Cerebellar structural and functional alterations during morphine self-administration are associated with motivation and disrupted goal-directed actions in male Wistar rats

Abstract

Opioid addiction is characterized by a strong motivational drive to obtain the drug, traditionally attributed to neuroadaptations within mesocorticolimbic reward circuits. Increasing evidence suggests that opioid-induced plasticity extends beyond these pathways, implicating the cerebellum in addiction, although its contribution to drug seeking remains poorly defined. Here, we hypothesized that morphine self-administration would induce cerebellum-associated behavioral alterations alongside structural and functional remodeling. Male Wistar rats (N = 27) were trained to self-administer morphine (0.1 mg/kg/infusion) or saline under fixed-ratio (FR1, 3 h/day, 20 days) and progressive-ratio (PR 9-4, 6 h/day, 25 days) schedules. Behavioral assessments included open field, elevated plus maze, novel object recognition, and Morris water maze tasks. Structural and functional magnetic resonance imaging was acquired longitudinally using a 7T scanner. Morphine self-administering rats showed a progressive increase in infusions and motivation. Exploratory activity increased without affecting anxiety-like behavior or recognition memory. In the Morris water maze, spatial learning was preserved; however, rats exhibited increased Whishaws error (path complexity) and a shift from serial to disorganized navigation strategies, indicating impaired movement sequencing. We also found cerebellar volume changes in Crus1, 7Cb, and 8Cb that were accompanied by altered cerebello-cerebral functional connectivity with insular, striatal, hippocampal, motor, and reticular networks. Multivariate analysis further suggested a brain-behavior covariance pattern in which motivational measures showed the strongest contribution, involving a distributed structural network including the cerebellum and insular cortex. These findings indicate that morphine self-administration preserves drug-seeking motivation while disrupting the organization of goal-directed actions, alongside cerebellar remodeling and altered cerebello-cerebral coupling.