Psychopharmacology最新文献

{"title":"Repeated toluene inhalation in male and female adolescent rats induces persistent drug preference and impairs cognitive and social behavior.","authors":"Joannes Luke B Asis, Ajina C Carampel, Jariel Naomi B Bacar, Johanna C Munar, Cynthia Grace C Gregorio, Paul Mark B Medina, Leslie Michelle M Dalmacio, Jesus Emmanuel A D Sevilleja, Gregory J Quirk, Rohani Cena-Navarro","doi":"10.1007/s00213-024-06731-5","DOIUrl":"10.1007/s00213-024-06731-5","url":null,"abstract":"<p><strong>Rationale: </strong>Adolescent inhalant use is an understudied and undertreated disorder, particularly in females. Chronic exposure to inhalants, like toluene, can have long-lasting effects on behavior. However, most animal studies lack the incorporation of both sexes and do not focus on the abstinence period.</p><p><strong>Objective: </strong>We assessed the behavioral effects during prolonged abstinence following repeated toluene inhalation in adolescent male and female rats.</p><p><strong>Methods: </strong>We repeatedly exposed adolescent male and female Sprague Dawley rats to toluene vapor (1500 or 3000 ppm) for 6 days using the conditioned place preference (CPP) procedure. We tested drug-associated context preference, locomotion, anxiety-like behavior, object memory, social preference, and cognitive flexibility across 22 days of abstinence.</p><p><strong>Results: </strong>In females, 3000 ppm toluene increased CPP on days 8 and 22 of abstinence but this effect did not reach significance in males. Instead, males showed a significant increase in locomotion on days 7 and 21. Toluene also impaired social novelty preference and reversal learning during long-term abstinence, but not anxiety-like behavior or object recognition memory.</p><p><strong>Conclusions: </strong>Our rodent findings suggest that female inhalant users may show persistent drug preference during abstinence following chronic use. Furthermore, prolonged cognitive and social deficits should be addressed in treatment programs for adolescents.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1335-1349"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847552","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":"Molecular pathways of ketamine: A systematic review of immediate and sustained effects on PTSD.","authors":"Nathan J Wellington, Ana P Boųcas, Jim Lagopoulos, Bonnie L Quigley, Anna V Kuballa","doi":"10.1007/s00213-025-06756-4","DOIUrl":"10.1007/s00213-025-06756-4","url":null,"abstract":"<p><strong>Rationale: </strong>Existing studies predominantly focus on the molecular and neurobiological mechanisms underlying Ketamine's acute treatment effects on post-traumatic stress disorder (PTSD). This emphasis has largely overlooked its sustained therapeutic effects, which hold significant potential for the development of targeted interventions.</p><p><strong>Objectives: </strong>This systematic review examines the pharmacokinetic and pharmacodynamic effects of ketamine on PTSD, differentiating between immediate and sustained molecular effects.</p><p><strong>Method: </strong>A comprehensive search across databases (Web of Science, Scopus, Global Health, PubMed) and grey literature yielded 317 articles, where 29 studies met the inclusion criteria. These studies included preclinical models and clinical trials, through neurotransmitter regulation, gene expression, synaptic plasticity, and neural pathways (PROSPERO ID: CRD42024582874).</p><p><strong>Results: </strong>We found accumulating evidence that the immediate effects of ketamine, which involve changes in GABA, glutamate, and glutamine levels, trigger the re-regulation of BDNF, enhancing synaptic plasticity via pathways such as TrkB and PSD-95. Other molecular influences also include c-Fos, GSK-3, HDAC, HCN1, and the modulation of hormones like CHR and ACTH, alongside immune responses (IL-6, IL-1β, TNF-α). Sustained effects arise from neurotransmitter remodulations and involve prolonged changes in gene expression. These include mTOR-mediated BDNF expression, alterations in GSK-3β, FkBP5, GFAP, ERK phosphorylation, and epigenetic modifications (DNMT3, MeCP2, H3K27me3, mir-132, mir-206, HDAC).</p><p><strong>Conclusion: </strong>These molecular changes promote long-term synaptic stability and re-regulation in key brain regions, contributing to prolonged therapeutic benefits. Understanding the sustained molecular and epigenetic mechanisms behind ketamine's effects is critical for developing safe and effective personalised treatments, potentially leading to more effective recovery.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1197-1243"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650338","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":"Substance use disorder severity is associated with sensitivity to effort-related decision-making constraints.","authors":"Samuel F Acuff, Louisa Kane, Zachary J Stewart, Justin Riddle, Stacey B Daughters","doi":"10.1007/s00213-024-06732-4","DOIUrl":"10.1007/s00213-024-06732-4","url":null,"abstract":"<p><strong>Rationale: </strong>Several studies have reported associations between substance use and effort-related decision making, or the degree to which effort expenditure impacts the choice between lower and higher value rewards. However, previous research has not explored effort-related decision making in populations with severe substance use disorder.