Fentanyl overdose: Temporal effects and prognostic factors in SKH1 mice.

Fentanyl exposure and overdose are growing concerns in public health and occupational safety. This study aimed to establish parameters of fentanyl lethality in SKH1 mice for future overdose research. Lethality was determined using the up-down procedure, with subjects monitored post-administration using pulse oximetry (5 min) and then whole-body plethysmography (40 min). Following the determination of subcutaneous dose-response, [18F]Fluorodeoxyglucose positron emission tomography (18 F-FDG PET) was performed after LD10 fentanyl at 40 min, 6 h, 24 h or 7 days post-dose. LD10 and LD50 were observed to be 110 and 135 mg/kg, respectively, and consistent with four-parameter logistic fit values of 111.2 and 134.6 mg/kg (r2  = 0.9996). Overdose (LD10 or greater) yielded three distinct cardiovascular groups: survival, non-survival with blood oxygen saturation (SpO2) minimum ≥37% and non-survival with SpO2 <37%. Breaths per minute, minute volume and inspiratory quotient were significantly different between surviving and non-surviving animals for up to 40 min post-injection. 18 F-FDG PET revealed decreased glucose uptake in the heart, lungs and brain for up to 24 h. These findings provide critical insights into fentanyl lethality in SKH1 mice, including non-invasive respiratory effects and organ-specific impacts that are invaluable for future translational studies investigating the temporal effects of fentanyl overdose.

Preliminary assessment of the subjective effects of electronic-cigarettes in young-adult low-dose electronic-cigarette users: Effects of nicotine dose and e-liquid flavor.

OBJECTIVE: The present study evaluated the effects of nicotine concentration (0-10 mg/ml) and flavor (gummy bear vs unflavored) on the subjective experiences of vaporized nicotine in young adult low-dose nicotine (3 mg/ml) ECIG users. PARTICIPANTS: Eight young adult ECIG users were recruited. METHODS: A single blinded crossover study was used. Participants were instructed to take ten 1.5 second puffs, each separated by 20 seconds. After self-administration, heart rate was recorded, and participants completed the Drug Effects, Direct Effects of Nicotine, and Direct Effects of ECIG questionnaires. RESULTS: ECIG user's standard daily nicotine dose influenced the rewarding and aversive effects of nicotine as the 10 mg/ml dose was found to be aversive in this user group. The combination of flavor and nicotine increased the subjective effects of ECIGs. CONCLUSIONS: Flavored e-liquids contribute to the reinforcing properties of nicotine by enhancing the subjective effects, which may lead to continued ECIG use.

Assessment of antidepressant-like effects of dextromethorphan on differential reinforcement of low-rate 72-s performance in rats.

The effectiveness of ketamine for treatment-resistant depression along with several other clinical advantages, such as rapid onset and reduced adverse effects associated with serotonin transporter inhibition, has garnered interest in other similar acting psychedelics as novel antidepressant drugs. The antitussive dextromethorphan exhibits glutamate N-methyl-d-aspartate receptor antagonism, sigma-1 receptor agonism, and serotonin reuptake inhibition, which has exhibited antidepressant effects in limited human studies and animal models. The present study sought to further examine dextromethorphan using a differential reinforcement of low-rate 72-s schedule, which can be used to screen antidepressant drugs, in male and female rats. The tricyclic antidepressant drug imipramine and the psychostimulant d-amphetamine also were examined. Sex differences were not shown for baseline performance or for the drugs tested. Further, performance did not differ between the estrus and diestrus stages. Dextromethorphan alone and with quinidine produced an antidepressant-like effect by reducing the number of responses emitted, increasing the number of reinforcers earned, and shifting inter-response times to the right, although significant response suppression occurred at these doses. An antidepressant-like effect was shown with imipramine, but d-amphetamine increased the number of responses emitted and did not affect the number of reinforcers earned. The present findings provide additional support for antidepressant effects produced by dextromethorphan.

Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression.

BACKGROUND: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. METHODS: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. RESULTS: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. CONCLUSIONS: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.

Differential phosphoprotein signaling in the cortex in mouse models of Gulf War Illness using corticosterone and acetylcholinesterase inhibitors.

AIMS: Veterans from the 1990-91 Gulf War were exposed to acetylcholinesterase inhibitors (AChEIs), and, following service, an estimated one-third began suffering from a medically unexplained, multi-symptom illness termed Gulf War Illness (GWI). Previous research has developed validated rodent models that include exposure to exogenous corticosterone (CORT) and AChEIs to simulate high stress and chemical exposures encountered in theater. This combination of exposures in mice resulted in a marked increase in neuroinflammation, which is a common symptom of veterans suffering from GWI. To further elucidate the mechanisms associated with these mouse models of GWI, an investigation into intracellular responses in the cortex were performed to characterize the early cellular signaling changes associated with this exposure-initiated neuroinflammation. MAIN METHODS: Adult male C57BL/6J mice were exposed to CORT in the drinking water (200 µg/mL) for 7 days followed by a single intraperitoneal injection of diisopropyl fluorophosphate (DFP; 4.0 mg/kg) or chlorpyrifos oxon (CPO; 8.0 mg/kg), on day 8 and euthanized 0.5, 2, and 24 h post-injection. Eleven post-translationally modified protein targets were measured using a multiplexed ELISA. KEY FINDINGS: Phosphoprotein responses were found to be exposure specific following AChEI insult, with and without CORT. Specifically, CORT + CPO exposure was found to sequentially activate several phosphoproteins involved in mitogen activated protein kinase signaling (p-MEK1/2, p-ERK1/2, and p-JNK). DFP alone similarly increased proteins in this pathway (p-RPS6, and p-JNK), but the addition of CORT ameliorated these affects. SIGNIFICANCE: The results of this study provide insight into differentially activated pathways depending on AChEI in these GWI models.

Corticosterone and chlorpyrifos oxon exposure elicits spatiotemporal MAPK phosphoprotein signaling in a mouse brain.

Chlorpyrifos (CPF) is one of the most widely-used pesticides globally for agricultural purposes. Certain occupations (e.g., farmers, military) are at an increased risk for high-dose exposure to CPF, which can lead to seizures and irreversible brain injury. Workers with the highest risk of exposure typically experience increased circulating cortisol levels, which is related to physiological stress. To better represent this exposure scenario, a mouse model utilized exogenous administration of corticosterone (CORT; high physiologic stress mimic) in combination with chlorpyrifos oxon (CPO; oxon metabolite of CPF); this combination increases neuroinflammation post-exposure. In the present study adult male C57BL/6J mice were given CORT (200 µg/mL) in drinking water for seven days followed by a single intraperitoneal injection of CPO (8.0 mg/kg) on day eight, and euthanized 0.5, 2, and 24 h post-injection. Ten post-translationally modified proteins were measured in the frontal cortex and striatum to evaluate brain region-specific effects. The spatiotemporal response to CORT + CPO sequentially activated phosphoproteins (p-ERK1/2, p-MEK1/2, p-JNK) involved in mitogen-activated protein kinase (MAPK) signaling. Observed p-ZAP70 responses further integrated MAPK signaling and provided a spatiotemporal connection between protein phosphorylation and neuroinflammation. This study provides insight into the spatiotemporal cellular signaling cascade following CORT + CPO exposure that represent these vulnerable populations.