Pharmacology Biochemistry and Behavior最新文献

{"title":"Amplification of the therapeutic potential of AMPA receptor potentiators from the nootropic era to today.","authors":"Daniel P Radin, Arnold Lippa, Sabhya Rana, David D Fuller, Jodi L Smith, Rok Cerne, Jeffrey M Witkin","doi":"10.1016/j.pbb.2025.173967","DOIUrl":"https://doi.org/10.1016/j.pbb.2025.173967","url":null,"abstract":"<p><p>α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPA receptors or AMPARs) are involved in fast excitatory neurotransmission and as such control multiple important physiological processes. AMPARs also are involved in the dynamics of synaptic plasticity in the nervous system where they impact neuroplastic responses such as long-term facilitation and long-term potentiation that regulate biological functions ranging from breathing to cognition. AMPARs also regulate neurotrophic factors that are strategically involved in neural plastic changes in the nervous system. As with other major ionotropic receptors, modulation of AMPARs can have prominent effects on biological systems that can include marked tolerability issues. AMPAR potentiators (AMPAkines) are positive allosteric modulators of AMPARs which have clear therapeutic potential. Medicinal chemistry combined with new pharmacological findings have defined AMPAkines with favorable oral bioavailability and pharmacological safety parameters that enable clinical advancement of their therapeutic utility. AMPAkines are being investigated in patients with diverse neurological and psychiatric disorders including spinal cord injury (breathing and bladder function), cognition, attention-deficit-hyperactivity disorder, and major depressive disorder. The present discussion of this class of compounds focuses on their general value as therapeutics through their impact on synaptic plasticity.</p>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":" ","pages":"173967"},"PeriodicalIF":3.3,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Desvenlafaxine with mindfulness-based cognitive therapy reduces Hamilton anxiety scores compared to escitalopram with mindfulness-based cognitive therapy in treatment-resistant generalized anxiety disorder","authors":"Karthik Sankar ,&nbsp;Sandhiya Ramesh ,&nbsp;Natarajan Shanmugasundaram ,&nbsp;Deepika Anbalagan ,&nbsp;Varadharajan Sivaraman ,&nbsp;Venkatesan Singaram ,&nbsp;Srikanth Jeyabalan","doi":"10.1016/j.pbb.2025.173959","DOIUrl":"10.1016/j.pbb.2025.173959","url":null,"abstract":"<div><h3>Background</h3><div>This study aims to assess the effectiveness of low-dose Escitalopram (10 mg) or low-dose Desvenlafaxine (25 mg) combined with mindfulness-based cognitive therapy (MBCT) in addressing challenges in treating generalized anxiety disorder (GAD), particularly in patients resistant to conventional therapies.</div></div><div><h3>Methods</h3><div>A prospective cohort study was conducted with individuals diagnosed with treatment-resistant GAD. group A included patients unresponsive to citalopram, imipramine, paroxetine, and sertraline, who were then treated with low-dose Escitalopram (10 mg) combined with MBCT. group B comprised those unresponsive to venlafaxine and duloxetine, who were treated with Desvenlafaxine (25 mg) alongside MBCT. Participants were monitored over 24 weeks for changes in Hamilton Anxiety Rating Scale (HAM-A) and Mindful Attention Awareness Scale (MAAS) scores, with medication adherence measured using the Medication Adherence Rating Scale (MARS). The primary outcomes focused on the improvement in anxiety symptoms and overall mental well-being.</div></div><div><h3>Results</h3><div>Comparative analysis between the groups showed significant improvement in HAM-A and MAAS scores at week 16 in group B compared to group A (<em>P</em> &lt; 0.01). Within-group analysis also demonstrated a significant reduction in scores at week 12 in group B compared to group A at week 16 (P &lt; 0.01). No significant difference was observed in medication adherence between the two groups (<em>P</em> = 0.122).