The behavioral effects of phencyclidines may be due to their blockade of potassium channels
The action of phencyclidine [1-(1-phenylcyclohexyl)piperidine; PCP] and its behaviorally active analog (m-amino-PCP) and of two behaviorally inactive analogs [m-nitro-PCP and 1-piperidinocyclohexanecarbonitrile (PCC)] were examined in this study. In a test of spatial alternation performance in rats, PCP and m-amino-PCP were much more potent behavior modifiers than were PCC and m-nitro-PCP. We studied the effects of the drugs on the ionic channels of the electrically excitable membrane and of the nicotinic acetylcholine (AcCho) receptors at the neuromuscular junction of frog skeletal muscle. All four compounds blocked the indirectly elicited muscle twitch and depressed the amplitude and rate of rise of directly elicited muscle action potentials. They also caused a voltage- and concentration-dependent decrease in the peak amplitude of the endplate current but did not react with the nicotinic AcCho receptor. These observations indicate that the four compounds have comparable blocking effects on the ionic channels associated with the nicotinic AcCho receptor. In contrast, the behaviorally active agents could be distinguished from behaviorally inactive ones by their effects on K+ conductance. PCP and m-amino-PCP blocked delayed rectification in frog sartorius muscles, prolonged the muscle action potential more than 2-fold, and markedly potentiated the directly elicited muscle twitch. The behaviorally active compound also blocked depolarization-induced 86Rb+ efflux from rat brain synaptosomes (presumably a measure of K+ conductance) and increased quantal content at the frog neuromuscular junction. In these actions, m-nitro-PCP was much less effective, and PCC was relatively ineffective. Because PCP and m-amino-PCP are much more potent behavior modifiers than PCC and m-nitro-PCP, we suggest that the behavioral effects of PCP and m-amino-PCP, may be due to a block of K+ conductance and enhancement of transmitter release at central neurons.