Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"A \"Furious\" Effort to Develop Novel 3,4-Methylenedioxymethamphetamine-Like Therapeutics.","authors":"William E Fantegrossi,Brenda M Gannon","doi":"10.1124/jpet.124.002183","DOIUrl":"https://doi.org/10.1124/jpet.124.002183","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255550","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":"Aloperine Attenuates Hepatic Ischemia/Reperfusion-Induced Liver Injury via STAT-3 Signaling in a Murine Model.","authors":"Shichao Wei, Junshen Xiao, Feng Ju, Jiaxue Li, Ting Liu, Zhaoyang Hu","doi":"10.1124/jpet.123.001992","DOIUrl":"10.1124/jpet.123.001992","url":null,"abstract":"<p><p>Hepatic ischemia/reperfusion (I/R) damage is one of the most common side effects of liver surgery. This pathophysiological process may lead to excessive hepatic damage. Aloperine is an active ingredient isolated from <i>Sophora alopecuroides</i> Linn and has a variety of therapeutic effects, including organ protection. However, the hepatoprotective effect of aloperine against hepatic I/R damage has not yet been determined. C57BL/6 mice were allocated to the sham-operated (sham), hepatic ischemia/reperfusion (I/R), and aloperine groups. The mice were exposed to 30 min of hepatic hilum occlusion. Then a 3-h reperfusion was performed. Mice in the sham group underwent sham surgery. Hepatic injury was evaluated by plasma aspartate aminotransferase (AST) and transaminase alanine aminotransferase (ALT) levels, histological evaluation, cell apoptosis, the number of activated inflammatory cells, and the expression levels of inflammatory cytokines, including tumor necrosis factor-<i>α</i> and interleukin-6. The protein phosphorylation status of the reperfusion-associated survival pathways was evaluated. Mice with hepatic I/R injury presented increased plasma ALT and AST levels, increased hepatic apoptosis, abnormal histological structure, and elevated inflammatory responses. However, aloperine ameliorated hepatic I/R-induced injury. Moreover, aloperine enhanced the level of signal transducer and activator of transcription (STAT)-3 phosphorylation after I/R. Ag490, an agent that inhibits STAT-3 activity, abolished aloperine-induced STAT-3 phosphorylation and liver protection. Aloperine ameliorates hepatic I/R-induced liver injury via a STAT-3-mediated protective mechanism. Patients with hepatic I/R injury may benefit from aloperine treatment. SIGNIFICANCE STATEMENT: Hepatic I/R can cause excessive liver damage. This study revealed that aloperine, an active component isolated from <i>Sophora alopecuroides</i> Linn, ameliorates hepatic I/R injury and related liver damage in vivo. The underlying protective mechanism may involve the STAT-3 signaling pathway. These findings may lead to the development of a novel approach for treating hepatic I/R damage in clinical practice.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008956","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":"Novel Benzofuran Derivatives Induce Monoamine Release and Substitute for the Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine.","authors":"Candace B Johnson, Donna Walther, Matthew J Baggott, Lisa E Baker, Michael H Baumann","doi":"10.1124/jpet.123.001837","DOIUrl":"10.1124/jpet.123.001837","url":null,"abstract":"<p><p>3,4-Methylenedioxymethamphetamine (MDMA) has shown efficacy as a medication adjunct for treating post-traumatic stress disorder (PTSD). However, MDMA is also used in nonmedical contexts that pose risk for cardiovascular and neurologic complications. It is well established that MDMA exerts its effects by stimulating transporter-mediated release of the monoamines 5-hydroxytryptamine (5-HT), norepinephrine, and dopamine. Current research efforts are aimed at developing MDMA-like monoamine releasers with better efficacy and safety profiles. To this end, we investigated neurochemical and behavioral effects of novel analogs of the designer drug 5-(2-methylaminopropyl)benzofuran (5-MAPB). We used in vitro transporter assays in rat brain synaptosomes to examine transmitter uptake inhibition and releasing properties for enantiomers of 5-(2-methylaminobutyl)benzofuran (5-MABB) and 6-(2-methylaminobutyl)benzofuran (6-MABB) compared with MDMA. We then tested these same compounds in male Sprague-Dawley rats trained to discriminate MDMA (1.5 mg/kg) from saline. In vitro results revealed that <i>S</i> isomers of 5- and 6-MABB are efficacious