In vivo functional interaction between phencyclidine binding sites and σ receptors to produce head-weaving behavior in rats

To investigate the in vivo functional interaction between phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP) binding sites and σ receptors, we examined the effects of σ receptor ligands on stereotyped head-weaving behavior induced by PCP, a putative PCP/σ receptor ligand, and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclo-hepten- 5,10-imine ((+)-MK-801; dizocilpine), a selective PCP binding site ligand, in rats. PCP (7.5 mg/kg, i.p.)-induced head-weaving behavior was inhibited by both N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]- ethylamine (NE-100; 0.03-1.0 mg/kg, p.o.), a selective σ₁ receptor ligand, and α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperidine butanol (BMY-14802; 3 and 10 mg/kg, p.o.), a prototype σ receptor ligand, in a dose-dependent manner, whereas NE-100 (0.1-1.0 mg/kg, p.o.) and BMY-14802 (3 and 10 mg/kg, p.o.) did not inhibit dizocilpine (0.25 mg/kg, s.c.)-induced head-weaving behavior. These results suggest that NE-100 and BMY-14802 act via σ receptors. Dizocilpine-induced head-weaving behavior was potentiated by 1,3-di-o-tolyl-guanidine (DTG; 0.03-0.3 μg/kg, i.v.) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)3-PPP; 3 and 6 mg/kg, i.p.), σ₁/σ₂ receptor ligands, as well as by (+)-N-allyl-normetazocine ((+)-SKF-10,047; 8 mg/kg, i.p.), a σ₁ receptor ligand, while DTG (0.3 μg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and(+)-SKF-10,047 (8 mg/kg, i.p.) did not induce this behavior. Potentiation of dizocilpine-induced head-weaving behavior by DTG (0.3 μg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) was completely blocked by NE-100 (0.1 mg/kg, p.o.) and BMY-14802 (10 mg/kg, p.o.). These results suggest that PCP binding sites and σ receptors are involved in PCP-induced head-weaving behavior, and that σ₁ receptors play an important role in modulation of the head-weaving behavior.