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
Aguayo, L.G.; Warnick, J.E.; Maayani, S.; Glick, S.D.; Weinstein, H.; Albuquerque, E.X.
Molecular Pharmacology 21(3): 637-647
1982
ISSN/ISBN: 0026-895X PMID: 6287200 Document Number: 194666
The effects of 1-(1-phenylcyclohexyl)piperidine [phenylcyclidine (PCP)] and 3 of its analogs were studied on the ionic channels of the electrically excitable membrane and of nicotinic acetylcholine (ACh) receptors in frog sciatic nerve-sartorius msucle preparations and in a behavioral paradigm in rats. Of these analogs, i.e., 1-piperidinocyclohexanecarbonitrile (PCC) and 1-(1-m-nitrophenylcyclohexyl)piperidine (m-nitro-PCP) were not active behaviorally, whereas the 3rd had the same effects as PCP. 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 increased the error ratio of alternation 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 was partially blocked by m-nitro-PCP. Neither PCC nor m-nitro-PCP affected the error score in the behavioral tests. Although they differ behaviorally, the 4 compounds were similar in their action on the ionic channel of the nicotinic ACh receptor. All 4 compounds produced a concentration-dependent depression of peak end-plate current (EPC) amplitude. The time constant of EPC decay (.tau.EPC) was shortened by m-amino-PCP and m-nitro-PCP, which induced a change in voltage sensitivity at higher concentrations. PCC had no effect on .tau.EPC but significantly depressed peak EPC amplitude. All 4 agents interacted 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 was in contrast to their inactivity in the behavioral tests. The rank order of potency of these drugs on muscarinic receptors did not match their potency in the behavioral paradigm. These 2 cholinergic mechanisms are not adequate to account for the behavioral effects of PCP and its other psychoactive analogs (e.g., m-amino-PCP). A blockade of K conductance in the electrically excitable membrane and subsequent effects on transmitter release at central synapses by these psychoactive drugs may account for the observed behavioral alterations. PCC and m-nitro-PCP have only negligible effects on K permeability.