202190 in alleviating neurobehavioral changes and memory dysfunction associated with chronic unpredictable stress.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174071"},"PeriodicalIF":3.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659809","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 : 2025-07-12DOI: 10.1016/j.pbb.2025.174062
Guanyun Bian , Jian Liu , Yanping Hui , Libo Li , Yaxin Yang , Qiaojun Zhang
Non-motor symptoms such as cognitive deficits are often observed in Parkinson's disease, and the effect of L-3,4-dihydroxyphenylalanin (L-DOPA) treatment on working memory in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra compacta (SNc) and underlying mechanisms are unclear. In adult male Sprague-Dawley rats, we found that L-DOPA treatment in SNc-lesioned rats reversed working memory impairment, decreased the firing rate of the lateral habenula (LHb) neurons, increased dopamine (DA) levels in the medial prefrontal cortex (mPFC) and hippocampus, and reversed reduced expression of M-channel Kv7.2 subunit in the LHb compared with SNc-lesioned rats treated with normal saline (NS). Intra-LHb injection of M-channel activator retigabine or blocker XE-991 induced enhancement or impairment of working memory in SNc-lesioned rats treated with L-DOPA, along with alterations of DA levels in the mPFC and hippocampus. However, the same doses of the two drugs produced no significant effects on working memory and DA levels in SNc-lesioned rats treated with NS. Further, M-channel activate or blockade decreased or increased the firing rate of LHb neurons, and the duration of M-channel stimulation on the firing rate of the neurons in SNc-lesioned rats treated L-DOPA was longer than those in SNc-lesioned rats treated with NS, which was consistent with up-regulation of Kv7.2 subunit in the LHb. Collectively, these findings suggest that L-DOPA treatment up-regulates the expression of M-channel Kv7.2 subunit in the LHb, and then induces decreased activity of LHb neurons and increased DA levels in the mPFC and hippocampus, which reverse working memory impairment in parkinsonian rats.
{"title":"L-DOPA reverses the impaired working memory via lateral habenula Kv7.2 subunit-containing M-channels in experimental parkinsonism","authors":"Guanyun Bian , Jian Liu , Yanping Hui , Libo Li , Yaxin Yang , Qiaojun Zhang","doi":"10.1016/j.pbb.2025.174062","DOIUrl":"10.1016/j.pbb.2025.174062","url":null,"abstract":"<div><div>Non-motor symptoms such as cognitive deficits are often observed in Parkinson's disease, and the effect of L-3,4-dihydroxyphenylalanin (L-DOPA) treatment on working memory in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra compacta (SNc) and underlying mechanisms are unclear. In adult male Sprague-Dawley rats, we found that L-DOPA treatment in SNc-lesioned rats reversed working memory impairment, decreased the firing rate of the lateral habenula (LHb) neurons, increased dopamine (DA) levels in the medial prefrontal cortex (mPFC) and hippocampus, and reversed reduced expression of M-channel Kv7.2 subunit in the LHb compared with SNc-lesioned rats treated with normal saline (NS). Intra-LHb injection of M-channel activator retigabine or blocker XE-991 induced enhancement or impairment of working memory in SNc-lesioned rats treated with L-DOPA, along with alterations of DA levels in the mPFC and hippocampus. However, the same doses of the two drugs produced no significant effects on working memory and DA levels in SNc-lesioned rats treated with NS. Further, M-channel activate or blockade decreased or increased the firing rate of LHb neurons, and the duration of M-channel stimulation on the firing rate of the neurons in SNc-lesioned rats treated L-DOPA was longer than those in SNc-lesioned rats treated with NS, which was consistent with up-regulation of Kv7.2 subunit in the LHb. Collectively, these findings suggest that L-DOPA treatment up-regulates the expression of M-channel Kv7.2 subunit in the LHb, and then induces decreased activity of LHb neurons and increased DA levels in the mPFC and hippocampus, which reverse working memory impairment in parkinsonian rats.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174062"},"PeriodicalIF":3.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626938","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 : 2025-07-10DOI: 10.1016/j.pbb.2025.174063
Shannon M. Lopez , Magdalena R. Gonzales , Bryan D. Alvarez , Leslie R. Amodeo , Dionisio A. Amodeo