releasing agents at transporters for 5-HT (SERT), norepinephrine (NET), and dopamine (DAT). By contrast, <i>R</i> isomers are efficacious releasers at SERT and partial releasers at NET but lack releasing activity at DAT. In vivo results showed that all compounds produce dose-dependent increases in MDMA-lever responding and full substitution at the highest dose tested. The diminished NET and DAT releasing activities for <i>R</i> isomers of 5- and 6-MABB are associated with reduced potency for inducing behavioral effects. Collectively, these findings indicate that the aminoalkyl benzofuran scaffold may be a viable template for developing compounds with MDMA-like properties. SIGNIFICANCE STATEMENT: Despite the clinical utility of 3,4-methylenedioxymethamphetamine (MDMA), the drug is associated with certain cardiovascular risks and metabolic side effects. Developing a therapeutic alternative with MDMA-like monoamine releasing activity is of interest. Our in vitro and in vivo findings indicate that the aminoalkyl benzofuran scaffold may be useful for developing compounds with MDMA-like properties.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139563358","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":"The Effects of Eating a Traditional High Fat/High Carbohydrate or a Ketogenic Diet on Sensitivity of Female Rats to Morphine.","authors":"Nina M Beltran, Alyssa N Parra, Ana Paulina Serrano, Jazmin Castillo, Isabella M Castro, Madeline K Elsey, Vanessa Minervini, Katherine M Serafine","doi":"10.1124/jpet.124.002188","DOIUrl":"10.1124/jpet.124.002188","url":null,"abstract":"<p><p>Patients diagnosed with obesity are prescribed opioid medications at a higher rate than the general population; however, it is not known if eating a high fat diet might impact individual sensitivity to these medications. To explore the hypothesis that eating a high fat diet increases sensitivity of rats to the effects of morphine, 24 female Sprague-Dawley rats (<i>n</i> = 8/diet) ate either a standard (low fat) laboratory chow (17% kcal from fat), a high fat/low carbohydrate (ketogenic) chow (90.5% kcal from fat), or a traditional high fat/high carbohydrate chow (60% kcal from fat). Morphine-induced antinociception was assessed using a warm water tail withdrawal procedure, during which latency (in seconds) for rats to remove their tail from warm water baths was recorded following saline or morphine (0.32-56 mg/kg, i.p.) injections. Morphine was administered acutely and chronically (involving 18 days of twice-daily injections, increasing in 1/4 log dose increments every 3 days: 3.2-56 mg/kg, i.p., to induce dependence and assess tolerance). The adverse effects of morphine (i.e., tolerance, withdrawal, and changes in body temperature) were assessed throughout the study. Acute morphine induced comparable antinociception in rats eating different diets, and all rats developed tolerance following chronic morphine exposure. Observable withdrawal signs and body temperature were also comparable among rats eating different diets; however, withdrawal-induced weight loss was less severe for rats eating ketogenic chow. These results suggest that dietary manipulation might modulate the severity of withdrawal-related weight loss in ways that could be relevant for patients.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11415821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766412","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":"Comparison of the Genomic Activity of an EP₄-Receptor and β₂-Adrenoceptor Agonist in BEAS-2B Human Bronchial Epithelial Cells: In Search of Compartmentalized, cAMP-Dependent Gene Expression.","authors":"Radhika Joshi, Tamkeen U Paracha, Mahmoud M Mostafa, Andrew J Thorne, Varuna Jayasinghe, Dong Yan, Omar Hamed, Robert Newton, Mark A Giembycz","doi":"10.1124/jpet.124.002226","DOIUrl":"10.1124/jpet.124.002226","url":null,"abstract":"<p><p>It has been proposed that inhaled E-prostanoid 4 (EP₄)-receptor agonists could represent a new class of bronchodilators for the treatment of asthma that are as effective as <i>β</i> ₂-adrenoceptor agonists. However, the genomic impact of such drugs is unknown despite being potentially deleterious to respiratory health. Herein, we used mRNA-seq to compare the transcriptomic responses produced by 2-[3-[(1R,2S,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-5-[2-(methoxymethyl)phenyl]pent-1-enyl]-5-oxo-cyclopentyl]sulphanylpropylsulphanyl] acetic