Effect Of Agmatine And Morphine On Learning And Memory In Mice And Rats

Long-term use of opioids induces drug abuse. Drug addiction has been increasingly considered as a neuro-psychiatric disorder, which is related to adaptive alteration of learning and memory. As a new neurotransmitter or neuromodulator, agmatine inhibits naloxone precipitated abstinent symptoms in morphine dependent mice and rats, while the underlying mechanism is unclear. Agmatine was found to antagonize NMDA receptor, inhibit NOS activity and block voltage-dependent calcium channel, all of which are play important roles in adaptive alteration of brain function. This research is aimed to determine the effect of agmatine on learning and memory in morphine-treated mice and rats.First, the effect of agmatine and morphine on spatial memory was evaluated in Morris water maze model. Morphine (5, 10 and 20 mg/kg, s.c.) impaired spatial memory implicated by the prolongation of latency for mice to find the platform; while chronic morphine treatment (10, 20, 30, 40, 50, 60 and 70 mg/kg, twice per day, one dose every two day) facilitated spatial memory, implicated by the reduction of latency for mice to find the platform. Acute agmatine (10 mg/kg, i.p.) treatment facilitated spatial memory while chronic co-administrated of agmatine (10 mg/kg, three times per day, 5 d, 30 min before morphine injection, i.p.) treatment with morphine had no effect on the facilitation of spatial memory.Second, the effect of agmatine and morphine on escape response was studied in step-down test. Acute morphine (2.5 and 5 mg/kg 30 min before training, s.c.) treatment impaired the formation of memory, the latency for the animal to step down from the platform was shortened, while had no effect on the retention and retrieval of memory after training or before test. Chronic treatment with morphine (30, 40, 50, 60 and 70 mg/kg, three times per day, 7 d) facilitated the formation of memory. Acute agmatine (10 and 20 mg/kg 30 min before training or test, s.c.) treatment improved the formation and retrieval of memory, while had no effect on the retention of memory after training injection. Chronic agmatine treatment (10mg/kg, three times per day, 7 d) had no effect on memory. Moreover, agmatine (30 min before morphine injection) improved the formation and retrieval of memory in morphine-treated mice though activation of imidazoline receptor (15 min before agmatine injection, i.p.). Last, the mechanism of agmatine and morphine was inspected in whole-cell LTP recording in rats'hippocampus. Acute morphine (30 mg/kg, 30 min before test) treatment significantly inhibited the amplitude of PS, attenuated LTP while chronic treatment (10, 20, 30, 40 and 50 mg/kg, three times per day, 5 d) increased the amplitude of PS, facilitated LTP. Acute agmatine (10 mg/kg, 30 min before test) treatment increased the amplitude of PS, facilitated LTP while chronic agmatine treatment (10 mg/kg, three times per day, 5 d) had no effect on LTP. Agmatine (10 mg/kg, 30 min before morphine injection) co-administrated with morphine significantly attenuated the effect of morphine on LTP. However, acute agmatine (10 mg/kg) treatment had no effect on the facilitation of LTP after chronic morphine treatment. Imidazoline receptor antagonist idazoxan (5 mg/kg) reversed the effect of agmatine.In conclusion, acute and chronic morphine treatment influenced the learning and memory of animals, agmatine influenced the effect of morphine on memory through activation of imidazoline receptor.