Search

Opioid receptors modulate neurochemical and behavioral responses to drugs of abuse in nonclinical models. Samidorphan (SAM) is a new molecular entity that binds with high affinity to human mu- (μ), kappa- (κ), and delta- (δ) opioid receptors and functions as a μ-opioid receptor antagonist with partial agonist activity at κ- and δ-opioid receptors. Based on its in vitro profile, we hypothesized that SAM would block key neurobiological effects of drugs of abuse. Therefore, we assessed the effects of SAM on ethanol-, oxycodone-, cocaine-, and amphetamine-induced increases in extracellular dopamine (DA ext ) in the nucleus accumbens shell (NAc-sh), and ethanol and cocaine self-administration behavior in rats. In microdialysis studies, administration of SAM alone did not result in measurable changes in NAc-sh DA ext when given across a large range of doses. However, SAM markedly decreased average and maximal increases in NAc-sh DA ext produced by each of the drugs of abuse tested. In behavioral studies, SAM attenuated fixed-ratio ethanol self-administration and progressive ratio cocaine self-administration. These results highlight the potential of SAM to counteract the neurobiological and behavioral effects of several drugs of abuse with differing mechanisms of action., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to examine the pharmacokinetics of cocaine in two inbred mouse strains, C57BL/6 (B6) and DBA/2 (D2). Male and female mice were administered 30 mg kg(-1) cocaine IP and killed after 5, 15, 30, or 60 minutes postinjection. Brains were removed quickly and assayed for total brain cocaine concentration. Quantification of cocaine was conducted using gas chromatography and mass spectrometry. The results of this study revealed a strain difference in total brain cocaine kinetics. Specifically, we observed that at 5 min onward, B6 mice cleared cocaine from the brain with a t1/2 estimated at 22.3 min, while distribution in D2 mice appeared to be incomplete until 15 min with a subsequent t1/2 estimated at 11.2 min. These results show that despite faster clearance by D2 mice, the prolonged time to distribution in this strain may help explain why D2 mice show initial greater locomotor activation by cocaine, compared to B6s.