Interactions of phencyclidine with ion channels of nerve and muscle: behavioral implications

Phencyclidine (1-(1-phenylcyclohexyl)piperidine [PCP]), a behaviorally active analogue (1-(1-m-aminophenylcyclohexyl)piperidine [m-amino-PCP]), and two behaviorally inactive analogues (1-(1-m-nitrophenylcyclohexyl)piperidine and 1-piperidinocyclohexanecarbonitrile) block neuromuscular transmission, depress the amplitude and rate of rise of directly elicited action potentials in frog sartorius muscle, and cause voltage- and concentration-dependent decreases of the peak end-plate current amplitude. This implies that all four compounds block the ion channel of the acetylcholine (ACh) receptors. Only PCP and m-amino-PCP prolong the action potential, block delayed rectification, potentiate muscle twitch, increase quantal content of end-plate potentials, and block K+-induced 86Rb+ efflux from rat brain synaptosomes. PCP also possesses central and peripheral antimuscarinic activity but is much less potent than 3-quinuclidinyl benzilate (QNB). Atropine, scopolamine, and QNB require much higher concentrations to induce behavioral alterations than to block muscarinic receptors. Thus PCP and some of its behaviorally active and inactive derivatives share two common effects, blockade of the nicotinic ACh receptor-ion channel complex and blockade of central and peripheral muscarinic receptors. The feature that apparently separates behaviorally active from inactive derivatives of PCP is their ability to block K+ conductance (gK) and thereby potentiate muscle twitch and increase the release of transmitters from central and peripheral synapses. The similarity between PCP-induced behavioral alterations and primary schizophrenia in humans raises the possibility of involvement of an altered gK in the human disease.