Abstract

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/ kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch- clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABAA receptor α and δ subunits at AD14 in heroin and saline self- administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex.

Document Type

Article

Publication Date

9-2024

Notes/Citation Information

0197-0186/© 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.neuint.2024.105785

Funding Information

This study was funded by the PhRMA Foundation Faculty Starter grant in Drug Discovery and Marshall University Research Corporation Startup funds to SM. This work was also supported by the National Institutes of Health Grants DA055879, DA044479, DA046526, DA049130, and DA045881 to CDG. SM conceptualized the study with inputs from SNK, KL, and HRA. DM and MNR synthesized DM506. KL and CS performed behavioral experiments. MM, KC, AFC, and CM performed biochemical experiments. SNK performed electrophysiological recordings. SM and SNK wrote the manuscript with inputs from CDG and HRA.

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