Inhibition Of Agmatine On Psychological Dependence Induced By Morphine And The Possible Mechanism

Agmatine is the endogenous ligand of imidazoline receptor. In our previous work, agmatine was proved to enhance morphine analgesia, inhibit tolerance to and physical dependence on morphine. In the present study, the effect of agmatine on the psychological dependence on morphine and the possible mechanism was evaluated.In rat CPP model, agmatine (0.75-20 mg/kg, sc) co-administered with morphine inhibited the development, expression and the priming of CPP induced by morphine. In rat behavioral sensitization model, after 4 d of treatment and 3 d of withdrawal, morphine 3mg/kg induced significant increase of locomotion in morphine treatment group on d 8 compared with saline group, which could be called sensitization. Agmatine (0.05-80 mg/kg, sc) inhibited this sensitization significantly. The effect of agmatine was related to activation of imidazoline receptor.In rat behavioral sensitization model, the extracellular level of dopamine in the striatum was determined by employing the microdialysis technique in free-moving animals. After 4 d of morphine treatment and 3 d of withdrawal, the release of dopamine in striatum was not different from saline group, while the quantity of DOPAC/HVA was higher than that of control. Co-administration of agmatine with morphine inhibited the increase of DOPAC and HVA. After primed by morphine on d 8, the release of dopamine in morphine treated rats was increased significantly and agmatine inhibited this increase. This result inferred that agmatine modulated the adaptation after chronic morphine treatment.The counts of cell that expressed FosB in the nuclear accumbens in morphine-induced CPP rats were found increased. Agmatine 2.5-20 mg/kg significantly inhibited the expression of FosB in morphine treated rats. In rat behavioral sensitization...