CNS depressants: Effects on post-synaptic pharmacology

Summary o (1) The effects of 5 anesthetics (chloralose, chloroform, ethanol, pentobarbital and urethane) and one anticonvulsant (diphenylhydantoin) were studied on the membrane properties and post-synaptic responses of crustacean neuromuscular junction preparations and molluscan neurons to putative transmitters and peptides. (2) In crustacean preparations pentobarbital selectively depressed, in a dosedependent, reversible manner, post-synaptic, Na+-dependent, depolarizing responses to the putative transmitter glutamate without altering post-synaptic, Cl--dependent inhibitory responses to the putative transmitter γ-aminobutyric acid. (3) The effects of all the agents on post-synaptic pharmacology of a molluscan neurosecretory cell were studied either by causing the cell to hyperpolarize to about—100 mV through repeated application of acetylcholine (ACh) in a K+-free, Ca++-containing solution or by hyperpolarization through injection of intracellular current in a K+-free solution. Effects of these agents on post-synaptic responses on other molluscan neurons were studied using intracellular current injection to manipulate membrane potential. (4) All of the agents tested selectively depressed the depolarizing Na+-K+-dependent post-synaptic responses of the neurosecretory cell to ACh in a dosedependent reversible manner without appreciably altering the membrane properties of the cell (over the potential range of the ACh responses). (5) Pentobarbital did not alter the inversion potential of the ACh response. (6) Reciprocal plot analysis of all of the agents tested revealed that the antagonism of the ACh response was primarily non-competitive. (7) None of the agents tested altered hyperpolarizing, K+-dependent responses to dopamine and glutamate on the neurosecretory cell, nor did they affect either the induction or enhancement of BPP activity by the vertebrate peptide vasopressin on this cell. (8) None of the agents tested altered either hyperpolarizing or depolarizing, Cl−-dependent responses to ACh or depolarizing responses to 5-HT or ACh on other molluscan neurons which were associated with increases in input resistance (9) The ability of all of the agents tested to reduce the ACh response by 50% was highly correlated with the logarithm of the octanol-water partition coefficient (r = 0.96), indicating that the hydrophobicity of an agent determined the agent's activity. (10) Analysis of previously published data on the effects of general anesthetic agents at vertebrate synapses showed that the ability of these agents to depress excitatory transmission was highly correlated with hydrophobicity (r = 0.97), as was the ability of these agents to block axonal conduction (r = 0.97). The ratio of synapseblocking ability to axon-blocking ability was also highly correlated with hydrophobicity (r = 0.92), indicating that hydrophobicity primarily determines whether these agents will attack the axon and/or the synapse. (11) These data suggest that much of the depression of neuronal excitability observed with these CNS depressants is due to a selective post-synaptic depression of the Na+-K+-dependent conductance mechanism coupled to post-synaptic receptors. Depression of axonal conduction also contributes to the effects seen in inverse relation to the hydrophobicity of the agent.