Role of catecholaminergic and cyclic AMP systems in psychological dependence on phencyclidine: A study in mutant mice

Catecholaminergic and/or cyclic AMP (cAMP) systems have been demonstrated to be involved in the development of drug dependence. We investigated the involvement of both systems in psychological dependence on phencyclidine (PCP) by using 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 once a day for 28 days). In these mice, the level of cAMP in the striatum, but not in the thalamus, was increased one day after the last injection of PCP (10 mg/kg). In TH(+/-) and CBP(+/-) mice pretreated with PCP (10 mg/kg per day for 28 days), however, no PCP (8 mg/kg)-induced place preference was observed. The level of cAMP in the striatum was increased in CBP(+/-) mice, but not TH(+/-) mice. Furthermore, we have demonstrated that the place preference induced by PCP is attenuated by 6-hydroxydopamine, a dopaminergic neurotoxin, and (+)SCH-23390, a dopamine-D1 receptor antagonist, but not by DSP-4, a noradrenergic neurotoxin, and (-)sulpiride, a dopamine-D2 receptor antagonist. These findings suggest that catecholamines and CBP are involved in the development of psychological dependence on PCP and that changes in dopaminergic and/or cAMP systems induced by repeated PCP treatment play an important role in the addiction to PCP.