Background <p>Cocaine Use Disorder (CUD) remains a significant problem in the United States, with high rates of relapse and no present FDA-approved treatment. The acetylcholine neurotransmitter system, specifically through modulation of muscarinic acetylcholine receptor (mAChR) function, has shown promise as a therapeutic target for multiple aspects of CUD. Enhancement of the M₄ mAChR subtype via positive allosteric modulation has been shown to inhibit the behavioral and neurochemical effects of cocaine across several rodent models of CUD. However, it is unclear how cocaine exposure affects M₄ mAChR expression or distribution.</p> Objectives <p>To evaluate the effects of cocaine self-administration on M₄ mAChR availability using [¹¹C]MK-6884 in vivo PET imaging in rats that self-administered cocaine (cocaine SA) or sucrose pellets (control).</p> Methods <p>Sprague-Dawley rats self-administered cocaine or sucrose pellets for 15 days under 2-h or 4-h sessions followed by PET imaging with [¹¹C]MK-6884, a radiolabeled M₄ selective positive allosteric modulator to determine the effects of cocaine on [¹¹C]MK-6884 standard uptake values with cerebellum as reference (SUVr).</p> Results <p>Cumulative cocaine intake ranged between 324 and 776&#xa0;mg/kg. Cocaine self-administration was associated with significantly lower [¹¹C]MK-6884 SUVrs in the cortex, hippocampus, and striatum compared to cocaine-naive rats, with a negative correlation between radiotracer SUVrs and cocaine intake in the hippocampus.</p> Conclusions <p>These results suggest that cocaine self-administration decreases M₄ mAChR availability, providing further support for pursuing activation/enhancement of M₄ mAChR function as a viable pharmacotherapeutic approach for CUD.</p>