</div></div><div><h3>Conclusion</h3><div>Patients treated with low-dose Desvenlafaxine combined with MBCT exhibited greater improvements in managing treatment-resistant GAD compared to those treated with low-dose Escitalopram. This approach highlights the potential for more inclusive and effective mental health strategies, contributing to enhanced quality of life and well-being.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"248 ","pages":"Article 173959"},"PeriodicalIF":3.3,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NMDA-induced lesions of the nucleus accumbens core increase the innately rewarding saccharin solution intake and methamphetamine-induced conditioned place preference but not conditioned taste aversion in rats","authors":"Cai-N Cheng ,&nbsp;Anna Kozłowska ,&nbsp;Wei-Lun Li ,&nbsp;Chi-Wen Wu ,&nbsp;Ying-Chou Wang ,&nbsp;Andrew Chih Wei Huang","doi":"10.1016/j.pbb.2025.173957","DOIUrl":"10.1016/j.pbb.2025.173957","url":null,"abstract":"<div><div>The role of the nucleus accumbens (NAc) core in determining the valence of innately rewarding saccharin solution intake, methamphetamine (MAMPH)-induced conditioned taste aversion (CTA), and conditioned place preference (CPP) reward remains unclear. The present study utilized the “pre- and post-association” experimental paradigm (2010) to test whether the rewarding and aversive properties of MAMPH can be modulated by an <em>N</em>-methyl-D-aspartic acid (NMDA) lesion in the NAc core. Moreover, it tested how an NAc core NMDA lesion affected the innate reward of saccharin solution intake. The results demonstrate that MAMPH could simultaneously induce an aversive CTA and a rewarding CPP effect, supporting the paradoxical effect hypothesis of abused drugs, in particular amphetamine. Meanwhile, the NMDA-lesioned NAc core increased the reward effect of CPP but did not alter the aversive CTA effect. The NAc core NMDA lesion also enhanced the innate reward of saccharin solution intake. The NAc core therefore seemingly plays an inhibitory role in the innate reward of saccharin solution intake and in the CPP effect. The paradoxical effect hypothesis of abused drugs provides some explanations for the present data in the case of MAMPH administrations. The NAc core may play an essential role in modulating the rewarding but not the aversive properties of MAMPH. The present findings could contribute to the understanding and eventual advancement of clinical interventions for drug addiction and the development of novel pharmacological treatments.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"248 ","pages":"Article 173957"},"PeriodicalIF":3.3,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential reductions in alcohol consumption and cue-induced alcohol-seeking behavior following mGlu5 receptor inhibition in the prelimbic vs. infralimbic subregions of the rat prefrontal cortex","authors":"Jonna M. Leyrer-Jackson ,&nbsp;Peter R. Kufahl ,&nbsp;M. Foster Olive","doi":"10.1016/j.pbb.2025.173958","DOIUrl":"10.1016/j.pbb.2025.173958","url":null,"abstract":"<div><div>Glutamatergic signaling is one of the primary targets of actions of alcohol in the brain, and dysregulated excitatory transmission in the prefrontal cortex (PFC) may contribute problematic drinking and relapse. A prominent component of glutamate signaling is the type 5 metabotropic glutamate (mGlu5) receptor. However, little is known about the role of this receptor type in subregions of the PFC that regulate either alcohol intake or alcohol-seeking behavior. Here we examined the effects of microinfusions of the selective mGlu5 inhibitor 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) into either the prelimbic (PL) or infralimbic (IL) regions of the PFC on alcohol intake or cue-evoked reinstatement of alcohol-seeking behavior. Adult male Wistar rats were trained to self-administer 10 % alcohol in the presence of compound discriminative stimuli (SD) signaling alcohol availability (S+) or non-availability (S-). In one group of animals, effects of locally administered MTEP (0, 0.5 or 1 μg/μl) into either the PL or IL on active alcohol intake were examined. MTEP was without effect on alcohol self-administration when infused into the PL, but decreased alcohol intake at both doses tested when infused into the IL. In separate groups of animals, we examined