Involvement of signal transduction cascade via dopamine-D1 receptors in phencyclidine dependence.

We investigated the molecular mechanisms of development to phencyclidine (PCP)-induced rewarding effect by using tyrosine hydroxylase (TH) heterozygous (TH(+/-)) mice. PCP (8 mg/kg) induced the place preference in wild-type mice pretreated with PCP (10 mg/kg/day for 28 days). 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. In TH(+/-) mice pretreated with PCP (10 mg/kg/day for 28 days), no PCP (8 mg/kg)-induced place preference was observed. In wild-type mice pretreated with PCP, the levels of cAMP, cAMP response element binding protein (CREB), and c-fos mRNA in the nucleus accumbens were increased. The levels of cAMP, CREB, and c-fos mRNA in the nucleus accumbens were not increased by the same treatment schedule of PCP in TH(+/-) mice. These findings suggest that changes in dopaminergic and/or cAMP signal cascades induced by repeated PCP treatment play an important role in the development of PCP-induced rewarding effect.