M3 muscarinic receptor antagonism attenuates cocaine-induced hippocampal oligodendroglial changes and relapse-like behavior in male mice.
Acetylcholine (ACh) signaling regulates oligodendrocyte lineage progression via muscarinic ACh receptors (mAChRs), yet its role in cocaine-induced myelin-associated and relapse-like changes remains unexplored. Here, we examined whether hippocampal cholinergic and oligodendroglial alterations were associated with cocaine-related outcomes and pharmacologically sensitive to M3-preferential antagonism. Adult male C57BL/6J mice were subjected to cocaine-conditioned place preference (CPP), extinction, and cocaine-primed reinstatement, and treated with benztropine (BZT), the M1-selective mAChR antagonist VU0255035, or the M3-preferential mAChR antagonist solifenacin (SOL). Cocaine conditioning increased dorsal hippocampal ACh levels and reduced the expression of selected myelin-related genes and oligodendroglial transcription factors, including Mbp, Plp, Olig2, and Olig1, predominantly in the dorsal hippocampus. These changes were accompanied by reduced myelin basic protein (MBP) immunoreactivity, increased cholinergic terminal apposition to oligodendrocyte-lineage cells, and upregulation of Chrm3 in O4-sorted hippocampal oligodendrocytes. BZT reduced cocaine-primed reinstatement and increased Mbp and Plp expression and MBP immunoreactivity in several hippocampal layers. BZT also normalized cocaine-induced changes in Fosb, ΔFosb, Creb, and Slc6a3 in the dorsal hippocampus, whereas dorsal Bdnf remained different from vehicle-treated controls. SOL reduced reinstatement relative to both cocaine-conditioned and VU0255035-treated mice. SOL also increased open-arm time and entry ratio in the elevated plus maze test relative to cocaine-conditioned mice. In CD140a-sorted oligodendrocyte precursor cell-derived cultures, SOL increased MBP-positive oligodendrocyte volume relative to cocaine alone; however, the lack of a SOL-VU0255035 difference precluded conclusions about subtype specificity. These findings provide evidence consistent with a contribution of M3-sensitive muscarinic mechanisms to cocaine-associated oligodendroglial and behavioral alterations.