The mechanisms of morphine dependence and it's withdrawal syndrome: Study in mutant mice

To investigate the involvement of catecholamines and/or the cyclic AMP (cAMP) systems in the development of drug dependence, we examined whether morphine dependence was developed in tyrosine hydroxylase (TH) heterozygous (TH^+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP^+/-) mice. Morphine (10 mg/kg) induced place preference in the wild-type mice. In the TH^+/- and CBP^+/- mice, however, we could not find any morphine-induced place preference. When the wild-type mice pretreated with morphine (10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg), they showed increased numbers of jumping, rearing and forepaw tremor as a sign of withdrawal symptom and increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. However, increased numbers of jumping and forepaw tremor in the TH^+/- and CBP^+/- mice and increased level of cAMP in the thalamus/hypothalamus of TH^+/- mice were not observed. These results suggest that catecholamines and CBP are involved in the development of morphine dependence, and that some changes in the catecholaminergic and/or cAMP system induced by repeated morphine treatment play an important role in the addiction of morphine.