</p><p><strong>Objectives: </strong>Investigate the association between effort-related decision-making and substance use disorder severity.</p><p><strong>Methods: </strong>Adults with substance use disorders (n = 106) enrolled in intensive outpatient treatment completed clinician administered diagnostic interviews and the effort expenditure for rewards task (EEfRT). General linear mixed methods tested the interactive effect of substance use disorder severity and trial-level probability and value on the likelihood of selecting a high-effort choice.</p><p><strong>Results: </strong>There was a significant interaction between SUD severity and both reward value and reward probability on high-effort choice. The strength of the association between both reward value and probability on high-effort choice significantly increased with SUD severity.</p><p><strong>Conclusions: </strong>These results support theories of reward sensitivity and behavioral economics and highlight an emerging risk factor that may serve as a useful target for treatment.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1351-1362"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847556","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":"Acute effects of psilocybin on attention and executive functioning in healthy volunteers: a systematic review and multilevel meta-analysis.","authors":"P Yousefi, Morten P Lietz, F J O'Higgins, R C A Rippe, G Hasler, M van Elk, S Enriquez-Geppert","doi":"10.1007/s00213-024-06742-2","DOIUrl":"10.1007/s00213-024-06742-2","url":null,"abstract":"<p><strong>Rationale: </strong>Psilocybin shows promise for treating neuropsychiatric disorders. However, insight into its acute effects on cognition is lacking. Given the significant role of executive functions in daily life and treatment efficacy, it is crucial to evaluate how psilocybin influences these cognitive domains.</p><p><strong>Objectives: </strong>This meta-analysis aims to quantify the acute effects of psilocybin on executive functions and attention, while examining how dosage, timing of administration, cognitive domain, and task characteristics moderate these effects.</p><p><strong>Methods: </strong>A systematic review and multilevel meta-analysis were conducted on empirical studies assessing psilocybin's acute effects on working memory, conflict monitoring, response inhibition, cognitive flexibility, and attention. Effect sizes for reaction time (RT) and accuracy (ACC) were calculated, exploring the effects of timing (on-peak defined as 90-180 min post-administration), dosage, cognitive function categories, and task sensitivity to executive functions as potential moderators.</p><p><strong>Results: </strong>Thirteen studies (42 effect sizes) were included. In the acute phase, psilocybin increased RTs (Hedges' g = 1.13, 95% CI [0.57, 1.7]) and did not affect ACC (Hedges' g = -0.45, 95% CI [-0.93, 0.034]). Effects on RT were dose dependent. Significant between-study heterogeneity was found for both RT and ACC. Task sensitivity to executive functions moderated RT effects. Publication bias was evident, but the overall effect remained significant after adjustment for this.</p><p><strong>Conclusions: </strong>Our meta-analysis shows that psilocybin impairs executive functions and results in a slowing down of RT. We discuss potential neurochemical mechanisms underlying the observed effects as well as implications for the safe use of psilocybin in clinical and experimental contexts.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1171-1196"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024461","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":"Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice.","authors":"Yueyi Chen, Tiange Xiao, Adam Kimbrough","doi":"10.1007/s00213-024-06739-x","DOIUrl":"10.1007/s00213-024-06739-x","url":null,"abstract":"<p><strong>Rationale: </strong>The rise in overdose deaths from synthetic opioids, especially fentanyl, necessitates the development of preclinical models to study fentanyl use disorder (FUD). While there has been progress with rodent models, additional translationally relevant models are needed to examine excessive fentanyl intake and withdrawal signs.</p><p><strong>Objective: </strong>The current study aimed to develop a translationally relevant preclinical mouse model of FUD by employing chronic intravenous fentanyl self-administration (IVSA).</p><p><strong>Methods: </strong>The study performed intravenous self-administration (IVSA) of fentanyl in male and female C57BL/6J mice for 14 days. Mechanical pain sensitivity during withdrawal was assessed using the von Frey test. Anxiety-like behavior was evaluated via the open field test one week into abstinence, and drug seeking behavior after extended abstinence was assessed at four weeks abstinence.</p><p><strong>Results: </strong>Both male and female mice demonstrated a significant escalation in fentanyl intake over the 14 days of self-administration, with significant front-loading observed in the final days of self-administration. Mice showed increased mechanical pain sensitivity at 36 and 48hours withdrawal from fentanyl. At 1-week abstinence from fentanyl, mice exhibited increased anxiety-like behavior compared to naive mice. Four weeks into abstinence from fentanyl, mice maintained lever-pressing behavior on the previous reward-associated active lever, with significantly higher active lever pressing compared to inactive lever pressing.