The serotonin (5-HT) 6 receptor has recently emerged as a novel target for the treatment of cognitive deficits seen in known neuropsychiatric disorders. While much of the research has concentrated on understanding the therapeutic effects of 5-HT6 receptor antagonists, much less is known regarding the behavioral impact of 5-HT6 agonist treatment. The current study examined the impact of 5-HT6 receptor partial agonist EMD 386088 on behavioral flexibility in an operant probabilistic reversal learning paradigm. Female and male C57BL/6J mice were trained on an 80 %/20 % probabilistic discrimination task until the learning criterion was reached. As predicted, mice did not differ in trials or days to reach criterion during this initial acquisition phase. Once the learning criterion was met, the probabilistic 80 %/20 % contingencies were reversed. Mice received EMD 386088 (1 or 5 mg/kg) or vehicle control administration before each reversal learning session. Mice treated with 1 mg/kg EMD 386088 took significantly fewer trials to reach reversal learning criterion compared to controls. Conversely, the 5 mg/kg dosage did not affect trials or days to reach reversal criterion. While EMD 386088 treated female mice tended to display enhanced reversal learning, there were no significant sex differences. Enhanced reversal learning in the 1 mg/kg group coincided with an increase in the probability of win-stay behavior compared to controls. Thus, the 1.0 mg/kg dose of EMD 386088 may lead to an increase the animals' sensitivity to the reinforced trials during learning. These findings highlight the benefits of repeated 5-HT6 receptor activation on facilitating behavioral flexibility.
{"title":"Repeated 5-HT6 receptor activation facilitates flexible behavior in C57BL/6J mice","authors":"Shannon M. Lopez , Magdalena R. Gonzales , Bryan D. Alvarez , Leslie R. Amodeo , Dionisio A. Amodeo","doi":"10.1016/j.pbb.2025.174063","DOIUrl":"10.1016/j.pbb.2025.174063","url":null,"abstract":"<div><div>The serotonin (5-HT) 6 receptor has recently emerged as a novel target for the treatment of cognitive deficits seen in known neuropsychiatric disorders. While much of the research has concentrated on understanding the therapeutic effects of 5-HT6 receptor antagonists, much less is known regarding the behavioral impact of 5-HT6 agonist treatment. The current study examined the impact of 5-HT6 receptor partial agonist EMD 386088 on behavioral flexibility in an operant probabilistic reversal learning paradigm. Female and male C57BL/6J mice were trained on an 80 %/20 % probabilistic discrimination task until the learning criterion was reached. As predicted, mice did not differ in trials or days to reach criterion during this initial acquisition phase. Once the learning criterion was met, the probabilistic 80 %/20 % contingencies were reversed. Mice received EMD 386088 (1 or 5 mg/kg) or vehicle control administration before each reversal learning session. Mice treated with 1 mg/kg EMD 386088 took significantly fewer trials to reach reversal learning criterion compared to controls. Conversely, the 5 mg/kg dosage did not affect trials or days to reach reversal criterion. While EMD 386088 treated female mice tended to display enhanced reversal learning, there were no significant sex differences. Enhanced reversal learning in the 1 mg/kg group coincided with an increase in the probability of win-stay behavior compared to controls. Thus, the 1.0 mg/kg dose of EMD 386088 may lead to an increase the animals' sensitivity to the reinforced trials during learning. These findings highlight the benefits of repeated 5-HT6 receptor activation on facilitating behavioral flexibility.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174063"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619713","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 : 2025-07-10DOI: 10.1016/j.pbb.2025.174061
Belle Buzzi , Burhan Buttar , Yasmine Groener , M. Imad Damaj
