Advances in drug and alcohol research最新文献

{"title":"<ArticleTitle xmlns:ns0=\"http://www.w3.org/1998/Math/MathML\">Alcohol and pregnenolone interaction on cerebral arteries through targeting of vascular smooth muscle <ns0:math><ns0:msup><ns0:mrow><ns0:mi>C</ns0:mi><ns0:mi>a</ns0:mi></ns0:mrow><ns0:mrow><ns0:mn>2</ns0:mn><ns0:mo>+</ns0:mo></ns0:mrow></ns0:msup></ns0:math>- and voltage-gated K⁺ channels of big conductance.","authors":"Kelsey C North, Andrew A Shaw, Luiz Moreira, Anna N Bukiya, Alex M Dopico","doi":"10.3389/adar.2023.11735","DOIUrl":"10.3389/adar.2023.11735","url":null,"abstract":"<p><p>Despite the significant number of people who may be taking pregnenolone supplements while drinking alcohol (ethanol), the widely documented cerebrovascular actions of pregnenolone and ethanol, and the critical dependence of cerebrovascular function on cerebral artery diameter, there are no studies addressing the effect of pregnenolone + ethanol in combination on cerebral artery diameter. We investigated this by evaluating the effect of this combination on middle cerebral artery diameter in male and female C57BL/6J mice, both <i>in vivo</i> and <i>in vitro</i>. The use of de-endothelialized, <i>in vitro</i> pressurized middle cerebral artery segments allowed us to conduct a concentration-response study of constriction induced by pregnenolone ± ethanol, in which drug action could be evaluated independently of circulating and endothelial factors. In both male and female animals, pregnenolone at lower concentrations (≤1 μM) was found to synergize with 50 mM ethanol to cause vasoconstriction. In both sexes, this synergism was lost as one or both vasoconstrictors approached their maximally effective concentrations (75 mM and 10 μM for ethanol and pregnenolone, respectively), whether this was evaluated <i>in vitro</i> or <i>in vivo</i> using a cranial window. Vasoconstriction by pregnenolone + ethanol was abolished by 1 μM paxilline, indicating BK channel involvement. Moreover, cell-free recordings of BK channel activity in cerebral artery myocyte membranes showed that 10 μM pregnenolone and pregnenolone +50 mM ethanol reduced channel activity to an identical extent, suggesting that these drugs inhibit cerebrovascular BK channels <i>via</i> a common mechanism or mechanisms. Indeed, pregnenolone was found to disrupt allosteric coupling to <math><msup><mrow><mi>C</mi><mi>a</mi></mrow><mrow><mn>2</mn><mo>+</mo></mrow></msup></math>-driven gating, as previously reported for ethanol.</p>","PeriodicalId":72092,"journal":{"name":"Advances in drug and alcohol research","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41241537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Substance abuse and early development.","authors":"Anna N Bukiya,&nbsp;Declan W Ali","doi":"10.3389/adar.2023.11836","DOIUrl":"https://doi.org/10.3389/adar.2023.11836","url":null,"abstract":"While misuse of psychoactive substances can be traced back to pre-historic times, their effects on invisible target—such as the developing fetus—only gained recognition within the last century [1–4]. Initial seminal findings in humans and laboratory rodents quickly grew from isolated observations to well-planned, multidisciplinary studies. Despite the involvement of numerous methodologies, large teams of researchers, and widely different experimental organisms, there has been an unusual consensus on the meaning of findings: principally that prenatal exposure to drugs of misuse has deleterious consequences for the developing fetus.","PeriodicalId":72092,"journal":{"name":"Advances in drug and alcohol research","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10424723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10358891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial knockdown does not affect acute withdrawal but delays analgesic tolerance from oxycodone in male and female C57BL/6J mice.","authors":"Omar El Jordi, Kathryn D Fischer, Timothy B Meyer, Brady K Atwood, Adrian L Oblak, Raymond W Pan, David L McKinzie","doi":"10.3389/adar.2022.10848","DOIUrl":"10.3389/adar.2022.10848","url":null,"abstract":"<p><p>Opioid Use Disorder (OUD) affects approximately 8%-12% of the population. In dependent individuals, abrupt cessation of opioid taking results in adverse withdrawal symptoms that reinforce drug taking behavior. Considerable unmet clinical need exists for new pharmacotherapies to treat opioid withdrawal as well as improve long-term abstinence. The neuroimmune system has received much scientific attention in recent years as a potential therapeutic target to combat various neurodegenerative and psychiatric disorders including addiction. However, the specific contribution of microglia has not been investigated in oxycodone dependence. Chronic daily treatment with the CSF1R inhibitor Pexidartinib (PLX3397) was administered to knockdown microglia expression and evaluate consequences on analgesia and on naloxone induced withdrawal from