Psychopharmacology最新文献

{"title":"SK609, a novel dopamine D3 receptor agonist and norepinephrine transporter blocker with putative pro-cognitive actions, does not induce psychostimulant-like increases in risky choice during probabilistic discounting.","authors":"Christopher P Knapp, Brooke Fallon, Sandhya Kortagere, Barry D Waterhouse, Stan B Floresco, Rachel L Navarra","doi":"10.1007/s00213-024-06727-1","DOIUrl":"10.1007/s00213-024-06727-1","url":null,"abstract":"<p><strong>Rationale: </strong>Psychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter. SK609 has been shown to improve cognitive performance without increasing psychostimulant-like spontaneous locomotor activity, suggesting SK609 may benefit neurocognitive function without psychostimulant-like side effect liability.</p><p><strong>Objectives: </strong>We compared AMPH, MPH, and SK609 within dose ranges that display their cognitive enhancing properties in a probabilistic discounting task (PDT) of risk/reward decision making behavior to assess their potential to increase risky choice preference.</p><p><strong>Methods: </strong>Rats chose between small/certain rewards delivered with 100% certainty and large/risky rewards delivered with descending probabilities across a session (100 - 6.25%) following administration of AMPH (0.25-1 mg/kg), MPH (2-8 mg/kg), and SK609 (4 mg/kg).</p><p><strong>Results: </strong>AMPH and MPH increased risky choice behavior at doses previously reported to enhance cognition, whereas SK609 did not. AMPH and MPH also reduced sensitivity to non-rewarded risky choices.</p><p><strong>Conclusions: </strong>These data highlight the combination of NE transporter blockade and selective D3 activation in pro-cognitive action without psychostimulant-like side effect liability. The absence of DA transporter blockade and non-selective dopaminergic activation are beneficial properties of SK609 that differentiates it from the traditional pro-cognitive psychostimulants.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1291-1301"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TSPO activation ameliorates maternal immune activation induced PV interneuron deficits via BDNF/TrkB signaling.","authors":"Ming-Jie Mao, Hui-Ling Yu, Qing-Zhen Liu, Ya-Zhou Wen, Ming Jiang, Hong-Mei Yuan, Hua-Bei Zeng, Li-Dong Zhang, Shan-Wu Feng","doi":"10.1007/s00213-024-06728-0","DOIUrl":"10.1007/s00213-024-06728-0","url":null,"abstract":"<p><strong>Rationale: </strong>Prenatal maternal immune activation (MIA) is an etiological risk factor for schizophrenia in offspring. Recently, parvalbumin (PV) positive interneuron deficits has been considered a critical pathology of many psych-cognitive disorders. Nevertheless, whether and how prenatal MIA affected PV interneuron in offspring remains largely unknown.</p><p><strong>Objectives: </strong>Here, we aimed to assess the relationship between MIA with PV interneuron deficits in offspring, and explored the underling mechanisms.</p><p><strong>Methods and results: </strong>Mouse model of MIA was induced using lipopolysaccharide (120 µg/kg) on gestational day 15-17. Open field, elevated plus maze, Y-Maze and novel object recognition tests were performed and local field potential was recorded on adult male offspring. PV interneuron, Translocator protein 18 kDa (TSPO), and BDNF/TrkB signaling were then evaluated. Using TPSO agonist and TrkB antagonist, the function of TSPO on PV interneuron deficits was elucidated. Our results showed that MIA induced cognitive symptoms in the adult male offspring, accompanied by down-regulated PV and TSPO expression as well as decreased theta oscillation. Notably, activating TSPO reversed MIA-induced PV interneuron defects and behavioral abnormalities. Furthermore, specific inhibition of BDNF/TrkB signaling intercepted the protective effect of TSPO activation on PV interneuron deficits.</p><p><strong>Conclusions: </strong>Our results highlight TSPO activation might prevented PV interneuron deficits and behavioral abnormalities after MIA via BDNF/TrkB signaling.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1303-1319"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discriminative stimulus properties of α-ethyltryptamine (α-ET) in rats: α-ET-like effects of MDMA, MDA and aryl-monomethoxy substituted derivatives of α-ET.","authors":"Carmen Abate, Richard Young, Malgorzata Dukat, Richard A Glennon","doi":"10.1007/s00213-024-06738-y","DOIUrl":"10.1007/s00213-024-06738-y","url":null,"abstract":"<p><p>Rationale α-ET (α-ethyltryptamine), a homolog of the classical hallucinogen α-methyltryptamine, was once prescribed clinically as an antidepressant. Classical psychedelic drugs are currently of interest as potential pharmacotherapy for psychiatric disorders. Objectives Drug discrimination was used to (a) determine if α-ET-like stimulus effects could be engendered by the prototypical phenylalkylamines MDMA (\"Ecstasy\") or MDA (\"Love Drug\") and (b) evaluate the α-ET-like stimulus effects of four synthesized aryl-substituted monomethoxy analogs of α-ET (4-OMe-, 5-OMe-, 6-OMe- and 7-OMe-α-ET). Methods Rats were trained to discriminate α-ET (2.5 mg/kg) from saline using a two-lever operant task. Results The α-ET (ED₅₀ = 1.04 mg/kg) stimulus generalized to MDMA (ED₅₀ = 0.72 mg/kg) and MDA (ED₅₀ = 0.48 mg/kg). The four α-ET derivatives produced various results; 4-OMe α-ET yielded negligible (20% maximum) α-ET-like responding; 5-OMe α-ET occasioned a modest level (40% maximum) of α-ET-like substitution; 6-OMe α-ET (ED₅₀ = 6.26 mg/kg) generalized completely, but in a narrow dose range and in an inverted U-shaped manner; 7-OMe α-ET (ED₅₀ = 2.78 mg/kg) generalized completely. Conclusions α-ET stimulus effects are similar to those of MDMA, but appear more closely aligned to those of MDA and are produced by its stereoisomers which, when combined, exert MDA/MDMA-, hallucinogen- and some stimulant-like stimulus actions. Thus, α-ET exerts a complex (compound) stimulus and appears to be a tryptamine counterpart of these prototypic phenylalkylamines. The monomethoxy analogs of α-ET produced an assortment of α-ET-like outcomes such that future investigations of these agents will likely need to be performed on an individual basis; extrapolations of α-ET-like effects to these analogs should be done judiciously.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1407-1418"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bidirectional modulation of reward-guided decision making by dopamine.","authors":"Ana Antonia Dias Maile, Theo O J Gruendler, Adrian G Fischer, Hannah Kurtenbach, Luca F Kaiser, Monja I Froböse, Gerhard Jocham","doi":"10.1007/s00213-025-06816-9","DOIUrl":"https://doi.org/10.1007/s00213-025-06816-9","url":null,"abstract":"<p><strong>Rationale: </strong>The neuromodulator dopamine is known to play a key role in reward-guided decision making, where choice options are often characterized by multiple attributes. Different decision strategies can be used to merge these choice attributes with personal preferences (e.g., risk preferences) and integrate them into a single subjective value. While the influence of dopamine on risk preferences has been investigated, it is unknown whether dopamine is also involved in arbitrating between decision strategies.</p><p><strong>Objective: </strong>In the present study, we investigate the effects of pharmacological dopamine manipulations on arbitrating between different decision strategies in a healthy sample.</p><p><strong>Methods: </strong>31 healthy male participants performed a reward-guided decision-making task under the influence of the dopamine D₂/D₃-receptor antagonist amisulpride (400 mg), the dopamine precursor L-DOPA (100 mg L-DOPA + 25 mg cardidopa), or placebo in a double-blind within-subject design. The effect of dopamine on reward-guided decisions and decision strategies was analyzed using hierarchical implementations of regressions and Bayesian models.</p><p><strong>Results: </strong>Notably, we observed that the dopaminergic interventions shifted the (overall) weighting of option attributes without changing how option attributes are integrated into a subjective value (decision strategy). These effects were bidirectional: Amisulpride reduced whereas L-DOPA increased the degree to which choices were influenced by both reward magnitude and reward probability. These effects occurred in the absence of changes in statistically optimal behavior.</p><p><strong>Conclusion: </strong>Together, our data provide evidence for a role of dopamine in controlling the influence of value parameters on choice irrespective of decision strategies.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal and early postnatal cannabis exposure interactions with adolescent chronic stress on anxiety-like, depression-like, and risk-taking behaviour.","authors":"Colleen S Peterson, Ijeoma Ifionu, Fatima Hamood, Hadi Semizeh, Ahmad Ali, Duncan Noble, Min Qiao, Stephanie L Borgland","doi":"10.1007/s00213-025-06822-x","DOIUrl":"https://doi.org/10.1007/s00213-025-06822-x","url":null,"abstract":"<p><strong>Rationale: </strong>Low socioeconomic status people make up a majority of those who use cannabis during pregnancy. Both developmental cannabis exposure and developmental stress increase the risk of developing psychiatric disorders; however, the interaction of these factors has not been studied.</p><p><strong>Objectives: </strong>This study examined whether prenatal and early postnatal cannabis exposure (PPCE) impacted susceptibility to chronic adolescent stress in a dose- and environment-controlled animal model.</p><p><strong>Methods: </strong>Mouse dams orally consumed 5 mg/kg THC in whole cannabis oil daily from GD1-PD10. Offspring were exposed to chronic mild unpredictable stress throughout adolescence (PD28-56). From PD58, mice were challenged with a battery of tests to measure anxiety-like (elevated plus maze, open field test), stress coping (forced swim test, tail suspension test), anhedonia-like (sucrose preference), risk-taking behaviour (wire beam bridge), and social motivation (3 chamber sociability and social novelty task). Brain slices were taken 90 min after forced swim test to analyze c-Fos expression.