Commencement of smoking at an early age increases the number of cigarettes smoked per day and decreases the likelihood of successful cessation later in life. To date, little is known about the effects that adolescent nicotine exposure has on aspects of nicotine dependence in adulthood. In this study, we examined the effects of adolescent nicotine exposure on nicotine reward and withdrawal in adulthood. Adolescent mice [postnatal day (PND) 28–34] were exposed to nicotine short-term (0.5 mg/kg, subcutaneous (s.c.) twice a day for one day) or repeatedly (0.1 and 0.5 mg/kg, s.c. twice daily for seven days). In adulthood (PND 70) these mice were implanted with osmotic nicotine minipumps for 14 days and 24 h later spontaneous nicotine withdrawal affective (anxiety-like behavior and hyperalgesia) and physical (somatic signs) signs were assessed. Short-term pre-exposure to nicotine during adolescence did not produce alterations in affective or physical nicotine withdrawal signs in adulthood. However, repeated nicotine exposure during adolescence partially reduced nicotine withdrawal signs in adulthood but increases nicotine reward in the conditioned place preference (CPP) test. Interestingly, adult mice exposed to chronic nicotine (0.5 mg/kg,s.c. twice daily for seven days) did not affect nicotine withdrawal signs and reward later in adulthood. This mouse study highlights nicotine exposure during the unique period of adolescence as an important factor for nicotine dependence later in life.
{"title":"Adolescent nicotine exposure affects later-life nicotine reward and withdrawal in mice","authors":"Belle Buzzi , Burhan Buttar , Yasmine Groener , M. Imad Damaj","doi":"10.1016/j.pbb.2025.174061","DOIUrl":"10.1016/j.pbb.2025.174061","url":null,"abstract":"<div><div>Commencement of smoking at an early age increases the number of cigarettes smoked per day and decreases the likelihood of successful cessation later in life. To date, little is known about the effects that adolescent nicotine exposure has on aspects of nicotine dependence in adulthood. In this study, we examined the effects of adolescent nicotine exposure on nicotine reward and withdrawal in adulthood. Adolescent mice [postnatal day (PND) 28–34] were exposed to nicotine short-term (0.5 mg/kg, subcutaneous (s.c.) twice a day for one day) or repeatedly (0.1 and 0.5 mg/kg, s.c. twice daily for seven days). In adulthood (PND 70) these mice were implanted with osmotic nicotine minipumps for 14 days and 24 h later spontaneous nicotine withdrawal affective (anxiety-like behavior and hyperalgesia) and physical (somatic signs) signs were assessed. Short-term pre-exposure to nicotine during adolescence did not produce alterations in affective or physical nicotine withdrawal signs in adulthood. However, repeated nicotine exposure during adolescence partially reduced nicotine withdrawal signs in adulthood but increases nicotine reward in the conditioned place preference (CPP) test. Interestingly, adult mice exposed to chronic nicotine (0.5 mg/kg,s.c. twice daily for seven days) did not affect nicotine withdrawal signs and reward later in adulthood. This mouse study highlights nicotine exposure during the unique period of adolescence as an important factor for nicotine dependence later in life.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174061"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595928","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 : 2025-07-04DOI: 10.1016/j.pbb.2025.174059
Daniel Bussinger de Souza Penna , Samara Gumiéro Costa , Marina Pollis Davis , Karin da Costa Calaza , Alexandre dos Santos Rodrigues , Pablo Pandolfo
Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by impairments in executive functions, including behavioral inhibition and working memory. The most widely accepted neurobiological explanation for ADHD is related to dopaminergic hypofunction. The dopaminergic system is modulated by endocannabinoid ligands, primarily through the action of cannabinoid receptors type 1 and 2 (CB1R and CB2R) within frontostriatal circuits. Spontaneously hypertensive rats (SHR) are a widely used animal model for studying the neurobiology of ADHD. Our recent study demonstrated that acute treatment with synthetic CB1R and CB2R ligands increased hyperactivity and risk-taking behavior in SHR. We now investigate how chronic modulation of these receptors affects hyperactivity, risk-taking behavior, and working memory assessment in SHR. As expected, the SHR exhibited hyperactivity, difficulties in risk assessment, impaired working memory, and increased risk-taking behavior. Notably, females SHR displayed higher levels of locomotion and risk-taking behavior than their male counterparts, regardless of treatment. Chronic modulation of CB1R and CB2R did not lead to significant changes in any of the evaluated behavioral parameters. Further research is needed to understand both the acute and chronic effects of manipulating cannabinoid receptors and endocannabinoids in the context of ADHD.