oxycodone. In vivo results indicated that an approximately 40% reduction in brain IBA1 staining was achieved in the PLX treatment group, which was associated with a delay in the development of analgesic tolerance to oxycodone and maintained antinociceptive efficacy. Acute withdrawal behavioral symptoms, brain astrocyte expression, and levels of many neuroinflammatory markers were not affected by PLX treatment. KC/GRO (also known as CXCL1) was significantly enhanced in the somatosensory cortex in oxycodone-treated mice receiving PLX. Microglial knock-down did not affect the expression of naloxoneinduced opioid withdrawal but affected antinociceptive responsivity. The consequences of increased KC/GRO expression within the somatosensory cortex due to microglial reduction during opioid dependence are unclear but may be important for neural pathways mediating opioid-induced analgesia.</p>","PeriodicalId":72092,"journal":{"name":"Advances in drug and alcohol research","volume":" ","pages":"10848"},"PeriodicalIF":0.0,"publicationDate":"2022-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10880796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49657983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal exposure to alcohol: mechanisms of cerebral vascular damage and lifelong consequences.","authors":"Partha S Saha, William G Mayhan","doi":"10.3389/adar.2022.10818","DOIUrl":"10.3389/adar.2022.10818","url":null,"abstract":"<p><p>Alcohol is a well-known teratogen, and prenatal alcohol exposure (PAE) leads to a greater incidence of many cardiovascular-related pathologies. Alcohol negatively impacts vasculogenesis and angiogenesis in the developing fetal brain, resulting in fetal alcohol spectrum disorders (FASD). Ample preclinical evidence indicates that the normal reactivity of cerebral resistance arterioles, which regulate blood flow distribution in response to metabolic demand (neurovascular coupling), is impaired by PAE. This impairment of dilation of cerebral arteries may carry implications for the susceptibility of the brain to cerebral ischemic damage well into adulthood. The focus of this review is to consolidate findings from studies examining the influence of PAE on vascular development, give insights into relevant pathological mechanisms at the vascular level, evaluate the risks of ethanol-driven alterations of cerebrovascular reactivity, and revisit different preventive interventions that may have promise in reversing vascular changes in preclinical FASD models.</p>","PeriodicalId":72092,"journal":{"name":"Advances in drug and alcohol research","volume":" ","pages":"10818"},"PeriodicalIF":0.0,"publicationDate":"2022-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10880760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44921352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CB1 Cannabinoid Receptor is a Target for Neuroprotection in Light Induced Retinal Degeneration.","authors":"Manuel Soliño, Ignacio M Larrayoz, Ester María López, Manuel Rey-Funes, Mariana Bareiro, Cesar Fabián Loidl, Elena Girardi, Laura Caltana, Alicia Brusco, Alfredo Martínez, Juan José López-Costa","doi":"10.3389/adar.2022.10734","DOIUrl":"10.3389/adar.2022.10734","url":null,"abstract":"<p><p>In the last few years, an increasing interest in the neuroprotective effect of cannabinoids has taken place. The aim of the present work was to study the effects of modulating cannabinoid receptor 1 (CB1) in the context of light induced retinal degeneration (LIRD), using an animal model that resembles many characteristics of human age-related macular degeneration (AMD) and other degenerative diseases of the outer retina. Sprague Dawley rats (<i>n</i> = 28) were intravitreally injected in the right eye with either a CB1 agonist (ACEA), or an antagonist (AM251). Contralateral eyes were injected with respective vehicles as controls. Then, rats were subjected to continuous illumination (12,000 lux) for 24 h. Retinas from 28 animals were processed by GFAP-immunohistochemistry (IHC), TUNEL technique, Western blotting (WB), or qRT-PCR. ACEA-treated retinas showed a significantly lower number of apoptotic nuclei in the outer nuclear layer (ONL), lower levels of activated Caspase-3 by WB, and lower levels of glial reactivity by both GFAP-IHC and WB. qRT-PCR revealed that ACEA significantly decreased the expression of Bcl-2 and CYP1A1. Conversely, AM251-treated retinas showed a higher number of apoptotic nuclei in the ONL, higher levels of activated Caspase-3 by WB, and higher levels of glial reactivity as determined by GFAP-IHC and WB. AM251 increased the expression of Bcl-2, Bad, Bax, Aryl hydrocarbon Receptor (AhR), GFAP, and TNFα. In summary, the stimulation of the CB1 receptor, previous to the start of the pathogenic process, improved the survival of photoreceptors exposed to LIRD. The modulation of CB1 activity may be used as a neuroprotective strategy in retinal degeneration and deserves further studies.