Alterations in brain activation in response to prolonged morphine withdrawal-induced behavioral inflexibility in rats

Rationale The inability to stop a repetitive maladaptive behavior is a main problem in addictive disorders. Neuroadaptations that are associated with behavioral inflexibility may be involved in compulsive drug use. Objectives The aim of the present study was to investigate the pattern of behavioral inflexibility during morphine withdrawal and map brain activation that is linked to alterations in flexibility. Methods We first analyzed the effects of chronic morphine exposure on reversal learning after 2-week (short-term) and 6-week (prolonged) morphine withdrawal. We then compared the level of neuronal activation using cFos immunohistochemistry in 15 brain areas between rats that underwent morphine withdrawal and saline-control rats after a test of reversal learning. Results Only prolonged morphine withdrawal impaired reversal learning. Rats that exhibited impairments in reversal learning presented a significant decrease in cFos expression in the orbitofrontal cortex (OFC), including the medial, lateral, and ventral OFC. cFos expression significantly increased in the dorsomedial striatum and major subregions of the medial prefrontal cortex (mPFC) in the morphine group. Rats that underwent prolonged morphine withdrawal exhibited no significant changes in cFos expression in the dorsolateral striatum, nucleus accumbens, amygdala, paraventricular thalamic nucleus, or motor cortex. The rats that underwent short-term withdrawal did not present any changes in cFos expression in any of these brain regions. Conclusion Altogether, these data suggest that alterations in the function of the frontal cortex and its striatal connections during the late morphine withdrawal phase may underlie the disruption of inhibitory control in opioid dependence.