{"title":"Chronic modulation of endocannabinoid receptors does not impact hyperactivity, risk behavior, and working memory in an animal model of attention-deficit/hyperactivity disorder","authors":"Daniel Bussinger de Souza Penna , Samara Gumiéro Costa , Marina Pollis Davis , Karin da Costa Calaza , Alexandre dos Santos Rodrigues , Pablo Pandolfo","doi":"10.1016/j.pbb.2025.174059","DOIUrl":"10.1016/j.pbb.2025.174059","url":null,"abstract":"<div><div>Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by impairments in executive functions, including behavioral inhibition and working memory. The most widely accepted neurobiological explanation for ADHD is related to dopaminergic hypofunction. The dopaminergic system is modulated by endocannabinoid ligands, primarily through the action of cannabinoid receptors type 1 and 2 (CB1R and CB2R) within frontostriatal circuits. Spontaneously hypertensive rats (SHR) are a widely used animal model for studying the neurobiology of ADHD. Our recent study demonstrated that acute treatment with synthetic CB1R and CB2R ligands increased hyperactivity and risk-taking behavior in SHR. We now investigate how chronic modulation of these receptors affects hyperactivity, risk-taking behavior, and working memory assessment in SHR. As expected, the SHR exhibited hyperactivity, difficulties in risk assessment, impaired working memory, and increased risk-taking behavior. Notably, females SHR displayed higher levels of locomotion and risk-taking behavior than their male counterparts, regardless of treatment. Chronic modulation of CB1R and CB2R did not lead to significant changes in any of the evaluated behavioral parameters. Further research is needed to understand both the acute and chronic effects of manipulating cannabinoid receptors and endocannabinoids in the context of ADHD.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"254 ","pages":"Article 174059"},"PeriodicalIF":3.3,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563821","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 : 2025-07-04DOI: 10.1016/j.pbb.2025.174060
Rafaela Mostallino , Francesca Caria , Aurora Musa , Gessica Piras , Anastasija Ture , Maksims Vanejevs , Antonio Laus , Graziella Tocco , Gaetano Di Chiara , M. Paola Castelli , Maria Antonietta De Luca
The development of new μ-opioid receptor (MOR) antagonists has been stimulated by the opioid overdose crisis. Our earlier in silico investigations on ligand-MOR receptor interactions indicated that the ligand cis-equatorial conformation of the amine and phenol is the most likely orientation observed within the MOR receptor. Here, we synthesized and characterized AT-99 [3-(1,3-dimethyl-cis-5-(methyl(phenethyl)amino)cyclohexyl)phenol] as a new in vivo and in vitro MOR antagonist. AT-99 effectively blocked MOR-mediated G protein activation by the agonists fentanyl and DAMGO, similarly to the reference compound, the opioid antagonist naloxone (NAL). Moreover, AT-99 behaves as a neutral MOR antagonist since it failed to stimulate [35S]GTPγS binding, but it dose-dependently inhibited DAMGO-induced [35S]GTPγS binding. While 0.1 μM NAL significantly reduced DAMGO potency, AT-99 produced a comparable effect only at the highest concentration tested. Furthermore, in radioligand competition binding assays, AT-99 fully displaced specific [3H]DAMGO binding in a concentration-dependent manner, although with lower affinity than NAL. In vivo, AT-99 (1 or 3 mg/kg i.v.) dose-dependently reduced the increase of dialysate dopamine (DA) in the nucleus accumbens (NAc) shell induced by morphine (1 mg/kg i.v.). Notably, AT-99 at the highest dose tested counteracted the reduction of behavioral rating scale (BRS) induced by morphine. Altogether, these data indicate that, although AT-99 interacts with the MOR relatively weakly, it displays interesting MOR antagonist properties, and as such it might serve as a scaffold to develop more potent MOR antagonists.
