Morphine withdrawal affects both delayed-escape behaviour in Morris water maze and hippocampal NR2A/2B expression ratio

Repeated low-dose morphine treatment facilitates delayed-escape behaviour of hippocampus-dependent Morris water maze and morphine withdrawal influences hippocampal NMDA receptor-dependent synaptic plasticity. Here, we examined whether and how morphine withdrawal influenced delayed-escape behaviour and NR2A/2B expression ratio of hippocampal synaptosomes. We found that both delayed-escape behaviour and NR2A/2B expression ratio showed an inverted-U curve and peaked on 4-day withdrawal during a 20-day withdrawal period. Furthermore, treatment of the glucocorticoid receptor antagonist RU38486 for 3 days reduced delayed-escape behaviour and NR2A/2B ratio on 4-day withdrawal to a level similar to those of 18-h withdrawal. In contrast, elevated-platform stress enabled delayed-escape behaviour of 18-h withdrawal to a higher level similar to that of 4-day withdrawal, but had no significant effect on the NR2A/2B ratio. Similar behavioural effects were also found after intrahippocampal infusions of the NMDAR antagonist AP-5 or NR2B-containing NMDAR antagonist Ro25-6981 for 3 days. These findings suggest that delayed-escape behaviour enabled by repeated low-dose morphine treatment may be a useful and simple rat model for studying addictive memories to be retrieved by stress exposure.