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Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats.
Psychopharmacology (Berl). 2003 Feb; 165(4):378-85.P

Abstract

RATIONALE

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.

OBJECTIVES

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).

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Virginia Commonwealth University, PO Box 980613, Richmond, VA 23298-0613, USA. jwiley@hsc.vcu.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12459931

Citation

Wiley, Jenny L., et al. "Affinity and Specificity of N-methyl- D-aspartate Channel Blockers Affect Their Ability to Disrupt Prepulse Inhibition of Acoustic Startle in Rats." Psychopharmacology, vol. 165, no. 4, 2003, pp. 378-85.
Wiley JL, Harvey SA, Balster RL, et al. Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats. Psychopharmacology (Berl). 2003;165(4):378-85.
Wiley, J. L., Harvey, S. A., Balster, R. L., & Nicholson, K. L. (2003). Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats. Psychopharmacology, 165(4), 378-85.
Wiley JL, et al. Affinity and Specificity of N-methyl- D-aspartate Channel Blockers Affect Their Ability to Disrupt Prepulse Inhibition of Acoustic Startle in Rats. Psychopharmacology (Berl). 2003;165(4):378-85. PubMed PMID: 12459931.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats. AU - Wiley,Jenny L, AU - Harvey,Sarah A, AU - Balster,Robert L, AU - Nicholson,Katherine L, Y1 - 2002/11/30/ PY - 2002/05/04/received PY - 2002/10/02/accepted PY - 2002/12/3/pubmed PY - 2003/3/21/medline PY - 2002/12/3/entrez SP - 378 EP - 85 JF - Psychopharmacology JO - Psychopharmacology (Berl) VL - 165 IS - 4 N2 - RATIONALE: 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. OBJECTIVES: 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). SN - 0033-3158 UR - https://www.unboundmedicine.com/medline/citation/12459931/Affinity_and_specificity_of_N_methyl__D_aspartate_channel_blockers_affect_their_ability_to_disrupt_prepulse_inhibition_of_acoustic_startle_in_rats_ L2 - https://dx.doi.org/10.1007/s00213-002-1297-6 DB - PRIME DP - Unbound Medicine ER -