Clocinnamox blocks only mu receptors irreversibly: Binding evidence

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31197/1/0000099.pd

Role of anterior insula cortex in context-induced relapse of nicotine-seeking

Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the critical barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce craving and contribute to relapse. The insular cortex (IC) is thought to be a critical substrate of nicotine addiction and relapse. However, its specific role in context-induced relapse of nicotine-seeking is not fully known. In this study, we report a novel rodent model of context-induced relapse to nicotine-seeking after punishment-imposed abstinence, which models self-imposed abstinence through increasing negative consequences of excessive drug use. Using the neuronal activity marker Fos we find that the anterior (aIC), but not the middle or posterior IC, shows increased activity during context-induced relapse. Combining Fos with retrograde labeling of aIC inputs, we show projections to aIC from contralateral aIC and basolateral amygdala exhibit increased activity during context-induced relapse. Next, we used fiber photometry in aIC and observed phasic increases in aIC activity around nicotine-seeking responses during self-administration, punishment, and the context-induced relapse tests. Next, we used chemogenetic inhibition in both male and female rats to determine whether activity in aIC is necessary for context-induced relapse. We found that chemogenetic inhibition of aIC decreased context-induced nicotine-seeking after either punishment-or extinction-imposed abstinence. These findings highlight the critical role nicotine-associated contexts play in promoting relapse, and they show that aIC activity is critical for this context-induced relapse following both punishment and extinction-imposed abstinence

Oral Ethanol-Reinforced Responding in Rhesus Monkeys: Effects of Opioid Antagonists Selective for the Μ-,Κ-, or Δ-Receptor

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65904/1/j.1530-0277.1998.tb03960.x.pd

Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy

IntroductionA titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11–21 ng/ml) that are expected under the approved dose range (10–20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy.MethodsFollowing our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram.ResultsOf 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C).ConclusionBased on our findings, we propose a target range of 20–40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram’s reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873]

Naloxone's Pentapeptide Binding Site on Filamin A Blocks Mu Opioid Receptor–Gs Coupling and CREB Activation of Acute Morphine

Chronic morphine causes the mu opioid receptor (MOR) to switch its coupling from Gi/o to Gs, resulting in excitatory signaling via both Gαs and its Gβγ dimer. Ultra-low-dose naloxone (NLX) prevents this switch and attenuates opioid tolerance and dependence. This protective effect is mediated via a high-affinity interaction of NLX to a pentapeptide region in c-terminal filamin A (FLNA), a scaffolding protein interacting with MOR. In organotypic striatal slice cultures, we now show that acute morphine induces a dose-dependent Go-to-Gs coupling switch at 5 and 15 min that resolves by 1 hr. The acute Gs coupling induced by 100 µM morphine was completely prevented by co-treatment with 100 pM NLX, (+)NLX, or naltrexone (NTX), or their pentapeptide binding site (FLNA2561–2565), which we show can act as a decoy for MOR or bind to FLNA itself. All of these co-treatments presumably prevent the MOR–FLNA interaction. Since ultra-low-dose NTX also attenuates the addictive properties of opioids, we assessed striatal cAMP production and CREB phosphorylation at S133. Correlating with the Gs coupling, acute morphine induced elevated cAMP levels and a several-fold increase in pS133CREB that were also completely blocked by NLX, NTX or the FLNA pentapeptide. We propose that acute, robust stimulation of MOR causes an interaction with FLNA that allows an initially transient MOR–Gs coupling, which recovers with receptor recycling but persists when MOR stimulation is repeated or prolonged. The complete prevention of this acute, morphine-induced MOR–Gs coupling by 100 pM NLX/NTX or 10 µM pentapeptide segment of FLNA further elucidates both MOR signaling and the mechanism of action of ultra-low-dose NLX or NTX in attenuating opioid tolerance, dependence and addictive potential

Clocinnamox antagonism of opioid suppression of schedule-controlled responding in rhesus monkeys

The antagonist effects of clocinnamox were evaluated against opioid agonists, acting at μ, κ and ∂-receptors, in rhesus monkeys ( n =3–4) responding under a fixed-ratio 30 (FR 30) schedule for food delivery. Clocinnamox (0.032–0.1 mg/kg) dose-dependently antagonized fentanyl (0.001–0.32 mg/kg) after either a 3-h or 1-day pretreatment; there was substantial recovery of agonist potency by 1 week after clocinnamox. Etonitazene (0.0001–0.01 mg/kg) was also antagonized by clocinnamox (0.1 mg/kg), but to a lesser extent than fentanyl. The smaller extent of antagonism was not due to the appearance of non μ-opioid response-decreasing effects of etonitazene, since the competitive antagonist quadazocine (0.1 mg/kg) shifted the etonitazene dose-effect curve in the presence of clocinnamox (0.1 mg/kg). Clocinnamox (0.1–0.32 mg/kg) did not antagonize the rate-suppressing effects of the ∂-agonist BW373U86 (0.0.01-1.0 mg/kg) or the κ-agonist U69,593 (0.001–0.032 mg/kg). These results are consistent with previous in vivo and in vitro evidence that characterized clocinnamox as an insurmountable antagonist, with selectivity for μ-over κ- and δ-receptors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46352/1/213_2005_Article_BF02246641.pd

Researching In German - The Machiavelli For Scientists - And Those Who Still Want To Become One - German - Bar,s

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62950/1/362708a0.pd

Clocinnamox inhibits the intravenous self-administration of opioid agonists in rhesus monkeys: comparison with effects on opioid agonist-mediated antinociception

 The effects of CCAM, an insurmountable mu opioid receptor antagonist, were studied on the intravenous self-administration and thermoantinociception of alfentanil and nalbuphine, high- and low-efficacy opioid agonists, respectively, in rhesus monkeys. A single dose of 0.1 mg/kg CCAM IV reduced alfentanil’s reinforcing potency in an FR30 TO 45s schedule 10-fold within a 24-h period. The maximum response rates remained essentially unchanged. At 1 mg/kg, CCAM caused a 300-fold shift of the alfentanil dose-response curve and also depressed the maximum response rates. CCAM also blocked insurmountably responding for nalbuphine, which was essentially abolished in two of three animals after a dose of 0.1 mg/kg CCAM and in all animals after 1 mg/kg. The acute insurmountable antagonism of alfentanil and nalbuphine self-administration by CCAM was used to determine the (relative initial) efficacy values of both agonists. Efficacy values, tau, were 391 for alfentanil and 196 for nalbuphine; the apparent in vivo dissociation constants, K A , were 0.16 mg/kg per injection (i.e., 350 nmol/kg per injection) for alfentanil and 0.14 mg/kg (370 nmol/kg per injection) for nalbuphine. In comparison, in a rhesus monkey 50°C warm-water tail withdrawal assay, the tau values were 11 for alfentanil and 0.92 for nalbuphine, and the K A values were 0.2 mg/kg (440 nmol/kg) for alfentanil and 0.15 mg/kg (400 nmol/kg) for nalbuphine. Therefore, it seems that the higher potency of alfentanil and nalbuphine in self-administration as compared to thermal antinociception in rhesus monkeys is predominantly due to a larger efficacy of the same agonist in self-administration (i.e., a larger receptor pool) rather than differences in apparent in vivo affinity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41957/1/213-129-3-233_71290233.pd