Methocinnamox (MCAM), a mu opioid receptor antagonist with a long duration of action, attenuates heroin self-administration in rhesus monkeys, suggesting it could be an effective treatment for opioid use disorder (OUD). This study examined effects of acute and repeated MCAM administration on self-administration of the high-efficacy mu opioid receptor agonist fentanyl and characterized MCAM pharmacokinetics. Four rhesus monkeys self-administered i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion).  https://www.selleckchem.com/pharmacological_epigenetics.html  MCAM (0.1-0.32 mg/kg) or the opioid receptor antagonist naltrexone (0.001-0.032 mg/kg) was injected prior to test sessions to evaluate acute effects. On a separate occasion, 0.32 mg/kg MCAM was injected every 12 days for 5 total injections to evaluate the effectiveness of repeated treatment. Following acute injection, MCAM and naltrexone decreased fentanyl self-administration on the day of treatment, with attenuation lasting for up to 2 weeks after the larger MCAM dose and less then 1 day after naltrexone. Repeated MCAM administration decreased fentanyl self-administration for more than 2 months without altering cocaine self-administration. MCAM plasma concentrations peaked 15-45 min after injection, with a half-life ranging from 13.7 to 199.8 min, and decreased markedly 1 day after injection. MCAM selectively reduced opioid self-administration and remained effective with repeated administration. Moreover, MCAM was effective at times when plasma levels were very low, suggesting that pharmacodynamic (i.e., pseudoirreversible binding to mu opioid receptors) and not pharmacokinetic factors play a significant role in its long-lasting effects. Taken together with previous studies, these data indicate that MCAM could be a safe, effective, and long-acting treatment for OUD.A large body of work has focused on understanding stimulus-driven behavior, sex differences in these processes, and the neural circuits underlying them. Many preclinical mouse models present rewarding or aversive stimuli in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes. In addition, the context (or reinforcement schedule under) in which stimuli are encountered can engender different behavioral responses to the same stimulus. Thus, delineating neural control of behavior requires a dissociation between stimulus valence and stimulus-driven behavior. We developed the Multidimensional Cue Outcome Action Task (MCOAT) to dissociate motivated action from cue learning and valence in mice. First, mice acquire positive and negative reinforcement in the presence of discrete discriminative stimuli. Next, discriminative stimuli are presented concurrently allowing for parsing innate behavioral strategies based on reward seeking and avoidance. Lastly, responding in the face of punishment is assessed, thus examining  how positive and negative outcomes are relatively valued. First, we identified sex-specific behavioral strategies, showing that females prioritize avoidance of negative outcomes over seeking positive, while males have the opposite strategy. Next, we show that chemogenetically inhibiting D1 medium spiny neurons (MSNs) in the nucleus accumbens-a population that has been linked to reward-driven behavior-reduces positive and increases negative reinforcement learning rates. Thus, D1 MSNs modulate stimulus processing, rather than motivated responses or the reinforcement process itself. Together, the MCOAT has broad utility for understanding complex behaviors as well as the definition of the discrete information encoded within cellular populations.BACKGROUND Antibiotic therapy during preterm labor with intact membranes has been associated with an increased risk of neonatal death. OBJECTIVES Using an established rat model of group B Streptococcus (GBS)-induced chorioamnionitis, we hypothesized that ampicillin treatment increases placental inflammation, as shown in other bacterial infections. METHODS At gestational day 19, 19 Lewis dams were intraperitoneally (i.p.) inoculated by 108 CFU of β-hemolytic serotype Ia GBS (strain #16955 susceptible to ampicillin). Dams were treated i.p. with either 200 mg/kg of ampicillin (n = 9) or 0.9% saline (n = 10) at 48 and 60 h post-GBS inoculation. Cesarean sections were performed 72 h post-GBS inoculation. RESULTS Ampicillin treatment was associated with an increased number of polymorphonuclear cells (PMN) infiltrating the decidua (mean 1,536 vs. 532 PMN/mm2; p less then 0.001) and a higher placental concentration of IL-1β (mean 26.4 vs. 7.9 pg/mg; p less then 0.01) compared to saline-treated dams. These effects were observed in dams without GBS bacteremia. Conversely, ampicillin treatment was associated with a decreased placental concentration of proinflammatory cytokines in dams with GBS bacteremia. CONCLUSIONS Ampicillin increases placental inflammation in a rat model of GBS-induced chorioamnionitis without bacteremia. This proinflammatory effect of ampicillin could be due to bacterial lysis. Our findings do not query the intrapartum antibiotic prophylaxis against GBS disease. They pave the way for future preclinical studies combining anti-inflammatory treatments and antibiotic therapy for GBS-induced chorioamnionitis. © 2020 S. Karger AG, Basel.BACKGROUND Exosomes are nano-sized extracellular vesicles secreted by most cell types and abundantly present in body fluids, including blood, saliva, urine, cerebrospinal fluid, and breast milk. Exosomes can spread toxic amyloid-beta (Aβ) and hyperphosphorylated tau between cells, contributing to neuronal loss in Alzheimer's disease (AD). OBJECTIVE To explore changes in the morphology, number, and pathological protein levels of urinary exosomes in AD patients compared with age-matched healthy subjects. METHODS In this study, enzyme-linked immunosorbent assay was used to detect the levels of Aβ1-42 and P-S396-tau (normalized by CD63) in urinary exosomes of AD patients and matched healthy subjects. We used transmission electron microscopy and nanoparticle tracking analysis to observe the exosomes. RESULTS We found that the levels of Aβ1-42 and P-S396-tau in the urinary exosomes of AD patients were higher than those of matched healthy controls. Exosomes taken from AD patients were more numerous. CONCLUSION The differences in levels of Aβ1-42 and P-S396-tau and the quantity of urinary exosomes between AD patients and healthy controls may provide a basis for early diagnosis of AD.