Site of action of phencyclidine. IV. Interaction of phencyclidine and its analogues on ionic channels of the electrically excitable membrane and nicotinic receptor: Implications for behavioral effects

The effects of 1-(1-phenylcyclohexyl)piperidine [phenycyclidine (PCP)] and three of its analogues were studied on the ionic channels of the electrically excitable membrane and of nicotinic acetylcholine (ACh) receptors in frog sciatic nerve-sartorius muscle preparations and in a behavioral paradigm in rats. Two of these analogues, i.e., 1-piperidinocyclohexanecarbonitrile (PCC) and 1-(1-m-nitrophenylcyclohexyl)piperidine (m-nitro-PCP) are not active behaviorally, whereas the third one has the same effects as PCP. Thus, like PCP, 1-(1-m-aminophenylcyclohexyl)piperidine (m-amino-PCP) blocked the indirectly elicited contraction and potentiated the directly elicited contraction while prolonging the half-decay time of the action potential in muscle. These effects were associated with a block of delayed rectification, a reduction in the amplitude, and an increase in the threshold of the action potential. Like PCP, m-amino-PCP increases the error ratio of alteration tasks in the behavioral paradigm. Both m-nitro-PCP and PCC depressed the amplitude and rate of rise of the action potential, but only m-nitro-PCP caused a small increase in half-decay time of action potentials. Delayed rectification is only partially blocked by m-nitro-PCP. Neither PCC nor m-nitro-PCP affects the error score in the behavioral tests. Although they differ behaviorally, the four compounds are quite similar in their action on the ionic channel of the nicotinic ACh receptor. Thus, all four compounds produced a concentration-dependent depression of peak end-plate current (EPC) amplitude. The time constant of EPC decay (τ EPC) was shortened by m-amino-PCP and m-nitro-PCP, which induced a change in voltage sensitivity at higher concentrations. In contrast, PCC had no effect on τEPC but significantly depressed peak EPC amplitude. All four agents appear to interact with the open and closed conformations of the ionic channel of the ACh receptor. The marked potency of m-nitro-PCP and PCC on the ionic channel of the nicotinic ACh receptor is in contrast to their inactivity in the behavioral tests. We also show that the rank order of potency of these drugs on muscarinic receptors does not match their potency in the behavioral paradigm. These two cholinergic mechanisms are therefore not adequate to account for the behavioral effects of PCP and its other psychoactive analogues (e.g., m-amino-PCP). Rather, a blockade of potassium conductance in the electrically excitable membrane and subsequent effects on transmitter release at central synapses by these psychoactive drugs are here proposed to account for the observed behavioral alterations. PCC and m-nitro-PCP have only negligible effects on potassium permeability.