Phencyclidine-like drugs inhibit N-methyl-D-aspartate evoked striatal acetylcholine release and elicit ipsilateral turning in the rat

We have previously reported that phencyclidine (PCP) is a potent (IC₅₀ = 70 nM) inhibitor of N-methyl-D-aspartate (NMDA) evoked release of ³H-acetylcholine from rat striatal slices. This ability is shared by the σ opiates (±)cyclazocine (CYCL) and N-allylnormetazocine (NANM) as well as ketamine (KET) and etoxadrol (ETOX), drugs with reported ability to displace ³H-PCPP from rat cortical membranes. Here we extend our findings to show the rank order potency of these drugs: PCP=CYCL=ETOX > KET > NANM. The κ opiate, ethylketocyclazocine (EKC) was 70-fold less potent (IC₅₀ = 8.3 μM) while the μ opiate, morphine, had no effect on this response in concentrations up to 30 μM. Comparison of several active/inactive drug pairs, as defined by their affinity for the PCP binding site, revealed a significantly greater inhibitory effect by each active member: m-NH₂-PCP > n-NO₂-PCP; dexoxadrol > levoxadrol; (-)CYCL > (+)CYCL. When injected systematically into rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, these PCP-like drugs elicit ipsilateral turning with a similar rank order potency and stereoselectivity as that shown for ACh release inhibition. These results suggest that PCP-like drugs may cause ipsilateral turning via an indirect 'anticholinergic' mechanism mediated by striatal PCP/σ receptors.