Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats.
BACKGROUND
Phencyclidine (PCP) binds with high affinity to a site located within the ionophore of N-methyl- D-aspartate (NMDA) receptors. Previous studies have demonstrated that PCP and other high-affinity NMDA channel blockers reliably disrupt prepulse inhibition (PPI) of acoustic startle, an animal model of sensorimotor gating used to study attentional deficits associated with schizophrenia. Recently, a number of low-affinity NMDA channel blockers that exhibit minimal PCP-like effects in humans at therapeutic doses have been developed.


OBJECTIVE
The purpose of this study was to evaluate the effects on PPI of NMDA channel blockers with varying affinities for the channel site as well as different specificities for NMDA receptors.


METHODS
Sprague-Dawley rats were presented with multiple stimulus presentation trials, including pulse-alone and PPI trials.


RESULTS
As expected, the high-affinity ligands dizocilpine and dextrorphan disrupted PPI at doses that did not affect the response during pulse-alone trials. Low-affinity drugs produced a mixed pattern of results. Whereas dextromethorphan and memantine disrupted PPI, orphenadrine, amantadine, desipramine, and alaproclate did not affect this response. Ibogaine also disrupted PPI, but only within a dose range that severely decreased the startle response during pulse-alone trials.


CONCLUSIONS
These results suggest that not all NMDA channel blockers share PCP's effect of PPI disruption. In addition, they suggest caution in the use of supratherapeutic doses of these compounds and in their use in vulnerable populations (e.g., schizophrenic patients).
Wiley
Jenny L
JL
Department of Pharmacology and Toxicology, Virginia Commonwealth University, PO Box 980613, Richmond, VA 23298-0613, USA. jwiley@hsc.vcu.edu
Harvey
Sarah A
SA
Balster
Robert L
RL
Nicholson
Katherine L
KL
D000161:Acoustic Stimulation; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D003891:Desipramine / Q000494:pharmacology; D003915:Dextromethorphan / Q000494:pharmacology; D003917:Dextrorphan / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007050:Ibogaine / Q000494:pharmacology; D008144:Loudness Perception / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008559:Memantine / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects*; D009966:Orphenadrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D013216:Reflex, Startle / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000409:Alanine; D000547:Amantadine; D003891:Desipramine; D003915:Dextromethorphan; D003917:Dextrorphan; D016291:Dizocilpine Maleate; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D007050:Ibogaine; D008559:Memantine; D018727:Muscarinic Antagonists; D009966:Orphenadrine; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors; C025293:alaproclate