Phencyclidine and the midbrain dopamine system: electrophysiology and behavior.
Phencyclidine (PCP) and PCP-like drugs increased firing rates and the amount of burst activity of A10 dopamine neurons recorded extracellularly in anesthetized rats. These effects correlated to their potency as noncompetitive N-methyl-D-aspartate (NMDA) antagonists but not to their affinity for the sigma-receptor. In contrast, the direct acting NMDA antagonists, CGS 19755, (+)CPP and NPC 12626, produced no alterations in either firing rate or burst patterns. However, pretreatment with either CGS 19755 or (+)CPP effectively attenuated the excitatory effects of PCP. In contrast to the findings obtained in the whole animal, PCP in the midbrain slice preparation did not activate dopamine neurons, even though PCP selectively blocked the excitations induced by NMDA but not those of the nonNMDA agonists, kainate and AMPA. In the self-administration test system a progressive-ratio schedule of reinforcement was used to assess the reinforcing strength of PCP and the PCP congeners, TCP and BTCP. In comparison to BTCP, which produced breaking points comparable to those occurring with equivalent doses of cocaine, PCP and TCP had considerably less reinforcing efficacy. These behavioral differences appeared to reflect the affinity of the compounds for the dopamine reuptake site versus the PCP binding site on the NMDA-ion channel complex. Thus, PCP's psychotomimetic effects and abuse liability properties may result from the differential mechanisms by which it affects limbic and cortical dopamine neurotransmission.
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Department of Pharmacology, University of Arizona, College of Medicine, Tucson 85724.
D000200:Action Potentials / Q000187:drug effects; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007700:Kinetics; D008636:Mesencephalon / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010622:Phencyclidine / Q000008:administration & dosage / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017480:Receptors, sigma / Q000187:drug effects / Q000502:physiology; D012054:Reinforcement, Psychology; D012646:Self Administration
D000596:Amino Acids; D010875:Pipecolic Acids; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; C060212:NPC 12626; C053672:selfotel; D016291:Dizocilpine Maleate; D010622:Phencyclidine; C015068:1-(3-chlorophenyl)piperazine; D004298:Dopamine