</p><p><strong>Results: </strong>PPCE did not interact with chronic adolescent stress to impact anxiety-like, acute stress coping, or social motivation. However, co-exposed mice showed a significantly increased incidence of bridge crossing in the wire beam bridge task, whereas stress-only exposed animals did not. There were sex differences in c-FOS expression in the prefrontal cortex (PFC) in response to stress and PPCE.</p><p><strong>Conclusions: </strong>These data indicate that PPCE, when combined with adolescent stress, increases risk-taking behaviour.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adolescent female rats are resistant to the affective and cognitive impacts of Δ9-tetrahydrocannabinol exposure despite long-lasting molecular and neuronal disturbances in the hippocampal-hypothalamic network.","authors":"Marta De Felice, Hanna J Szkudlarek, Matthew J Jones, Taygun C Uzuneser, Mohammed H Sarikahya, Shawn N Whitehead, Walter J Rushlow, Steven R Laviolette","doi":"10.1007/s00213-025-06817-8","DOIUrl":"https://doi.org/10.1007/s00213-025-06817-8","url":null,"abstract":"","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-fat Fructose diet induces neuroinflammation and anxiety-like behaviors by modulating liver-brain axis communication.","authors":"Hongmei Du, Yuan Zhou, Jia Wang, Xianbing Bai, Borui Tao, Ming Chen","doi":"10.1007/s00213-025-06820-z","DOIUrl":"https://doi.org/10.1007/s00213-025-06820-z","url":null,"abstract":"<p><strong>Rationale: </strong>Patients with non-alcoholic fatty liver disease (NAFLD) may experience non-cognitive impairments such as anxiety and depression. However, the specific mechanism of the association between liver injury and neurological disorders is unclear.</p><p><strong>Objectives: </strong>In this study, we aimed to explore the relationship and underlying mechanism between high-fat fructose diet (HFFD)-induced liver injury and anxiety-like behavior in mice.</p><p><strong>Methods: </strong>A mouse model of NAFLD was established using an HFFD, and behavioral tests were performed to detect anxiety-like behaviors in mice; moreover, we used enzyme linked immunosorbent assay (ELISA) to detect glutamate levels in treated and normal diet (ND) mice, as well as to explore inflammation levels in mice using immunofluorescence and other methods.</p><p><strong>Results: </strong>Mice in the HFFD-treated group exhibited anxiety-like behaviors, as well as elevated serum lipid and glutamate levels, increased liver injury, and hepatic tissue fat accumulation. Additionally, HFFD-fed mice exhibited elevated levels of IL-6, IL-1β, and TNF-α in the liver, hippocampus, and cortex compared with the ND counterparts; HFFD-induced astrocyte and microglial activation was detected in the cortical and hippocampal regions. However, corilagin treatment alleviated these HFFD-associated pathological changes. Corilagin did not ameliorate anxiety behaviors in mice in the absence of liver injury.</p><p><strong>Conclusion: </strong>Our results indicated that the HFFD-induced NAFLD and mild hepatic fibrosis led to elevated levels of glutamate and aminotransferases, which infiltrated the brain, causing inflammation, and subsequently induced anxiety-like behaviors in mice. These pathological and behavioral manifestations were ameliorated through corilagin intervention. This study provides a possible underlying mechanism between HFFD and neurological disorders.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D2 receptor activation modulates NMDA receptor antagonist-enhanced high-frequency oscillations in the olfactory bulb of freely moving rats.","authors":"Jacek Wróbel, Daniel Krzysztof Wójcik, Mark Jeremy Hunt","doi":"10.1007/s00213-025-06808-9","DOIUrl":"https://doi.org/10.1007/s00213-025-06808-9","url":null,"abstract":"<p><strong>Rationale: </strong>NMDA receptor antagonists, used to model psychotic-like states and treat depression, enhance the power of high-frequency oscillations (HFO) in many mammalian brain regions. In rodents, the olfactory bulb (OB) is a particularly important site for generating this rhythm. OB projection neurons express D1 and D2 receptors (D1R and D2R) which interact with NMDA receptors.</p><p><strong>Objectives: </strong>The aim of this study was to explore the effect of dopamine (DA) signalling in the OB on MK801-enhanced HFO.</p><p><strong>Methods: </strong>Local field potentials from the OB and locomotor activity were recorded in adult male freely moving rats. MK801 was injected systemically or infused locally to the OB. The effects of D1R and D2R agonists (SKF38393, quinpirole) and antagonists (SCH23390, eticlopride), administered systemically or locally to the OB, were examined on MK801-enhanced HFO. Effects of the antipsychotics risperidone and aripiprazole were also examined.