Phencyclidine increases the affinity of dihydropyridine calcium channel antagonist binding in rat brain

Summary Phencyclidine (PCP) significantly reduces the apparent dissociation constant (K_D) of the dihydropyridine (DHP) calcium channel antagonist, [³H]nitrendipine, in synaptosomal membranes of rat and mouse brain without significantly effecting the maximum binding capacity (B_max). At an optimum concentration of PCP (10 M) the apparentK_D of [³H]nitrendipine was reduced from 178±9 pM to 112±9 pM in rat forebrain, a 58% increase in affinity. The structural derivatives of PCP, P-Br-PCP {1-[1-(4-bromophenyl-cyclohexyl)piperidine]}, m-NH₂-PCP {1-[1-(3-anilo)-cyclohexyl]piperidine}, (±)-PCMP [1-(1-phenyl)-cyclohexyl-3-methylpiperidine] also increased the apparent affinity of [³H]nitrendipine in the following order, p-Br-PCP PCMp>PCP>m-NH₂-PCP. Local anesthetics either reduced the apparent affinity of [³H]nitrendipine or had no effect. Kinetic analysis revealed that PCP both increased the microassociation rate constant and decreased the microdissociation rate contant of [³H]nitrendipine. The magnitude of this enhanced binding varied with the brain region studied; the greatest increase in apparent affinity of [³H]nitrendipine was observed in striatum, while no significant increase in affinity was observed in brainstem. In some brain areas, PCP was more effective in reducing theK_D in crude homogenates than in washed tissue. PCP (10 M) did not alter theK_D of [³H]nitrendipine to rat cardiac tissue. Both Ca²⁺ and Mg²⁺ inhibited the effect of PCP, while monovalent ions were ineffective in this regard. These data are consistent with an allosteric modulation of DHP calcium channel antagonist binding sites by PCP and structural derivatives that is not mediated through the brain PCP binding site. This modulation of DHP binding sites may account for some of the psychopharmacologic actions PCP and related compounds in vivo.