{"title":"The novel synthesized naltrexone-related MOR antagonist AT-99 counteracts dopamine releasing and behavioral depressant morphine-induced effects","authors":"Rafaela Mostallino , Francesca Caria , Aurora Musa , Gessica Piras , Anastasija Ture , Maksims Vanejevs , Antonio Laus , Graziella Tocco , Gaetano Di Chiara , M. Paola Castelli , Maria Antonietta De Luca","doi":"10.1016/j.pbb.2025.174060","DOIUrl":"10.1016/j.pbb.2025.174060","url":null,"abstract":"<div><div>The development of new μ-opioid receptor (MOR) antagonists has been stimulated by the opioid overdose crisis. Our earlier <em>in silico</em> investigations on ligand-MOR receptor interactions indicated that the ligand cis-equatorial conformation of the amine and phenol is the most likely orientation observed within the MOR receptor. Here, we synthesized and characterized AT-99 [3-(1,3-dimethyl-<em>cis</em>-5-(methyl(phenethyl)amino)cyclohexyl)phenol] as a new <em>in vivo</em> and <em>in vitro</em> MOR antagonist. AT-99 effectively blocked MOR-mediated G protein activation by the agonists fentanyl and DAMGO, similarly to the reference compound, the opioid antagonist naloxone (NAL). Moreover, AT-99 behaves as a neutral MOR antagonist since it failed to stimulate [<sup>35</sup>S]GTPγS binding, but it dose-dependently inhibited DAMGO-induced [<sup>35</sup>S]GTPγS binding. While 0.1 μM NAL significantly reduced DAMGO potency, AT-99 produced a comparable effect only at the highest concentration tested. Furthermore, in radioligand competition binding assays, AT-99 fully displaced specific [<sup>3</sup>H]DAMGO binding in a concentration-dependent manner, although with lower affinity than NAL. <em>In vivo</em>, AT-99 (1 or 3 mg/kg i.v.) dose-dependently reduced the increase of dialysate dopamine (DA) in the nucleus accumbens (NAc) shell induced by morphine (1 mg/kg i.v.). Notably, AT-99 at the highest dose tested counteracted the reduction of behavioral rating scale (BRS) induced by morphine. Altogether, these data indicate that, although AT-99 interacts with the MOR relatively weakly, it displays interesting MOR antagonist properties, and as such it might serve as a scaffold to develop more potent MOR antagonists.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174060"},"PeriodicalIF":2.5,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576019","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 : 2025-07-02DOI: 10.1016/j.pbb.2025.174057
Shuang Wang , Yuning Wang , Li Meng , Haishui Shi , Xueyong Yin , Hao Feng , Xincheng Li , Xiaoyu Liu , Yun Shi , Yuan Gao
Chronic stress has been widely reported to be related to alterations in emotional behaviors of individuals, yet the potential effects of post-weaning stress (PWS) and the associated mechanisms are still poorly understood. Mitochondria-associated endoplasmic reticulum membranes (MAM) play crucial roles in cellular energy metabolism, calcium homeostasis, lipid synthesis, and have been highlighted in recent studies for their importance in the nervous system. This study aims to explore how PWS affects behaviors, especially aggressive behavior and social hierarchy, and whether MAM plays a role in this process in ICR mice.
