Role of catecholamines and cyclic AMP systems in phencyclidine and morphine dependence. Study of mutant mice*

To investigate an involvement of catecholamines and/or the cyclic adenosine monophosphate (cAMP) systems in the development of drug dependence, we examined whether phencyclidine (PCP) and morphine dependence were developed in tyrosine hydroxylase (TH) heterozygous (TH) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP) mice. PCP (8 mg/kg) induced place preference in wild-type mice pretreated with PCP (10 mg/kg/day for 28 days) and increased the level of cAMP in the striatum, but not in the thalamus/hypothalamus. In TH and CBP mice, however, we could not find PCP-induced place preference. The increased level of cAMP in the striatum was observed in CBP, but not TH mice. When 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 jumping, rearing, and forepaw tremor counts as a sign of withdrawal and an increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. In TH and CBP mice, however, jumping and forepaw tremor counts were decreased compared to in wildtype mice. An increase in the level of cAMP in the thalamus/hypothalamus in CBP, but not in TH mice was observed. These results suggest that catecholamines and CBP are involved in the development of PCP and morphine dependence, and that changes in catecholaminergic and/or cAMP systems induced by repeated PCP and morphine treatments play an important role in the addiction to PCP and morphine.