Comparison of the actions of phencyclidine and sigma ligands on CA1 hippocampal pyramidal neurons in the rat.
To compare the actions of prototypic drugs which are selective for phencyclidine and sigma receptors, the electrophysiological effects of phencyclidine (PCP),3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [+)3-PPP), and 1,3-di(2-tolyl)guanidine (DTG) on CA1 hippocampal pyramidal neurons were examined. A wide range of concentrations of drug was tested to differentiate specific, receptor-mediated effects from nonselective, anesthetic-like actions. At relatively large concentrations (0.1-1 mM), each compound reversibly increased the threshold of action potentials driven by Schaffer collaterals, the duration of action potentials and membrane resistance. The low potencies and rank order of potency suggested that phencyclidine, (+)3-PPP, and DTG were not acting through either high affinity sigma or phencyclidine receptors. These compounds did have receptor-mediated effects at smaller concentrations. Since none of the compounds affected evoked excitatory or inhibitory postsynaptic potentials (EPSP or IPSP) or driven action potentials at subanesthetic concentrations (less than 100 microM), no evidence was found to support the hypothesis that the actions of phencyclidine result from enhanced release of transmitter, caused by the inhibition of a presynaptic potassium conductance. As observed in other neurons, phencyclidine blocked excitations in CA1 pyramidal cells mediated by N-methyl-D-aspartic acid (NMDA) at behaviorally relevant concentrations (1-10 microM). However, (+)3-PPP (1 microM-1 mM) enhanced the pyramidal cell response to NMDA. Alone, DTG did not effect the NMDA-induced response but did inhibit the enhancement induced by (+)3-PPP. The agonist and antagonist actions of the sigma-selective ligands, (+)3-PPP and DTG, suggests that they modify NMDA-induced responses by acting at the sigma receptor.
Malouf
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Department of Pharmacology, University of Washington, Seattle 98195.
Swearengen
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Chavkin
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D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects*; D010622:Phencyclidine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D017480:Receptors, sigma
D006146:Guanidines; D010880:Piperidines; D011957:Receptors, Opioid; D017480:Receptors, sigma; D001224:Aspartic Acid; D016202:N-Methylaspartate; C026539:preclamol; D010622:Phencyclidine; C050232:1,3-ditolylguanidine