acid (ONO-AE1-329; an EP₄-receptor agonist) and vilanterol (a <i>β</i> ₂-adrenoceptor agonist) in BEAS-2B human airway epithelial cells. We also determined if an increase in cAMP mediated by different G protein-coupled receptors (GPCRs) promoted distinct transcriptional signatures by expanding this inquiry to include the adenosine A_2B- and I-prostanoid receptor agonists, 2-[[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide (Bay60-6583) and taprostene, respectively. Maximally-effective concentrations of ONO-AE1-329 and vilanterol significantly regulated (<i>q</i> ≤ 0.05; ≥1.5-/≤0.67-fold) 232 and 320 genes, respectively of which 217 were shared. Spearman analysis showed these gene expression changes to be highly rank order correlated, indicating that the functional overlap between the two interventions should be considerable. Unexpectedly, the genomic effects of ONO-AE1-329, vilanterol, Bay 60-6583, and taprostene were also highly rank order correlated. This finding suggests that cAMP generated by any GPCR would initiate the same transcriptional program. Nevertheless, relative to vilanterol, ONO-AE1-329 typically behaved as a partial agonist that varied across transcripts. These data indicate that each ONO-AE1-329-regulated gene differs in sensitivity to cAMP and is defined by a unique receptor occupancy-response relationship. Moreover, if this relatively modest genomic response in BEAS-2B cells is retained in vivo, then inhaled EP₄-receptor agonists could represent an alternative, and possibly safer, class of bronchodilators. SIGNIFICANCE STATEMENT: The genomic consequences of <i>β</i> ₂-adrenoceptor agonists in asthma are often overlooked despite being potentially harmful to lung health. We determined that ONO-AE1-329, an EP₄-receptor agonist and effective bronchodilator, produced gene expression changes in BEAS-2B cells that were typically modest relative to the <i>β</i> ₂-adrenoceptor agonist vilanterol. Furthermore, ONO-AE1-329 behaved as a partial agonist that varied across transcripts. If this genomic activity is reproduced in vivo, then EP₄-receptor agonists could represent an alternative, and possibly safer, class of bronchodilators.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766369","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":"Dysregulation of Human Hepatic Drug Transporters by Proinflammatory Cytokines.","authors":"Tianran Hao, Yik Pui Tsang, Mengyue Yin, Qingcheng Mao, Jashvant D Unadkat","doi":"10.1124/jpet.123.002019","DOIUrl":"10.1124/jpet.123.002019","url":null,"abstract":"<p><p>Proinflammatory cytokines, elevated during inflammation caused by infection and/or autoimmune disorders, result in reduced clearance of drugs eliminated primarily by cytochrome P450 enzymes (CYPs). However, the effect of cytokines on hepatic drug transporter expression or activity has not been well-studied. Here, using plated human hepatocytes (PHHs; <i>n</i> = 3 lots), we investigated the effect of interleukin (IL)-6, IL-1<i>β</i>, tumor necrosis factor-<i>α</i> (TNF-<i>α</i>), and interferon-γ (IFN-γ), on the mRNA expression and activity of hepatic drug transporters. PHHs were incubated for 72 hours at their pathophysiologically relevant plasma concentrations, both individually (0.01, 0.1, 1, 10 ng/ml) or as a cocktail (i.e., when each was combined at 0.1 or 1 ng/ml). Following cytokine cocktail exposure (1 ng/ml), significant downregulation of mRNA expression of organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, sodium/taurocholate cotransporting polypeptide (NTCP), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein 1, multidrug resistance proteins (MRP) 2, 3, and 4 was observed. While the mRNA expression of organic anion transporter (OAT) 2 and organic cation transporter (OCT) 1 was downregulated in two lots, it was upregulated in one lot. In agreement (mostly), the 1 ng/ml cytokine cocktail reduced OATP1B1/3, OATP2B1, OAT2, OCT1, and NTCP activity by 75%, 44%, 82%, 47%, and 80%, respectively. Interestingly, upregulation of OAT2 and OCT1 mRNA in one donor did not translate into the same directional change in activity. Although significant interlot variability was observed, in general, the above effects, using individual cytokines, could be attributed to IL-1<i>β</i>, TNF-<i>α</i>, and IFN-γ. SIGNIFICANCE STATEMENT: To date, this is the first comprehensive study to investigate the effect of four major proinflammatory cytokines, both individually and as a cocktail, on the mRNA expression and activity of human hepatic drug transporters. The data obtained can be used in the future to predict transporter-mediated drug clearance changes during inflammation through physiologically based pharmacokinetic modeling and simulation.