Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats.

Phencyclidine (PCP) and other high-affinity NMDA receptor channel blockers disrupt prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating relevant to attentional deficits in schizophrenia. This study tested NMDA channel blockers with varying affinities in Sprague-Dawley rats. High-affinity drugs dizocilpine and dextrorphan disrupted PPI at doses that did not alter startle responses alone. Low-affinity drugs showed mixed results: dextromethorphan and memantine disrupted PPI, while orphenadrine, amantadine, desipramine, and alaproclate did not. Ibogaine disrupted PPI only at doses that severely reduced startle. Not all NMDA channel blockers share PCP's PPI-disrupting effect, and caution is warranted for supratherapeutic doses and vulnerable populations.

Study at a glance

Abstract

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