</p><p><strong>Conclusions: </strong>The study establishes a translationally relevant mouse model of IVSA of fentanyl, effectively encapsulating critical aspects of FUD, including escalation of drug intake, front-loading behavior, withdrawal signs, and drug-seeking behavior into extended abstinence. This model offers a robust basis for further exploration into behavioral and neurobiological mechanisms involved in fentanyl dependence and potential therapeutic strategies.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1419-1435"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896996","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":"Depression-like effects induced by chronic unpredictable mild stress in mice are rapidly reversed by a partial negative allosteric modulator of mGlu₅ receptor, M-5MPEP.","authors":"Agnieszka Pałucha-Poniewiera, Bartosz Bobula, Anna Rafało-Ulińska, Katarzyna Kaczorowska","doi":"10.1007/s00213-024-06724-4","DOIUrl":"10.1007/s00213-024-06724-4","url":null,"abstract":"<p><strong>Rationale: </strong>Due to the numerous limitations of ketamine as a rapid-acting antidepressant drug (RAAD), research is still being conducted to find an effective and safe alternative to this drug. Recent studies indicate that the partial mGlu₅ receptor negative allosteric modulator (NAM), 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), has therapeutic potential as an antidepressant.</p><p><strong>Objectives: </strong>The study aimed to investigate the potential rapid antidepressant-like effect of M-5MPEP in a mouse model of depression and to determine the mechanism of this action.</p><p><strong>Methods: </strong>Chronic unpredictable mild stress (CUMS) was used as an animal model of depression. The effects of single and four-day administration of M-5MPEP on CUMS-induced animal behaviors reflecting anhedonia, apathy, and helplessness were studied. Western blot was applied to measure the levels of proteins potentially involved in a rapid antidepressant effect, including mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), tropomyosin receptor kinase B (TrkB), and serotonin transporter (SERT), both in the hippocampus and the prefrontal cortex (PFC). Furthermore, excitatory synaptic transmission and long-term potentiation (LTP) were measured in the medial PFC (mPFC).</p><p><strong>Results: </strong>We showed that M-5MPEP administration for four consecutive days abolished CUMS-induced apathy- and anhedonia-like symptoms in a mouse model of depression. We also found that these effects were accompanied by changes in hippocampal TrkB levels and mTOR and eEF2 levels in the PFC. Using electrophysiological techniques, we showed that the four-day M-5MPEP treatment reversed chronic stress-induced increases in excitatory synaptic potential and CUMS-impaired LTP in the mPFC.</p><p><strong>Conclusions: </strong>Partial mGlu₅ receptor NAM, M-5MPEP, appears to be a potentially effective new RAAD and deserves further study.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1259-1273"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142771631","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":"Working memory processes and the histamine-3 receptor in schizophrenia: a [¹¹C]MK-8278 PET-fMRI study.","authors":"Atheeshaan Arumuham, Ekaterina Shatalina, Matthew M Nour, Mattia Veronese, Ellis Chika Onwordi, Stephen J Kaar, Sameer Jauhar, Eugenii A Rabiner, Oliver D Howes","doi":"10.1007/s00213-024-06730-6","DOIUrl":"10.1007/s00213-024-06730-6","url":null,"abstract":"<p><strong>Rationale: </strong>Working memory impairment is a prominent feature of schizophrenia which predicts clinical and functional outcomes. Preclinical data suggest histamine-3 receptor (H3R) expression in cortical pyramidal neurons may have a role in working memory, and post-mortem data has found disruptions of H3R expression in schizophrenia.</p><p><strong>Objectives: </strong>We examined the role of H3R in vivo to elucidate its role on working memory impairment in schizophrenia.</p><p><strong>Methods: </strong>We used positron emission tomography (PET) with the selective H3R radioligand [¹¹C]MK-8278 to measure H3R availability, and employed a task during functional magnetic resonance imaging (fMRI) to assess working memory-evoked brain activation and cognitive task performance, in patients with schizophrenia (n = 12) and matched healthy volunteers (n = 12). We assessed the relationship between H3R availability and both task performance and working memory-evoked brain activation in regions of interest (ROIs), including the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC).</p><p><strong>Results: </strong>Patients with schizophrenia showed a strong positive correlation, after corrections for multiple comparisons, between ACC H3R availability and task performance (rho = 0.73, p = 0.007), which was absent in the control group (rho = 0.03, p = 0.94). Further ROI analysis did not find a significant relationship between H3R availability and working memory-evoked brain activation.</p><p><strong>Conclusions: </strong>These results provide support for the role of H3R on working memory processes in patients with schizophrenia.