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Leu-enkephalin (300 μg/kg) impaired memory of a Y-maze response in mice when the animals were trained to obtain food in one arm of the maze. The dose-response function was U-shaped, with neither 100 nor 600 μg/kg having any effect. Des-Tyr-Leu-enkephalin, a nonopioid peptide, had no effect at doses equimolar to the leu-enkephalin. Finally, the leu-enkephalin (300 μg/kg) was without effect if the drug injection was delayed 90 min. The results show that leu-enkephalin affects appetitive conditioning in much the same way as avoidance conditioning, a finding that suggests that leu-enkephalin may generally influence learning and memory.