Vol. 286, Issue 1, 44-51, July 1998

Involvement of Dopaminergic System in Phencyclidine-Induced Place Preference in Mice Pretreated with Phencyclidine Repeatedly¹

Yukihiro Noda, Yoshiaki Miyamoto, Takayoshi Mamiya, Hiroyuki Kamei, Hiroshi Furukawa and Toshitaka Nabeshima

Department of Neuropsychopharmacology and Hospital Pharmacy (Y.N., Y.M., T.M., H.K., T.N), Nagoya University School of Medicine, Nagoya 466-8560, Japan and Department of Medicinal Chemistry (H.F.), Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan

In the conditioned place preference test, phencyclidine (PCP) produces place aversion in naive rats, whereas PCP produces place preference in rats treated with PCP repeatedly. Although the PCP-induced place aversion is thought to involve the serotonergic system, the mechanisms of the PCP-induced place preference are unclear. We investigated whether the dopaminergic system is involved in place preference induced by PCP in mice repeatedly treated with PCP, because it is well known that the dopaminergic system plays an important role in the rewarding effect of drugs. PCP (2-8 mg/kg s.c.) induced a dose-dependent place aversion in naive mice, whereas PCP (2-8 mg/kg s.c.) induced a dose-dependent place preference in mice pretreated with PCP (10 mg/kg/day s.c.) for 28 days. The place preference induced by PCP (8 mg/kg s.c.) was attenuated significantly by -methyl--tyrosine (100 mg/kg i.p.), a tyrosine hydroxylase inhibitor, 6-hydroxydopamine (100 µg/mouse i.c.v.), a dopaminergic neurotoxin, and R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.5 mg/kg s.c.), a dopamine D₁ receptor antagonist. These agents themselves produced neither the place preference nor aversion. In contrast to the attenuating effects of these agents, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (30 mg/kg i.p.), a noradrenergic neurotoxin, ritanserin (1 mg/kg i.p.), a serotonin₂ receptor antagonist, and () sulpiride (50 and 100 mg/kg i.p.), a dopamine D₂ receptor antagonist, failed to affect the PCP-induced place preference. In mice pretreated with methamphetamine (1 mg/kg/day s.c.) for 14 days, PCP (8 mg/kg s.c.) induced the place preference, but not aversion. These results demonstrate that the PCP-induced place preference depends on dopaminergic, but not on serotonergic and noradrenergic, neuronal systems and suggest a role for D₁ receptors in the mediation of the PCP-induced place preference.