effects of locally administered MTEP (0, 0.5 or 1 μg/μl) into either the PL or IL on reinstatement of alcohol seeking elicited by alcohol predictive stimuli (S+). When infused into the PL, MTEP attenuated cue-induced reinstatement only at the higher dose tested (1 μg/μl), but when infused into the IL, MTEP reduced cue-induced reinstatement at both doses tested (0.5 μg/μl and 1 μg/μl). Together, these results suggest a largely preferential role for mGlu5 signaling in the IL vs. PL in regulating both alcohol self-administration behavior and cue-elicited alcohol seeking. Neuromodulatory approaches aimed at reducing mGlu5 signaling in the IL may therefore be of potential therapeutic value in problematic alcohol use.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"248 ","pages":"Article 173958"},"PeriodicalIF":3.3,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneous activation of different subtypes of dopamine receptors may lead to activation of homeostatic sleep regulatory mechanisms","authors":"Dóra Keserű ,&nbsp;Tünde Hajnik ,&nbsp;Máté Pethő ,&nbsp;László Détári ,&nbsp;Maarten Van Den Bossche ,&nbsp;Attila Tóth","doi":"10.1016/j.pbb.2025.173954","DOIUrl":"10.1016/j.pbb.2025.173954","url":null,"abstract":"<div><div>Dopaminergic system gains importance in homeostatic sleep regulation, but the role of different dopamine receptors is not well-defined. 72 h rat electrocorticogram and sleep recordings were made after single application of dopaminergic drugs in clinical use or at least underwent clinical trials. The non-selective agonist apomorphine evoked short pharmacological sleep deprivation with intense wakefulness followed by pronounced sleep rebound. D2 agonist bromocriptine induced moderate and extended increase in wakefulness without a homeostatic sleep replacement but downregulated slow wave sleep need for 72 h. Selective D1 agonist SKF-38393 failed to induce enhanced waking sufficient for sleep replacement. High-dose D2 antagonism by sulpiride temporarily enhanced wakefulness. All drugs evoked extended (72 h) sleep changes after single application. Opposite sleep changes could be seen after the application of different doses in case of both bromocriptine and sulpiride.</div><div>Theta, beta and gamma power reflected intensity differences in drug-induced wakefulness stages. Apomorphine- and high sulpiride dose-induced waking showed elevated power in all three frequency bands. Bromocriptine-induced wakefulness dominated by beta activity. Enhancement of more, than one type of electrocorticogram activities during wakefulness was a prerequisite for the activation of sleep homeostasis.</div><div>According to present data, D1- or D2-like receptor agonism are not separately involved in the homeostatic regulation of slow wave sleep. Simultaneous and non-selective agonism on DA receptors is the most effective way to elicit intense W, which is followed by slow wave sleep rebound. REM sleep rebound could be evoked by D2 agonism. Rebound indicates the activation of homeostatic sleep regulation, but with unknown exact mechanisms.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"248 ","pages":"Article 173954"},"PeriodicalIF":3.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Photobiomodulation using an 830-nm laser alleviates hippocampal reactive gliosis and cognitive dysfunction in a mouse model of adolescent chronic alcohol exposure","authors":"Namgue Hong ,&nbsp;Sung-Ryeong Yoon ,&nbsp;Jin-Chul Ahn","doi":"10.1016/j.pbb.2025.173956","DOIUrl":"10.1016/j.pbb.2025.173956","url":null,"abstract":"<div><div>Chronic alcoholism is known to have detrimental effects on the brain, including cognitive impairment, neurotransmitter imbalances, and brain atrophy. The hippocampus, crucial for spatial memory and cognitive functions, is particularly susceptible to alcohol-induced changes. Photobiomodulation (PBM), a non-invasive therapeutic method that utilizes red or near-infrared light, has shown promising applications in the central and peripheral nervous systems. Near-infrared (NIR) light, in particular, has been shown to prevent apoptosis, and neuroinflammation, as well as to improve cognitive functions. In this study, we