In the present study the effect of ghrelin or ghrelin/nicotine injection into the anterior ventral tegmental area (aVTA) on morphine-induced amnesia in passive avoidance learning have been evaluated. Also, the role of the aVTA nicotinic receptors in possible ghrelin-induced effects has been investigated. All animals were bilaterally implanted with chronic cannulas in the aVTA. A step-through type passive avoidance task was used for measurement of memory. We found that post-training subcutaneous (s.c.) injection of morphine (0.5-7.5 mg/kg) dose-dependently reduced the step-through latency, indicating morphine-induced amnesia. Post-training bilateral infusion of ghrelin (0.3, 1.5 and 3 nmol/μl) in a dose-dependent manner reversed amnesia induced by morphine (7.5 mg/kg, s.c.). Furthermore, reversal effect of ghrelin (3 nmol/μl) was blocked by pre-treatment of intra-aVTA administration of mecamylamine (1-3 μg/rat), a nicotinic acetylcholine receptor antagonist. Intra-aVTA administration of the higher dose of mecamylamine (3 μg/rat) into the aVTA by itself decreased the step-through latency and induced amnesia. In addition, post-training intra-aVTA administration of nicotine (0.25, 0.5, 1 μg/rat) which alone cannot affect memory consolidation, decreased significantly the amnesia induced by morphine (7.5 mg/kg, s.c.). Co-treatment of an ineffective dose of ghrelin (0.3 nmol/μl) with an ineffective dose of nicotine (0.25 μg/rat) significantly increased step-through latency of morphine (7.5 mg/kg, s.c.) treated animals, indicating the synergistic effect of the drugs. Taken together, our results suggest that intra-aVTA administration of ghrelin reversed morphine-induced amnesia and that ghrelin interacts synergistically with nicotine to mitigate morphine-induced amnesia.