Various behavioral assessments were employed to measure different behaviors: the open field test (OFT) and elevated plus maze (EPM) for anxiety-like behavior, the resident-intruder test (RIT) and defensive aggression test (DAT) for aggressive behavior, and the social dominance test (SDT) to evaluate social hierarchy. Transmission electron microscopy and Immunofluorescence staining were used to analyze the MAM structure in the neurons of hypothalamus, a crucial brain region that regulates the various behaviors described above. The findings indicated that PWS reduced weight gain and elevated social hierarchy in male mice. Behavioral effects were assay-specific: aggression decreased in the RIT (attack frequency/time) but not the DAT, while anxiety-like behaviors showed mixed results (increased open-arm exploration in EPM but no OFT changes). Females exhibited reduced locomotion without aggression or anxiety alterations. Notably, a decrease in mitochondrial-endoplasmic reticulum contact was observed, accompanied by decreased voltage-dependent anion channel 1 (VDAC1) in males and increased inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in females. These alterations may influence energy metabolism and stress responses, potentially contributing to the observed behavioral changes. These findings emphasize the importance of understanding the neurobiological underpinnings of aggression and stress response, particularly in relation to stress experienced during early life.
{"title":"Post-weaning unpredictable mild stress affects social behaviors and mitochondria-associated endoplasmic reticulum membranes in adult mice","authors":"Shuang Wang , Yuning Wang , Li Meng , Haishui Shi , Xueyong Yin , Hao Feng , Xincheng Li , Xiaoyu Liu , Yun Shi , Yuan Gao","doi":"10.1016/j.pbb.2025.174057","DOIUrl":"10.1016/j.pbb.2025.174057","url":null,"abstract":"<div><div>Chronic stress has been widely reported to be related to alterations in emotional behaviors of individuals, yet the potential effects of post-weaning stress (PWS) and the associated mechanisms are still poorly understood. Mitochondria-associated endoplasmic reticulum membranes (MAM) play crucial roles in cellular energy metabolism, calcium homeostasis, lipid synthesis, and have been highlighted in recent studies for their importance in the nervous system. This study aims to explore how PWS affects behaviors, especially aggressive behavior and social hierarchy, and whether MAM plays a role in this process in ICR mice.</div><div>Various behavioral assessments were employed to measure different behaviors: the open field test (OFT) and elevated plus maze (EPM) for anxiety-like behavior, the resident-intruder test (RIT) and defensive aggression test (DAT) for aggressive behavior, and the social dominance test (SDT) to evaluate social hierarchy. Transmission electron microscopy and Immunofluorescence staining were used to analyze the MAM structure in the neurons of hypothalamus, a crucial brain region that regulates the various behaviors described above. The findings indicated that PWS reduced weight gain and elevated social hierarchy in male mice. Behavioral effects were assay-specific: aggression decreased in the RIT (attack frequency/time) but not the DAT, while anxiety-like behaviors showed mixed results (increased open-arm exploration in EPM but no OFT changes). Females exhibited reduced locomotion without aggression or anxiety alterations. Notably, a decrease in mitochondrial-endoplasmic reticulum contact was observed, accompanied by decreased voltage-dependent anion channel 1 (VDAC1) in males and increased inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in females. These alterations may influence energy metabolism and stress responses, potentially contributing to the observed behavioral changes. These findings emphasize the importance of understanding the neurobiological underpinnings of aggression and stress response, particularly in relation to stress experienced during early life.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"254 ","pages":"Article 174057"},"PeriodicalIF":3.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565086","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 : 2025-07-02DOI: 10.1016/j.pbb.2025.174058
Sari Izenwasser
{"title":"Novel insights into kappa and delta opioid receptor function across systems and disorders. Introduction to the special issue","authors":"Sari Izenwasser","doi":"10.1016/j.pbb.2025.174058","DOIUrl":"10.1016/j.pbb.2025.174058","url":null,"abstract":"","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"254 ","pages":"Article 174058"},"PeriodicalIF":3.3,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144536044","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 : 2025-06-28DOI: 10.1016/j.pbb.2025.174056