aimed to investigate whether 830-nm laser irradiation could mitigate cognitive deficits in a chronic alcohol mouse model. Chronic alcoholism was induced in C57BL/6 mice through continuous ethanol gavage for 4 weeks at a dosage of 5 g/kg/day. Gavaging was performed 3 times per week for 4 weeks. Mice were transcranial irradiated by 830-nm laser, following making a chronic alcohol mouse model. Laser irradiation (50 mW/cm²) was performed 5 times per week for 3 weeks. To verify memory and cognitive defeats of a chronic alcohol mouse model, we performed animal behavior tasks such as Morris water maze, Y maze, and novel objective recognition. Our results confirmed the cognitive impairment in the chronic alcohol mouse model compared to the control group in conducted tasks. However, cognitive and spatial memory significantly improved following 830-nm laser irradiation. Additionally, we confirmed whether the behavior tasks result from histological changes. We performed immunofluorescence staining in the hippocampus region (CA3, CA1 and hilus) using astrocyte (GFAP) and microglia (Iba1) markers. As a result, reactive astrocyte was significantly increased in the chronic alcohol mouse model compared to control mice, whereas the number of GFAP-positive cells was significantly reduced by 830-nm laser irradiation. These findings indicate that chronic alcohol exposure induces spatial memory and cognitive impairment, which can be effectively rescued through near-infrared laser irradiation.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"248 ","pages":"Article 173956"},"PeriodicalIF":3.3,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esketamine-mediated alleviation of electroconvulsive shock-induced memory impairment is associated with the regulation of mGluR5 in depressive-like rats","authors":"Yiwei Shen ,&nbsp;Wei Ran ,&nbsp;Dawei Liu ,&nbsp;Feng Lv ,&nbsp;Li Ren ,&nbsp;Su Min","doi":"10.1016/j.pbb.2025.173955","DOIUrl":"10.1016/j.pbb.2025.173955","url":null,"abstract":"<div><div>Electroconvulsive therapy (ECT) is recognized as one of the most efficacious interventions for depression. However, it is associated with impairments in learning and memory functions. Ketamine has demonstrated potential in mitigating cognitive deficits. Notably, the metabotropic glutamate system is hypothesized to play a pivotal role in cognitive process regulation. Nevertheless, the involvement of the metabotropic glutamate system in esketamine-mediated alleviation of electroconvulsive shock (ECS, an animal analogue of ECT)-induced memory impairment remains to be elucidated. In this study, a depressive rat model was established using chronic unpredictable mild stress. The depressive-like behavior and cognitive performance of the rats were evaluated using the sucrose preference test, the open field test, and the Morris water maze test, respectively. The expression levels of type-5 metabotropic glutamate receptor (mGluR5) and <em>N</em>-methyl-<span>d</span>-aspartate receptor 1 (NMDAR1) were quantified through immunofluorescence and real-time PCR techniques. Long-term potentiation (LTP) of hippocampal Schaffer collateral (SC)-CA1 synapses was observed in electrophysiological experiments. The results of this investigation revealed that a low dose of esketamine administration upregulated the expression of mGluR5 and NMDAR1 in the hippocampus of stressed rats, alleviated ECS-induced cognitive impairment, and ameliorated depressive-like behavior. Conversely, the mGluR5 antagonist MTEP effectively reversed esketamine-mediated changes in the rat hippocampus and counteracted its protective effect on learning and memory functions following ECS. In conclusion, the findings of this study support the hypothesis that esketamine upregulates mGluR5 and NMDAR1 expression, thereby enhancing NMDAR activation in the hippocampus. This mechanism may be responsible for the protective effects on spatial learning and memory function observed in depressed rats subjected to ECS.