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893638","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":"Primaquine-5,6-Orthoquinone Is Directly Hemolytic to Older G6PD Deficient RBCs in a Humanized Mouse Model.","authors":"Karolina H Dziewulska-Cronk, Julie A Reisz, Ariel M Hay, Travis Nemkov, Francesca I Cendali, Aaron Issaian, Derek R Lamb, Mitasha S Palha, Eric A Legenzov, Joseph P Y Kao, Larry A Walker, Babu L Tekwani, Paul W Buehler, Angelo D'Alessandro, James C Zimring","doi":"10.1124/jpet.124.002218","DOIUrl":"10.1124/jpet.124.002218","url":null,"abstract":"<p><p>Primaquine and Tafenoquine are the only approved drugs that can achieve a radical cure for <i>Plasmodium vivax</i> malaria but are contraindicated in patients who are deficient in glucose 6-phosphate dehydrogenase (G6PDd) due to risk of severe hemolysis from reactive oxygen species generated by redox cycling of drug metabolites. 5-hydroxyprimaquine and its quinoneimine cause robust redox cycling in red blood cells (RBCs) but are so labile as to not be detected in blood or urine. Rather, the quinoneimine is rapidly converted into primaquine-5,6-orthoquinone (5,6-POQ) that is then excreted in the urine. The extent to which 5,6-POQ contributes to hemolysis remains unclear, although some have suggested that it is a minor toxin that should be used predominantly as a surrogate to infer levels of 5-hydroxyprimaquine. In this report, we describe a novel humanized mouse model of the G6PD Mediterranean variant (hG6PD_Med-) that recapitulates the human biology of RBC age-dependent enzyme decay, as well as an isogenic matched control mouse with human nondeficient G6PD hG6PD_ND In vitro challenge of RBCs with 5,6-POQ causes increased generation of superoxide and methemoglobin. Infusion of treated RBCs shows that 5,6-POQ selectively causes in vivo clearance of older hG6PD_Med- RBCs. These findings support the hypothesis that 5,6-POQ directly induces hemolysis and challenges the notion that 5,6-POQ is an inactive metabolic waste product. Indeed, given the extreme lability of 5-hydroxyprimaquine and the relative stability of 5,6-POQ, these data raise the possibility that 5,6-POQ is a major hemolytic primaquine metabolite in vivo. SIGNIFICANCE STATEMENT: These findings demonstrate that 5,6-POQ, which has been considered an inert waste product of primaquine metabolism, directly induces ROS that cause clearance of older G6PDd RBCs. As 5,6-POQ is relatively stable compared with other active primaquine metabolites, these data support the hypothesis that 5,6-POQ is a major toxin in primaquine induced hemolysis. The findings herein also establish a new model of G6PDd and provide the first direct evidence, to our knowledge, that young G6PDd RBCs are resistant to primaquine-induced hemolysis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878928","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":"Identification of pyrimidine structure-based compounds as allosteric ligands of the dopamine transporter as therapeutic agents for NeuroHIV","authors":"Ana Catya Jimenez-Torres, Jamison A Hastie, Sarah E Davis, Katherine D Porter, Bin Lei, Omar Moukha-Chafiq, Sixue Zhang, Theresa H Nguyen, Subramaniam Ananthan, Corinne E Augelli-Szafran, Jun Zhu","doi":"10.1124/jpet.124.002138","DOIUrl":"https://doi.org/10.1124/jpet.124.002138","url":null,"abstract":"The disruption of dopamine neurotransmission by the HIV-1 Transactivator of transcription (Tat) during HIV-1 infection has been linked to the development of neurocognitive disorders, even under combined antiretroviral therapy (cART) treatment. We have demonstrated that SRI-32742, a novel allosteric modulator of dopamine (DA) transporter (DAT), attenuates cocaine- and Tat-binding to DAT, alleviates Tat-induced cognitive deficits and potentiation of cocaine reward in inducible Tat transgenic mice. The current study determined the <em>in vitro</em> pharmacological profile of SRI-32743 and its optimized second-generation analogs and their effects as allosteric modulators. Through structure-activity relationship studies of SRI-32743, 170 compounds were synthesized and evaluated for their ability to modulate DAT function. We