Antagonism of N-methyl-D-asparate-induced transmitter release in the rat striatum by phencyclidine-like drugs and its relationship to turning behavior

Representatives from several chemical classes known to share behavioral properties with phencyclidine [(1-phenylcyclohexyl)piperidine] (PCP) have been shown to antagonize the excitatory effects of N-methylaspartate on spinal neurons selectively. This study compared the abilities of several of these PCP-like drugs to inhibit N-methyl-D-aspartate (NMDA)-stimulated efflux of acetylcholine in rat striatum. PCP completely inhibited this parameter with an IC₅₀ value of 68 nM. The IC₅₀ values (nanomolar) found for the other drugs tested were as follows: etoxadrol (98), (-)-cyclazocine (120), N-allylnormetazocine (or SKF 10047) (940), ketamine (1600) and ethylketocyclazocine (8300). Morphine had no effect at concentrations as high as 30,000 nM. In addition, 100 nM dexoxadrol, 1-[1-(naphthyl)cyclohexyl]piperidine HCl (m-amino PCP) and (-)-cyclazocine inhibited NMDA-induced acetylcholine release by about 50%, whereas the same concentration of their enantiomers (or a structural analog in the case of m-amino-PCP) produced no significant effect. It was also found that 10 mg/kg of dexoxadrol, m-amino-PCP and (-)-cyclazocine induced significant ipsilateral turning in rats with unilateral destruction of the substantia nigra, whereas 10 mg/kg of levoxadrol, 1-[1-(m-nitrophenyl)cyclohexyl]piperidine HCL (m-nitro-PCP) and (+)-cyclazocine produced no such similar effect. In spite of the ability of several dopaminergic antagonists to block turning produced by (±)-cyclozocine, we concluded, based on our previously reported studies of the dopaminergic properties of these drugs, that turning is the result of nondopaminergic properties of these drugs, that turning is the result of nondopaminergic properties of the PCP-like drugs. This was substantiated by the observation that haloperidol had no effect on the inhibition of PCP of the NMDA response. Comparison of rank order potencies in inducing ipsilateral turning and in inhibiting NMDA-induced acetylcholine release suggests the possibility that PCP-like drugs may elicit turning via this indirect 'anticholinergic' effect. Similar comparisons with their reported affinity for the site labeled by [³H]PCP suggests that the action of PCP-like drugs to modulate the NMDA response may be a consequence of binding to the PCP/sigma receptor.