Electrophysiological and biochemical studies on enhancement of desensitization by phenothiazine neuroleptics.

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Abstract
The actions of the phenothiazines chlorpromazine, prochlorperazine and trifluoperazine were studied on the acetylcholine receptor-ionic channel complex of frog [Rana pipiens] and rat skeletal muscle and of Torpedo californica to determine their role in pharmacological desensitization and their interactions with different states of the receptor-ionic channel complex. The phenothiazines depressed the peak amplitude of spontaneous and evoked endplate currents while having negligible effect on the decay time constants. Mean channel lifetime and single channel conductance were not altered by these drugs. They also produced a frequency-dependent depression of the peak amplitude of endplate potentials evoked by repetitive microiontophoresis at the extrajunctional region. These drugs enhanced the ability of carbamoylcholine to displace 125I-labeled .alpha.-bungarotoxin from receptor-rich membrane preparations of T. californica when used in concentration that had no effect on 125I-labeled .alpha.-bungarotoxin binding alone (10 .mu.M). The phenothiazines inhibited the binding of 3H-ionic channel ligands, such as phencyclidine and perhydrohistrionicotoxin, a process also enhanced by the presence of carbamoylcholine. Apparently, the phenothiazines augment agonist-induced desensitization primarily by interacting with the receptor-ionic channel complex prior to channel opening.

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