</p><p><strong>Results: </strong>Local infusion of MK801 enhanced HFO power in the OB to levels similar to those observed after systemic injection. Neither systemic nor local blockade of D1R or D2R affected the MK801-enhanced HFO, despite reductions in hyperlocomotion. However, direct (systemic and local) D2R, but not D1R, stimulation caused a short-lasting reduction of MK801-enhanced HFO power and longer lasting reduction in frequency. Risperidone, but not aripiprazole, reduced MK801-enhanced HFO frequency.</p><p><strong>Conclusions: </strong>These results suggest that NMDA receptor antagonist-enhanced HFO in the OB is generated predominantly independently of DA influence, however exogenous stimulation of D2R can modulate this rhythm. A second, but not third generation antipsychotic reduced HFO frequency.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol mitigates activated astrocytes and microglia preventing Alzheimer's Disease (AD) progression and facilitates neuronal communication in Amyloid-β25-35 induced rat model for AD: A special emphasis on non-neuronal involvement in AD pathophysiology.","authors":"Kumar Surya, Anitha Rathinam, Meher Nisha Abubakkar, Kesavan Swaminathan Jayachandran, Mahesh Kandasamy, Muthuswamy Anusuyadevi","doi":"10.1007/s00213-025-06814-x","DOIUrl":"https://doi.org/10.1007/s00213-025-06814-x","url":null,"abstract":"<p><strong>Rationale: </strong>Amyloid deposits initiate neuroinflammation by activating astrocytes and microglia in the hippocampus, increasing neuronal vulnerability and loss. Astrocytes, while essential for cerebral function, can contribute to neuronal dysfunction by retracting neuronal synapses, that forms a consequence of neuroinflammation, leading to cognitive deficits in Alzheimer's disease (AD). Upon Amyloid-β (Aβ) deposition, astrocytes become reactive as part of a repair mechanism, however this process can impair neurogenesis resulting in AD progression.</p><p><strong>Objective: </strong>The current study hypothesizes that resveratrol (RSV) can address inflammation and promote neural regeneration, mitigating cognitive decline. Our previous research highlights RSV's homeostatic effect through SIRT1 normalization, which is crucial in preventing AD progression. However, its neurogenic potential in AD remains underexplored.</p><p><strong>Methods: </strong>In this study, Aβ25-35-induced AD rat model was used to study the anti-inflammatory, neurogenic and cellular homeostatic effect of RSV (30 mg/kg) for four weeks.</p><p><strong>Results: </strong>Results showed increased Doublecortin expressing cells, indicating favorable neurogenesis in hippocampus. Immunofluorescence of microglia and astrocytes in the hippocampus revealed that RSV counteracted their activation by reducing the formation of engulfing microglia and elongated astrocytes. Behavioral assessments using the Morris water maze and cued radial arm maze demonstrated significant improvements in spatial and learning memory. These cognitive improvements were supported by increased choline acetyltransferase and SIRT1 levels.</p><p><strong>Conclusion: </strong>These findings suggest that RSV effectively reduces neuroinflammation, promotes neurogenesis in the sub granular zone of the hippocampus, and improves learning and memory in both control and AD conditions via SIRT1. This study highlights RSV's potential as a suitable therapeutic agent for AD.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endocannabinoid modulation of defensive state transitions to innate and learned threat.","authors":"Niharika Loomba, Anyu Cao, Senna Charles, Isaac Kandil, Michelle Kwon, Sachin Patel","doi":"10.1007/s00213-025-06812-z","DOIUrl":"https://doi.org/10.1007/s00213-025-06812-z","url":null,"abstract":"<p><p>A hallmark of many psychiatric disorders is maladaptive and heightened fear responses to non-threatening stimuli. Adaptive defensive responses to threats involve transitions between passive behaviors, such as freezing, and active escape strategies, such as darting or fleeing. The endocannabinoid (eCB) system, particularly 2-arachidonoylglycerol (2-AG), plays a crucial role in modulating fear and stress responses. However, the extent to which 2-AG influences defensive behavioral state transitions to fear responses remains unclear. To address this, we investigated the role of 2-AG in shaping defensive behaviors to learned and innate threats using pharmacological manipulations in both the serial compound stimulus (SCS) and the looming shadow paradigm. During SCS, inhibition of 2-AG synthesis enhanced freezing to early cues and promoted active responses during cues associated with heightened threat imminence. In the looming shadow paradigm, 2-AG depletion biased defensive behavior toward freezing and increased time spent in a safe zone, suggesting a shift toward passive responses. These findings demonstrate that 2-AG signaling critically regulates the balance and transitions between passive and active defensive strategies in both learned and innate fear contexts. Thus, 2-AG plays a key role in the scaling of defensive response transitions and the promotion of active defensive responses to threats.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}