Lee-Yuan Liu-Chen, Peng Huang
Reports in the 1990s and 2000s showed that kappa opioid receptor (KOR) agonists might be promising for treatment and/or prevention of opioid use disorder (OUD) and cocaine use disorder (CUD). However, the side effects associated with KOR agonists available at the time, such as psychotomimesis, dysphoria and sedation, prevented clinical development. Subsequently, nalfurafine and recently triazole 1.1 and oxa-noribogaine, three centrally acting KOR agonists devoid of such side effects, have been studied in animal models of OUD and CUD. By and large, earlier findings with typical KOR agonists were replicated with nalfurafine and in limited studies with triazole 1.1 and oxa-noribogaine. KOR agonists reduced reinforcing effects of mu opioid receptor (MOR) agonists and decreased tolerance to and dependence on MOR agonists. Oxa-noribogaine suppressed cue-induced reinstatement of morphine and fentanyl seeking. KOR agonists countered itch elicited by MOR agonists and produced additive analgesic effects with MOR agonists, thus allowing use of lower doses of MOR and KOR agonists, resulting in lower degrees of MOR-related side effects (such as respiratory depression) and typical KOR-associated side effects. In addition, KOR agonists attenuated locomotor sensitization and conditioned place preference sensitization following repeated cocaine, reduced acquisition and maintenance of cocaine self-administration and decreased cocaine-induced increase in extracellular dopamine. KOR agonists also suppressed cocaine priming-induced reinstatement of cocaine seeking. Therefore, a combination of a KOR agonist and a MOR agonist or a compound with dual KOR/MOR agonist activities when used as analgesics will deter escalation use of MOR agonists, thus prevent OUD, and KOR agonists may be useful for treatment of cocaine abuse and relapse. Importantly, KOR agonists with no or fewer side effects of typical KOR agonists should be further investigated in animal models of OUD and CUD, particularly those that simulate stress-, cue- and drug priming-induced relapse for potential clinical development.
{"title":"KOR agonists for the treatment and/or prevention of opioid use disorder and cocaine use disorder","authors":"Lee-Yuan Liu-Chen, Peng Huang","doi":"10.1016/j.pbb.2025.174056","DOIUrl":"10.1016/j.pbb.2025.174056","url":null,"abstract":"<div><div>Reports in the 1990s and 2000s showed that kappa opioid receptor (KOR) agonists might be promising for treatment and/or prevention of opioid use disorder (OUD) and cocaine use disorder (CUD). However, the side effects associated with KOR agonists available at the time, such as psychotomimesis, dysphoria and sedation, prevented clinical development. Subsequently, nalfurafine and recently triazole 1.1 and oxa-noribogaine, three centrally acting KOR agonists devoid of such side effects, have been studied in animal models of OUD and CUD. By and large, earlier findings with typical KOR agonists were replicated with nalfurafine and in limited studies with triazole 1.1 and oxa-noribogaine. KOR agonists reduced reinforcing effects of mu opioid receptor (MOR) agonists and decreased tolerance to and dependence on MOR agonists. Oxa-noribogaine suppressed cue-induced reinstatement of morphine and fentanyl seeking. KOR agonists countered itch elicited by MOR agonists and produced additive analgesic effects with MOR agonists, thus allowing use of lower doses of MOR and KOR agonists, resulting in lower degrees of MOR-related side effects (such as respiratory depression) and typical KOR-associated side effects. In addition, KOR agonists attenuated locomotor sensitization and conditioned place preference sensitization following repeated cocaine, reduced acquisition and maintenance of cocaine self-administration and decreased cocaine-induced increase in extracellular dopamine. KOR agonists also suppressed cocaine priming-induced reinstatement of cocaine seeking. Therefore, a combination of a KOR agonist and a MOR agonist or a compound with dual KOR/MOR agonist activities when used as analgesics will deter escalation use of MOR agonists, thus prevent OUD, and KOR agonists may be useful for treatment of cocaine abuse and relapse. Importantly, KOR agonists with no or fewer side effects of typical KOR agonists should be further investigated in animal models of OUD and CUD, particularly those that simulate stress-, cue- and drug priming-induced relapse for potential clinical development.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"254 ","pages":"Article 174056"},"PeriodicalIF":3.3,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529152","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号