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1321-1334"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877753","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":"Ethanol self-administration targets GluA2-containing AMPA receptor expression and synaptic activity in the nucleus accumbens in a manner that drives the positive reinforcing properties of the drug.","authors":"Sara Faccidomo, Briana L Saunders, Ashley M May, Vallari R Eastman, Michelle Kim, Seth M Taylor, Jessica L Hoffman, Zoé A McElligott, Clyde W Hodge","doi":"10.1007/s00213-024-06740-4","DOIUrl":"10.1007/s00213-024-06740-4","url":null,"abstract":"<p><strong>Rationale: </strong>The positive reinforcing effects of alcohol (ethanol) drive repetitive use and contribute to alcohol use disorder (AUD). Ethanol alters the expression of glutamate AMPA receptor (AMPAR) subunits in reward-related brain regions, but the extent to which this effect regulates ethanol's reinforcing properties is unclear.</p><p><strong>Objective: </strong>This study investigates whether ethanol self-administration changes AMPAR subunit expression and synaptic activity in the nucleus accumbens core (AcbC) to regulate ethanol's reinforcing effects in male C57BL/6 J mice.</p><p><strong>Results: </strong>Sucrose-sweetened ethanol self-administration (0.81 g/kg/day) increased AMPAR GluA2 protein expression in the AcbC, without effect on GluA1, compared to sucrose-only controls. Infusion of myristoylated Pep2m in the AcbC, which blocks GluA2 binding to N-ethylmaleimide-sensitive fusion protein (NSF) and reduces GluA2-containing AMPAR activity, reduced ethanol-reinforced responding without affecting sucrose-only self-administration or motor activity. Antagonizing GluA2-lacking AMPARs, through AcbC infusion of NASPM, had no effect on ethanol self-administration. AcbC neurons receiving projections from the basolateral amygdala (BLA) showed increased sEPSC area under the curve (a measurement of charge transfer) and slower decay kinetics in ethanol self-administering mice as compared to sucrose. Optogenetic activation of these neurons revealed an ethanol-enhanced AMPA/NMDA ratio and significantly reduced paired-pulse ratio, suggesting elevated GluA2 contributions specifically within the BLA➔AcbC pathway.</p><p><strong>Conclusions: </strong>Ethanol use upregulates GluA2 protein expression in the AcbC and AMPAR synaptic activity in AcbC neurons receiving BLA projections and enhances synaptic plasticity directly within the BLA➔AcbC circuit. GluA2-containing AMPAR activity in the AcbC regulates the positive reinforcing effects of ethanol through an NSF-dependent mechanism, highlighting a potential therapeutic target in AUD.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1437-1452"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877751","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":"Genotype-dependent functional role of the anterior and posterior paraventricular thalamus in pavlovian conditioned approach.","authors":"Valeria Tarmati, Andrea Sepe, Alessandra Accoto, David Conversi, Daniela Laricchiuta, Anna Panuccio, Sonia Canterini, Maria Teresa Fiorenza, Simona Cabib, Cristina Orsini","doi":"10.1007/s00213-024-06726-2","DOIUrl":"10.1007/s00213-024-06726-2","url":null,"abstract":"<p><strong>Rationale: </strong>The specific location of deviations from normative models of brain function varies considerably across individuals with the same diagnoses. However, as pathological processes are distributed across interconnected systems, this heterogeneity of individual brain deviations may also reveal similarities and differences between disorders. The paraventricular nucleus of the thalamus (PVT) is a potential switcher to various behavioral responses where functionally distinct cell types exist across its antero-posterior axis.</p><p><strong>Objectives: </strong>This study aimed to test the hypothesis that genotype-dependent differences in the anterior and posterior PVT subregions (aPVT and pPVT) are involved in the Sign-tracking (ST) behavior expressed by C57BL/6J (C57) and DBA/2J (DBA) inbred mice.</p><p><strong>Methods: </strong>Based on previous findings, male mice of the two strains were tested at ten weeks of age. The density of c-Fos immunoreactivity along the antero-posterior axis of PVT was assessed following the expression of ST behavior. Selective excitotoxic lesions of the aPVT or the pPVT by the NMDA infusion were performed prior to development of ST behavior. Finally, the distribution of neuronal populations expressing the Drd2 and Gal genes (D2R + and Gal +) was measured by in situ hybridization (ISH).</p><p><strong>Results: </strong>The involvement of PVT subregions in ST behavior is strain-specific, as aPVT is crucial for ST acquisition in DBA mice while pPVT is crucial for C57 mice. Despite similar antero-posterior distribution of D2R + and Gal + neurons, density of D2R + neurons differentiate aPVT in C57 and DBA mice.</p><p><strong>Conclusions: </strong>These genotype-dependent results offer valuable insights into the nuanced organization of brain networks and individual variability in behavioral responses.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1275-1289"},"PeriodicalIF":3.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814016","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":"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}