Effects of acute and repeated administration of the selective M 4 PAM VU0152099 on cocaine versus food choice in male rats
Name
Addiction Biology - 2022 - Thomsen - Effects of acute and repeated administration of the selective M4 PAM VU0152099 on.pdf
Description
Published version
Size
1.69 MB
Format
Adobe PDF
Checksum (MD5)
33668c7b06e49af25f91afc99d8286bd
Author(s)
Thomsen, Morgane
Crittenden, Jill R
Lindsley, Craig W
Graybiel, Ann M
Date Issued
2022
Journal
Addiction Biology
Publisher
Wiley
Citation
Thomsen, Morgane, Crittenden, Jill R, Lindsley, Craig W and Graybiel, Ann M. 2022. "Effects of acute and repeated administration of the selective M 4 PAM VU0152099 on cocaine versus food choice in male rats." Addiction Biology, 27 (2).
Version
Final published version
Abstract
Ligands that stimulate muscarinic acetylcholine receptors 1 and 4 (M1 , M4 ) have shown promising effects as putative pharmacotherapy for cocaine use disorder in rodent assays. We have previously shown reductions in cocaine effects with acute M4 stimulation, as well as long-lasting, delayed reductions in cocaine taking and cocaine seeking with combined M1 /M4 receptor stimulation or with M1 stimulation alone. M4 stimulation opposes dopaminergic signalling acutely, but direct dopamine receptor antagonists have proved unhelpful in managing cocaine use disorder because they lose efficacy with long-term administration. It is therefore critical to determine whether M4 approaches themselves can remain effective with repeated or chronic dosing. We assessed the effects of repeated administration of the M4 positive allosteric modulator (PAM) VU0152099 in rats trained to choose between intravenous cocaine and a liquid food reinforcer to obtain quantitative measurement of whether M4 stimulation could produce delayed and lasting reduction in cocaine taking. VU0152099 produced progressively augmenting suppression of cocaine choice and cocaine intake, but produced neither rebound nor lasting effects after treatment ended. To compare and contrast effects of M1 versus M4 stimulation, we tested whether the M4 PAM VU0152100 suppressed cocaine self-administration in mice lacking CalDAG-GEFI signalling factor, required for M1 -mediated suppression of cocaine self-administration. CalDAG-GEFI ablation had no effect on M4 -mediated suppression of cocaine self-administration. These findings support the potential usefulness of M4 PAMs as pharmacotherapy to manage cocaine use disorder, alone or in combination with M1 -selective ligands, and show that M1 and M4 stimulation modulate cocaine-taking behaviour by distinct mechanisms.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1111/ADB.13145