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"248 ","pages":"Article 173955"},"PeriodicalIF":3.3,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging medications and pharmacological treatment approaches for substance use disorders","authors":"Joel S. Raymond ,&nbsp;Alexander G. Athanasopoulos ,&nbsp;Connie J. Badolato ,&nbsp;Tylah J. Doolan ,&nbsp;Rhianne L. Scicluna ,&nbsp;Nicholas A. Everett ,&nbsp;Michael T. Bowen ,&nbsp;Morgan H. James","doi":"10.1016/j.pbb.2024.173952","DOIUrl":"10.1016/j.pbb.2024.173952","url":null,"abstract":"<div><div>Medications to treat substance use disorders (SUDs) remain suboptimal or, in the case of stimulants and cannabis, non-existent. Many factors have contributed to this paucity, including the biological complexity of addiction, regulatory challenges, and a historical lack of enthusiasm among pharmaceutical companies to commit resources to this disease space. Despite these headwinds, the recent opioid crisis has highlighted the devastating consequences of SUDs for both individuals and society, stimulating urgent efforts to identify novel treatment approaches. In addition, several neurobiological systems have been recently implicated in unique aspects of drug reward, opening the door to candidate medications with novel mechanisms of action. Here, we provide an overview of efforts to target several of these new systems, with a focus on those that are the subject of ongoing clinical trials as well as being areas of interest among the authors’ research groups (MHJ, MTB, NAE). Specifically, we discuss new classes of medications targeting the serotonin 2A receptor (i.e., psychedelics), glucagon-like peptide 1 receptor, cannabidiol, dynorphin/kappa opioid receptor, orexin/hypocretin, and oxytocin receptor systems, as well as emergent approaches for modulating the more canonical dopaminergic system via agonist therapies for stimulant use disorders. Collectively, innovations in this space give reason for optimism for an improved therapeutic landscape for substance use disorders in the near future.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"248 ","pages":"Article 173952"},"PeriodicalIF":3.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Region-specific neuroadaptations of CRF1 and CRF2 expression following heroin exposure in female rats","authors":"Piper Schneider ,&nbsp;Danielle Goldbaum ,&nbsp;Ansh Agarwal ,&nbsp;Ashton Taylor ,&nbsp;Peyton Sundberg ,&nbsp;Eliot L. Gardner ,&nbsp;Robert Ranaldi ,&nbsp;Zhi-Bing You ,&nbsp;Ewa Galaj","doi":"10.1016/j.pbb.2024.173931","DOIUrl":"10.1016/j.pbb.2024.173931","url":null,"abstract":"<div><div>While stress increases vulnerability to development of addiction, the recruitment of corticotropin releasing factor (CRF) with excessive drug use heightens the risk of stress-induced relapse. CRF signaling is transmitted via CRF1 and CRF2 receptors, but the roles of these receptors in heroin self-administration and related neuroadaptations of the CRF system within mesolimbic brain loci are not well understood. In this study, we first investigated the causal role of CRF1 and CRF2 receptors in heroin self-administration. Intracerebroventricular (ICV) microinjections of antalarmin (a CRF1 antagonist) or astressin-2B (a CRF2 antagonist) caused brief, dose-dependent reductions in heroin self-administration in female rats, suggesting that these receptors play a critical role in heroin-motivated behaviors. We then used western blotting to examine neuroadaptive changes to CRF1 and CRF2 receptor expression in key forebrain and midbrain regions associated with opioid addiction. Female Long Evans rats treated with escalating doses of heroin for 16 days demonstrated significantly higher naloxone-precipitated withdrawal symptoms than saline-treated rats. Heroin-treated rats showed a significant decrease in CRF1 receptor protein expression in the ventral tegmental area (VTA) and an increase in the nucleus accumbens (NAc) but no changes in the prefrontal cortex (PFC), insula, dorsal striatum (dSTR), dorsal hippocampus (dHippo), anterior hypothalamus (HYPTH), amygdala, or substantia nigra (SN) as compared to saline-treated rats. After chronic heroin exposure, CRF2 receptor expression was significantly downregulated in the dHippo, VTA and HYPTH but not in the other brain regions we investigated. The results of this study suggest that: (1) CRF1 and CRF2 receptors play an important role in self-administration and (2) heroin exposure may lead to region-specific neuroadaptation of CRF1 and CRF2 receptors. Such neuroadaptations might in part contribute to the continuation of drug use and stress-induced relapse.