The effect of N-methyl-D-aspartate (NMDA) receptors activation in the ventral tegmental area (VTA) on retrieval of morphine-induced state-dependent memory by nicotine was investigated. A step-through inhibitory avoidance task was used for memory assessment in male Wistar rats. Subcutaneous (s.c.) administration of morphine (5 and 7.5 mg/kg) immediately after training decreased the step-through latency on the test day, which was reinstated by pre-test administration of the same doses of the opioid; this is known as state-dependent memory. Moreover, pre-test administration of nicotine (0.2, 0.4 and 0.6 mg/kg, s.c.) also reversed the decrease in the step-through latency due to post-training morphine (5 mg/kg). When infused into the VTA before testing, NMDA (0.01 and 0.1 microg/rat) reversed the effect of post-training morphine on the step-through latency. Interestingly, the sub-effective doses of NMDA (0.0001 and 0.001 microg/rat) in combination with a low dose of nicotine (0.1 mg/kg) which had no effects by themselves, synergistically improved reinstatement of the step-through latency on the test day. Our data indicate that activation of NMDA receptors in the VTA are involved in the reversing effect of nicotine on morphine induced state-dependency.
