The objective of this project is to continue our studies on the action of behaviorally active and inactive analogs and metabolites of phencyclidine (PCP) on motor nerve and skeletal muscle and the correlation of the observed changes in contractile, electrical and chemosensitive properties of membranes and synapses with the behavioral properties of these drugs. We will continue to assess the drugs' abilities to alter the muscle action potential and delayed rectification as measures of their effects on Na and K conductance activation and on Na conductance inactivation, and as a basis for any observed effects (i.e. potentiation or depression) of muscle twitch. The mechanism of blockade of neuromuscular transmission will also be assessed by measurement of nerve evoked muscle twitch, endplate and miniature endplate currents, nerve terminal action potentials and quantal release of acetylcholine. The latter will also serve as a measure of the ability of behaviorally active analogs to increase the evoked release of transmitter. Preliminary evidence strongly suggests an interaction between PCP and various ion channels. We will therefore extend our studies to a direct analysis of drug action on ACh channels of skeletal muscles and Na, K and Ca-coupled channels in mammalian skeletal muscle, myotubes, hippocampal neurons and spinal motoneurons maintained in tissue culture. These studies will focus mainly on the effects of PCP on the voltage-dependent Na and K conductances and on Na-Ca and K-Ca coupled conductances. In addition, we will examine the mechanism by which PCP (and specific active and inactive analogs) affect the reflex activity in the in vivo and in vitro spinal cord. The latter studies will focus on presynaptic and postsynaptic mechanisms. These studies will ultimately include an examination of PCP's effect on pre- and postsynaptic mechanisms at both inhibitory and excitatory synapses in the spinal cord to explain the varied behavioral effects of PCP. Finally, we will attempt to correlate the electrophysiological data on the behaviorally active and inactive analogs with the drugs behavioral effects in an effort to explain the bizarre behavioral patterns associated with PCP abuse in humans. The results may allow us to develop potential antagonists of PCP's toxic effects and possible to offer a unified explanation of some behavioral disorders especially since there is a remarkable similarity between the symptoms of PCP toxicity in humans and those of primary schizophrenia.
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NIH ExPorter