identified 21 analogs as atypical competitors of DAT (E_max {less than or equal to}60%). Four compounds, SRI-46564, SRI-47056, SRI-46286 and SRI-47867, displayed IC₅₀ values for [³H]DA uptake inhibition from 9.33 {plus minus} 0.50 to 0.96 {plus minus} 0.05 µM and from 3.96 {plus minus} 1.36 to 1.29 {plus minus} 0.19 for DAT binding, respectively. The four analogs also displayed high potency at two different concentrations (0.5 nM and 0.05 nM) to attenuate Tat-induced inhibition of [³H]DA uptake and cocaine-mediated dissociation of [³H]WIN35,428 binding in CHO cells expressing hDAT, suggesting that the effects occur through an allosteric mechanism. In further <em>ex vivo</em> studies using Fast-Scan Cyclic Voltammetry, we demonstrated that the analogs do not disrupt the baseline phasic-like DA release. These findings provide a new insight into the potential for development of novel therapeutic agents to attenuate DAT-Tat interactions to normalize DA neurotransmission in NeuroHIV.","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255587","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":"Alternative reinforcers enhance the effects of opioid antagonists, but not agonists, on oxycodone choice self-administration in nonhuman primates","authors":"Fernando B. de Moura, Stephen J. Kohut","doi":"10.1124/jpet.123.001911","DOIUrl":"https://doi.org/10.1124/jpet.123.001911","url":null,"abstract":"Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and non-pharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of FDA-approved opioid antagonist or agonist medications, as well as the non-opioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys (n=7; 4 females) responded under concurrent second-order FR3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032-1.0mg/kg), nalbuphine (0.32-10mg/kg), buprenorphine (0.0032-0.032mg/kg), methadone (0.32-1.0mg/kg), or flumazenil (1-3.2mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a m-opioid receptor antagonist, was &gt;30-fold more potent when milk was available compared to water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low efficacy m-agonist nalbuphine was most effective in the presence of milk compared to water, decreasing oxycodone preference to &lt;50% of control values. The higher efficacy m-agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil, did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse-related behaviors.","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269062","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":"Evaluating the potential for psilocybin as a treatment for post-traumatic stress disorder","authors":"Claire E Miller, Phillip R Zoladz","doi":"10.1124/jpet.124.002237","DOIUrl":"https://doi.org/10.1124/jpet.124.002237","url":null,"abstract":"Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition that develops following exposure to a traumatic event. Individuals with this condition experience numerous physiological and behavioral alterations, including intrusive memories, avoidance of trauma-related stimuli, heightened anxiety, hypervigilance, impaired cognition, elevated resting heart rate and blood pressure, and altered neuroendocrine function, to name a few. In most patients, currently available pharmacological and psychological treatments are insufficient to alleviate the array of symptoms associated with the disorder. Thus, novel treatment options that can more effectively target the core etiology of PTSD are desperately needed. Recent work demonstrating the psychoplastogenic effects of psychedelics has reinvigorated research to examine their therapeutic potential in psychiatric conditions. Psilocybin, one psychedelic found in the <em>Psilocybe </em>genus of mushrooms, has exhibited promising antidepressant and anxiolytic effects in preclinical and clinical studies. The purpose of this review is to summarize the existing research that has examined the behavioral effects of psilocybin and link it to potential efficacy in treating PTSD-related symptoms. The proposed mechanisms for psilocybin's effects are then explored, as are the benefits and drawbacks for the agent's therapeutic use. Finally, the challenges faced by investigators aiming to study psilocybin as a therapeutic aid in future studies are discussed in order to shed light on this budding area of research.","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255555","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}