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"247 ","pages":"Article 173931"},"PeriodicalIF":3.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluoxetine treatment reverses chronic stress-induced promotion on Fk506-binding protein 5 expression and multiple effects on glucocorticoid receptor phosphorylation in the paraventricular nucleus of mice","authors":"Bao-Lun Zhu ,&nbsp;Jin-Yan Tang ,&nbsp;Wei-Jia Chen ,&nbsp;Jun-Jie Qian ,&nbsp;Feng Zhang ,&nbsp;Xiao-Ling Zhang ,&nbsp;Ting-ting Chen ,&nbsp;Bo Jiang ,&nbsp;He-Yan Zhao","doi":"10.1016/j.pbb.2024.173916","DOIUrl":"10.1016/j.pbb.2024.173916","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Fluoxetine is widely used as a first-line antidepressant. However, the molecular mechanisms for its antidepressant effects are still not fully understood. Hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is a core pathogenic mechanism contributing to depression, and fluoxetine treatment prevents this dysfunction. The glucocorticoid receptor (GR) is a major negative feedback regulator of the HPA axis, while Fk506-binding protein 5 (Fkbp5) is a negative regulator of the GR signaling. Therefore, we examined the effects of fluoxetine on Fkbp5 and the GR signaling in the hypothalamic paraventricular nucleus (PVN) of depressed mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Mice were exposed to chronic social defeat stress (CSDS), chronic unpredictable mild stress (CUMS), or chronic restraint stress (CRS) with or without fluoxetine treatment (intraperitoneally injected, 20 mg/kg) and examined for changes in depression-like behaviors and HPA axis activity as well as Fkbp5 expression and GR phosphorylation in the PVN. We then examined if adeno-associated virus (AAV)-mediated Fkbp5 overexpression in the PVN affected the antidepressant actions of fluoxetine in mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Fluoxetine treatment significantly mitigated CSDS-, CUMS-, and CRS-induced depression-like behaviors and HPA axis hyperactivity in mice. Subsequent western blotting analyses showed that fluoxetine treatment fully reversed not only chronic stress-induced upregulation of Fkbp5 and CRH but also chronic stress-induced increase in Ser203 phosphorylation and decrease in Ser211 and Ser234 phosphorylation in GR in the PVN. Moreover, quantitative real-time reverse transcription PCR (qRT-PCR) analyses revealed that the enhanced mRNA levels of Fkbp5 and CRH in PVN neurons of mice subjected to CSDS/CUMS/CRS were also notably reversed by fluoxetine administration. Conversely, Fkbp5 overexpression in the PVN significantly eliminated the antidepressant effects of fluoxetine in mice without affecting their locomotor activity.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;These results together suggest that fluoxetine treatment reverses chronic stress-induced promotion on Fkbp5 expression and multiple effects on GR phosphorylation in the PVN of mice.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Significance statement&lt;/h3&gt;&lt;div&gt;The selective serotonin reuptake inhibitor fluoxetine (sold as Prozac) is a widely used treatment for depression, but the full spectrum of therapeutic mechanisms is still debated. Recent evidence suggests that these therapeutic mechanisms include suppression of chronic stress-activated hypothalamus–pituitary–adrenal (HPA) axis. The current study presents the first in vivo evidence showing that suppression of HPA axis hyperactivity by fluoxetine treatment involves reversal of glucocorticoid receptor (GR) phosphorylation via modulation of the GR negative regulator Fk506-binding protein 5 (Fkbp5) in the hypothalamic paraventricular nucleus (PVN). ","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"246 ","pages":"Article 173916"},"PeriodicalIF":3.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142757490","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}