Chronic stress could lead to a bias in behavioral strategies toward habits. However, it remains unclear which neuronal system modulates stress-induced behavioral abnormality during decision making. The corticotropinreleasing factor (CRF) system in the medial prefrontal cortex (mPFC), which has been implicated in governing strategy choice, is involved in the response to stress. The present study aimed to clarify whether altered function in cortical CRF receptors is linked to abnormal behaviors after chronic stress. In results, mice subjected to a 10day social defeat preferred to use a habitual strategy. The infralimbic cortex (IL), but not the prelimbic cortex (PL) or anterior cingulate cortex (ACC), showed higher cFos expression in stress-subjected mice than in control mice, which may be associated with habitual behavior choice. Furthermore, CRF receptor 1 (CRFR1) agonist and antagonist infusion in IL during behavioral training mimicked and rescued stress-caused behavioral change in the decision-making assessment, respectively. An electrophysiological approach showed that the frequencies of both spontaneous IPSC and spontaneous EPSC, but not their amplitude, increased after stress and were modulated by CRFR1 agents. Further recordings revealed that an increased ratio of excitation to inhibition (E/I ratio) of IL by stress was rescued under conditions with CRFR1 antagonist. Collectively, these data indicate that CRFR1 plays a critical role in stress-permitted or enhanced glutamatergic and GABAergic presynaptic transmission in direct or indirect ways, as well as the modulation for E/I ratio in the IL. Thus, CRFR1 in the mPFC may be a proper target for treating cases of chronic stress-altered behavior.

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.