</p>","PeriodicalId":72092,"journal":{"name":"Advances in drug and alcohol research","volume":" ","pages":"10734"},"PeriodicalIF":0.0,"publicationDate":"2022-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10880786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49332573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-Dependent Synaptic Remodeling of the Somatosensory Cortex in Mice With Prenatal Methadone Exposure.","authors":"Gregory G Grecco, Jui Yen Huang, Braulio Muñoz, Emma H Doud, Caliel D Hines, Yong Gao, Brooke Rodriguez, Amber L Mosley, Hui-Chen Lu, Brady K Atwood","doi":"10.3389/adar.2022.10400","DOIUrl":"10.3389/adar.2022.10400","url":null,"abstract":"<p><p>Rising opioid use among pregnant women has led to a growing population of neonates exposed to opioids during the prenatal period, but how opioids affect the developing brain remains to be fully understood. Animal models of prenatal opioid exposure have discovered deficits in somatosensory behavioral development that persist into adolescence suggesting opioid exposure induces long lasting neuroadaptations on somatosensory circuitry such as the primary somatosensory cortex (S1). Using a mouse model of prenatal methadone exposure (PME) that displays delays in somatosensory milestone development, we performed an un-biased multi-omics analysis and investigated synaptic functioning in the primary somatosensory cortex (S1), where touch and pain sensory inputs are received in the brain, of early adolescent PME offspring. PME was associated with numerous changes in protein and phosphopeptide abundances that differed considerably between sexes in the S1. Although prominent sex effects were discovered in the multi-omics assessment, functional enrichment analyses revealed the protein and phosphopeptide differences were associated with synapse-related cellular components and synaptic signaling-related biological processes, regardless of sex. Immunohistochemical analysis identified diminished GABAergic synapses in both layer 2/3 and 4 of PME offspring. These immunohistochemical and proteomic alterations were associated with functional consequences as layer 2/3 pyramidal neurons revealed reduced amplitudes and a lengthened decay constant of inhibitory postsynaptic currents. Lastly, in addition to reduced cortical thickness of the S1, cell-type marker analysis revealed reduced microglia density in the upper layer of the S1 that was primarily driven by PME females. Taken together, our studies show the lasting changes on synaptic function and microglia in S1 cortex caused by PME in a sex-dependent manner.</p>","PeriodicalId":72092,"journal":{"name":"Advances in drug and alcohol research","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10569410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41221539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction With the Lipid Membrane Influences Fentanyl Pharmacology.","authors":"Katy J Sutcliffe, Robin A Corey, Norah Alhosan, Damiana Cavallo, Sam Groom, Marina Santiago, Chris Bailey, Steven J Charlton, Richard B Sessions, Graeme Henderson, Eamonn Kelly","doi":"10.3389/adar.2022.10280","DOIUrl":"10.3389/adar.2022.10280","url":null,"abstract":"<p><p>Overdose deaths from fentanyl have reached epidemic proportions in the USA and are increasing worldwide. Fentanyl is a potent opioid agonist that is less well reversed by naloxone than morphine. Due to fentanyl's high lipophilicity and elongated structure we hypothesised that its unusual pharmacology may be explained by its interactions with the lipid membrane on route to binding to the μ-opioid receptor (MOPr). Through coarse-grained molecular dynamics simulations, electrophysiological recordings and cell signalling assays, we determined how fentanyl and morphine access the orthosteric pocket of MOPr. Morphine accesses MOPr via the aqueous pathway; first binding to an extracellular vestibule, then diffusing into the orthosteric pocket. In contrast, fentanyl may take a novel route; first partitioning into the membrane, before accessing the orthosteric site by diffusing through a ligand-induced gap between the transmembrane helices. In electrophysiological recordings fentanyl-induced currents returned after washout, suggesting fentanyl deposits in the lipid membrane. However, mutation of residues forming the potential MOPr transmembrane access site did not alter fentanyl's pharmacological profile <i>in vitro</i>. A high local concentration of fentanyl in the lipid membrane, possibly in combination with a novel lipophilic binding route, may explain the high potency and lower susceptibility of fentanyl to reversal by naloxone.