dc.contributor.author | van de Wetering, Ross | |
dc.contributor.author | Ewald, Amy | |
dc.contributor.author | Welsh, Susan | |
dc.contributor.author | Kornberger, Lindsay | |
dc.contributor.author | Williamson, Samuel E. | |
dc.contributor.author | McElroy, Bryan D. | |
dc.contributor.author | Butelman, Eduardo R. | |
dc.contributor.author | Prisinzano, Thomas E. | |
dc.contributor.author | Kivell, Bronwyn M. | |
dc.date.accessioned | 2023-07-10T21:52:26Z | |
dc.date.available | 2023-07-10T21:52:26Z | |
dc.date.issued | 2023-06-19 | |
dc.identifier.citation | van de Wetering, R.; Ewald, A.; Welsh, S.; Kornberger, L.; Williamson, S.E.; McElroy, B.D.; Butelman, E.R.; Prisinzano, T.E.; Kivell, B.M. The Kappa Opioid Receptor Agonist 16-Bromo Salvinorin A Has Anti-Cocaine Effects without Significant Effects on Locomotion, Food Reward, Learning and Memory, or Anxiety and Depressive-like Behaviors. Molecules 2023, 28, 4848. https://doi.org/10.3390/molecules28124848 | en_US |
dc.identifier.uri | https://hdl.handle.net/1808/34578 | |
dc.description.abstract | Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with no significant effects in the elevated plus maze, light–dark test, forced swim test, sucrose self-administration, or novel object recognition; however, it did exhibit conditioned aversive effects. 16-BrSalA increased dopamine transporter (DAT) activity in HEK-293 cells coexpressing DAT and KOR, as well as in rat nucleus accumbens and dorsal striatal tissue. 16-BrSalA also increased the early phase activation of extracellular-signal-regulated kinases 1 and 2, as well as p38 in a KOR-dependent manner. In NHPs, 16-BrSalA caused dose-dependent increases in the neuroendocrine biomarker prolactin, similar to other KOR agonists, at doses without robust sedative effects. These findings highlight that G-protein-biased structural analogues of SalA can have improved pharmacokinetic profiles and fewer side effects while maintaining their anticocaine effects. | en_US |
dc.publisher | MDPI | en_US |
dc.rights | © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Kappa opioid receptor | en_US |
dc.subject | Salvinorin A | en_US |
dc.subject | Cocaine | en_US |
dc.subject | Addiction | en_US |
dc.subject | Side effects | en_US |
dc.title | The Kappa Opioid Receptor Agonist 16-Bromo Salvinorin A Has Anti-Cocaine Effects without Significant Effects on Locomotion, Food Reward, Learning and Memory, or Anxiety and Depressive-like Behaviors | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Williamson, Samuel E. | |
kusw.kuauthor | Prisinzano, Thomas E. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.3390/molecules28124848 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-1387-444X | en_US |
dc.identifier.orcid | https://orcid.org/0009-0002-0108-8764 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-0649-8052 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-9699-553X | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC10304272 | en_US |
dc.rights.accessrights | openAccess | en_US |