Browsing by Subject "Withdrawal"

Now showing 1 - 4 of 4
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    Effects of chronic intermittent ethanol exposure and withdrawal on neuroblastoma cell transcriptome
    (Elsevier, 2020-06) McClintick, Jeanette N.; Thapa, Kriti; Liu, Yunlong; Xuei, Xiaoling; Edenberg, Howard J.; Biochemistry and Molecular Biology, School of Medicine
    Cycles of heavy drinking and abstinence can lead to ethanol abuse disorder. We studied the effects of chronic intermittent ethanol exposure (CIE) over three weeks on neuroblastoma cells, using an ethanol concentration frequently attained in binge drinking (40 mM, 184 mg/dl). There were many changes in gene expression but most were small. CIE affected pathways instrumental in the development or plasticity of neurons, including axonal guidance, reelin signaling and synaptogenesis. Genes involved in dopamine and serotonin signaling were also affected. Changes in transporters and receptors could dampen both NMDA and norepinephrine transmissions. Decreased expression of the GABA transporter SLC6A11 could increase GABA transmission and has been associated with a switch from sweet drinking to ethanol consumption in rats. Ethanol increased stress responses such as unfolded protein response. TGF-β and NFκB signaling were increased. Most of the genes involved in cholesterol biosynthesis were decreased in expression. Withdrawal for 24 h after CIE caused most of the CIE-induced expression changes to move back toward unexposed levels.
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    Home Cage Voluntary Alcohol Consumption Increases Binge Drinking without Affecting Abstinence-Related Depressive-Like Behaviors or Operant Responding in Crossed High Alcohol-Preferring (cHAPs)
    (Elsevier, 2024) Winkler, Garrett A.; Grahame, Nicholas J.; Psychology, School of Science
    Chronic alcohol consumption can lead to tolerance and escalation of drinking in humans and animals, but mechanisms underlying these changes are not fully characterized. Preclinical models can delineate which mechanisms are involved. The chronic intermittent ethanol exposure (CIE) procedure uses forced exposure to vaporized alcohol that elicits withdrawal and increased responding for alcohol in operant tasks in C57BL/6J inbred mice. Chronic two-bottle choice (2BC) drinking in the same strain elicits abstinent-related depression-like behavior, suggestive of allostatic changes. Selected lines such as crossed High Alcohol Preferring (cHAP) mice voluntarily drink to blood alcohol concentrations comparable to those attained in CIE and could be used to assess how alcohol affects these same endpoints without the confounds of involuntary vapor inhalation. In three experiments, we assess how 2BC drinking in cHAP mice affects abstinence-related depressive- and anxiety-like behavior, operant responding for alcohol, and binge consumption using drinking-in-the-dark (DID). We hypothesized that cHAPs with home-cage drinking experience would exhibit more depressive behavior after abstinence, increased responding for alcohol in the operant box, and increased DID intake. Of these, a drinking history increased DID intake in female cHAPs only and increased sucrose preference and intake following abstinence, but had no effects on operant responding or NSFT latency and FST immobility following forced abstinence. These results are consistent with recent findings using slice electrophysiology showing tolerance to alcohol's actions on the dorsolateral striatum following 2BC drinking in female, but not male cHAP mice. Overall, these data suggest that cHAPs may require procedures allowing rapid intoxication, such as DID, to demonstrate changes in alcohol's rewarding effects.
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    Microglial knockdown does not affect acute withdrawal but delays analgesic tolerance from oxycodone in male and female C57BL/6J mice
    (Frontiers Media, 2022-12-16) El Jordi, Omar; Fischer, Kathryn D.; Meyer, Timothy B.; Atwood, Brady K.; Oblak, Adrian L.; Pan, Raymond W.; McKinzie, David L.; Pharmacology and Toxicology, School of Medicine
    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.
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    Prevention of Withdrawal in Pediatric Patients Receiving Long-term Dexmedetomidine Infusions
    (Allen Press, 2021) Berrens, Zachary J.; Sauro, Ashley L.; Tillman, Emma M.; Pediatrics, School of Medicine
    Objective: Determine if the addition of clonidine was associated with a decreased incidence of dexmedetomidine withdrawal in patients who received prolonged dexmedetomidine infusions. Methods: This was a retrospective observational cohort study conducted at a single-center PICU in an academic children's hospital. Children 1 month to 18 years of age who received dexmedetomidine infusion for 5 days or longer were included in the study. Results: Fifty patients met the inclusion criteria with 15 patients who received clonidine and 35 who received a dexmedetomidine wean alone. Withdrawal criteria included blood pressure changes, heart rate changes, and documented agitation. Overall, there was no difference in change in blood pressure or documented agitation between groups. Patients who did not receive clonidine had a greater number of heart rate readings above normal for age following discontinuation of the infusion, yet this was not statistically significant. Potentially more importantly, the addition of clonidine did not impact the duration of dexmedetomidine wean or the PICU length of stay after dexmedetomidine discontinuation. Conclusions: The addition of clonidine while weaning a long-term dexmedetomidine infusion did not lead to lower blood pressures or agitation, but did lead to decreased percentage of heart rates above the age-appropriate range. The clinical significance of this is unknown, and further investigation is warranted. The addition of clonidine did not decrease time to weaning off dexmedetomidine or shorten PICU length of stay.