</p>","PeriodicalId":72092,"journal":{"name":"Advances in drug and alcohol research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40571838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut-Microbiome Implications in Opioid Use Disorder and Related Behaviors.","authors":"Bridget Herlihy, Sabita Roy","doi":"10.3389/adar.2022.10311","DOIUrl":"10.3389/adar.2022.10311","url":null,"abstract":"<p><p>Substance use disorder (SUD) is a prevalent disease that has caused hundreds of thousands of deaths and affected the lives of even more. Despite its global impact, there is still no known cure for SUD, or the psychological symptoms associated with drug use. Many of the behavioral consequences of drug use prevent people from breaking the cycle of addiction or cause them to relapse back into the cycle due to the physical and psychological consequences of withdrawal. Current research is aimed at understanding the cause of these drug related behaviors and therapeutically targeting them as a mechanism to break the addiction cycle. Research on opioids suggests that the changes in the microbiome during drug use modulated drug related behaviors and preventing these microbial changes could attenuate behavioral symptoms. This review aims to highlight the relationship between the changes in the microbiome and behavior during opioid treatment, as well as highlight the additional research needed to understand the mechanism in which the microbiome modulates behavior to determine the best therapeutic course of action.</p>","PeriodicalId":72092,"journal":{"name":"Advances in drug and alcohol research","volume":" ","pages":"10311"},"PeriodicalIF":0.0,"publicationDate":"2022-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10880781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45949777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contributions of the International Narcotics Research Conference to Opioid Research Over the Past 50 years.","authors":"Brian M Cox, Lawrence Toll","doi":"10.3389/adar.2022.10115","DOIUrl":"10.3389/adar.2022.10115","url":null,"abstract":"<p><p>The International Narcotics Research Conference (INRC), founded in 1969, has been a successful forum for research into the actions of opiates, with an annual conference since 1971. Every year, scientists from around the world have congregated to present the latest data on novel opiates, opiate receptors and endogenous ligands, mechanisms of analgesic activity and unwanted side effects, etc. All the important discoveries in the opiate field were discussed, often first, at the annual INRC meeting. With an apology to important events and participants not discussed, this review presents a short history of INRC with a discussion of groundbreaking discoveries in the opiate field and the researchers who presented from the first meeting up to the present.</p>","PeriodicalId":72092,"journal":{"name":"Advances in drug and alcohol research","volume":" ","pages":"10115"},"PeriodicalIF":0.0,"publicationDate":"2022-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10880772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44621391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Acetaldehyde in Ethanol Reversal of Tolerance to Morphine-Induced Respiratory Depression in Mice.","authors":"Rob Hill, Alexandra Conibear, William Dewey, Eamonn Kelly, Graeme Henderson","doi":"10.3389/adar.2021.10143","DOIUrl":"10.3389/adar.2021.10143","url":null,"abstract":"<p><strong>Background: </strong>Opioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol rapidly reverses tolerance to morphine-induced respiratory depression. However, recent research has suggested that the primary metabolite of ethanol, acetaldehyde, may play a key role in mediating the CNS effects seen after ethanol consumption. This research investigated the role of acetaldehyde in ethanol reversal of tolerance to morphine-induced respiratory depression.</p><p><strong>Methods: </strong>Tolerance was induced in mice by 6-days implantation of a 75 mg morphine pellet with control mice implanted with a placebo pellet. Tolerance was assessed by acute morphine administration on day 6 and respiration measured by plethysmography. Levels of acetaldehyde were inhibited or enhanced by pre-treatments with the acetaldehyde chelator D-penicillamine and the inhibitor of acetaldehyde dehydrogenase disulfiram respectively.</p><p><strong>Results: </strong>Morphine pellet implanted mice displayed tolerance to an acute dose of morphine compared to placebo pellet implanted controls. Acute acetaldehyde administration dose-dependently reversed tolerance to morphine respiratory depression. As previously demonstrated, ethanol reversed morphine tolerance, and this was inhibited by D-penicillamine pre-treatment. An acute, low dose of ethanol that did not significantly reverse morphine tolerance was able to do so following disulfiram pre-treatment.</p><p><strong>Conclusion: </strong>These data suggest that acetaldehyde, the primary metabolite of ethanol, is responsible for the reversal of morphine tolerance observed following ethanol administration.</p>","PeriodicalId":72092,"journal":{"name":"Advances in drug and alcohol research","volume":"1 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40572883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}