Memory reactivation mediates emotional valence updating of contextual memory in mice with protracted morphine withdrawal.

Mice subjected to morphine locomotor sensitization develop increased anxiety-behavior expression during protracted morphine withdrawal. This behavioral change is dependent on reexposure to the context of locomotor sensitization and reflects a state of conditioned anxiety. In this study, the effect of memory reconsolidation on the expression of conditioned anxiety in mice with protracted morphine withdrawal was examined. Five experimental protocols involving male C57BL/6 mice were used in which the animals were subjected to locomotor sensitization induced by morphine and reexposed to the context associated with the drug effect 28 days after locomotor sensitization and immediately after subjected to elevated plus maze. In experiment 1, mice were subjected or not to memory reactivation session and was observed that memory reactivation 27 days after sensitization reduced conditioned anxiety. In experiment 2, mice were subjected to memory reactivation, 24 h, 6 h or 1 h before contextual reexposure, and the effect of memory reactivation coincided with the temporal requirement for reconsolidation. In experiment 3, which involved exposure to a situation of acute stress immediately before memory reactivation, the mice demonstrated a return to increased conditioned anxiety. To confirm the influence of reconsolidation, in experiments 4 and 5, mice subjected to memory reactivation were treated with Nimodipine, diazepam or cyclohexamine, substances commonly used as pharmacological controls in reconsolidation experiments. Treatment with each substance separately inhibited the effect of reactivation in experiment 5 (presence of acute stressor) but not in experiment 4 (absence of acute stressor). These results suggest that, in our experimental model, reconsolidation is mediated through updating of the emotional valence of contextual memory associated with the administration of morphine.

Anxiety-like behavior in acute and protracted withdrawal after morphine-induced locomotor sensitization in C57BL/6 male mice: The role of context.

Contextual memory plays an important role in development and maintenance of drug addiction. However, little is known about of the role contextual memory in the emergence of a negative emotional state in the withdrawal period. Therefore, this study investigated anxiety-like behavior in acute and protracted morphine withdrawal of mice submitted to a locomotor sensitization protocol and the influence of contextual memory on this behavior. Male adult C57Bl6 mice were subjected to morphine locomotor sensitization and anxiety-like behavior was assessed by using the elevated plus maze test (EPM). To evaluate associative memory, the mice were re-exposed to the context of locomotor sensitization immediately before EPM. As expected, repeated morphine administrations promoted locomotor sensitization, seen as a gradual increase in the distance traveled during the acquisition phase. There was an increase in anxiety-like behavior upon acute withdrawal, as indicated by a decrease in open arms activity (OAA), but this effect dissipated over time. However, when the context was presented, mice in protracted withdrawal showed enhanced anxiety-like behavior, indicated by an increase in closed arms activity (CAA). This effect was context specific since re-exposure in an alternative context did not change the anxiety-like behavior. Treatment with diazepam counteracted the decrease in OAA in acute withdrawal and the increase in CAA induced by context re- exposure during protracted abstinence. Thus, repeated morphine administration induced a negative emotional state when the drug was discontinued. The context associated with drug exposure played a pivotal role in the appearance of anxiety-like behavior, even long after drug discontinuation. There were differences in the patterns of anxiety behaviors in acute (unconditioned anxiety-like behavior) and protracted (conditioned anxiety-like behavior) withdrawal since the former was characterized by a passive behavioral strategy and the latter by an active behavioral strategy.