Effects of acute and repeated administration of the selective M 4 PAM VU0152099 on cocaine versus food choice in male rats.

Ligands that stimulate muscarinic acetylcholine receptors 1 and 4 (M 1 , M 4 ) have shown promising effects as putative pharmacotherapy for cocaine use disorder in rodent assays. We have previously shown reductions in cocaine effects with acute M 4 stimulation, as well as long-lasting, delayed reductions in cocaine taking and cocaine seeking with combined M 1 /M 4 receptor stimulation or with M 1 stimulation alone. M 4 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 M 4 approaches themselves can remain effective with repeated or chronic dosing. We assessed the effects of repeated administration of the M 4 positive allosteric modulator (PAM) VU0152099 in rats trained to choose between intravenous cocaine and a liquid food reinforcer to obtain quantitative measurement of whether M 4 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 M 1 versus M 4 stimulation, we tested whether the M 4 PAM VU0152100 suppressed cocaine self-administration in mice lacking CalDAG-GEFI signalling factor, required for M 1 -mediated suppression of cocaine self-administration. CalDAG-GEFI ablation had no effect on M 4 -mediated suppression of cocaine self-administration. These findings support the potential usefulness of M 4 PAMs as pharmacotherapy to manage cocaine use disorder, alone or in combination with M 1 -selective ligands, and show that M 1 and M 4 stimulation modulate cocaine-taking behaviour by distinct mechanisms.