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Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N-methyl-D-aspartate receptor antagonists: preferential involvement of the NR2B rather than NR2A subunit.
Behav Pharmacol. 2003 Sep; 14(5-6):477-87.BP

Abstract

The non-competitive NMDA receptor antagonist phencyclidine (PCP) is known to produce a discriminative stimulus in rats. The first aim of the present study was to investigate which NMDA receptor subtype(s) is involved in this effect of PCP. Rats were trained to discriminate PCP (2 mg/kg; i.p.) from saline in a two lever operant task. The NMDA channel blocker, (+)MK-801 (0.1 mg/kg; i.p.) and the competitive NMDA receptor antagonist SDZ 220-581 (3 mg/kg; i.p.) produced 76% of PCP-lever selection (ED50=0.045 and 2 mg/kg, respectively), whereas their respective inactive enantiomers (-)MK-801 (0.025-0.1 mg/kg) and SDZ 221-653 (2-5 mg/kg) induced less than 30% of PCP-appropriate responding. Another competitive NMDA antagonist, SDZ EAB-515 (30 mg/kg; i.p.), induced 63% of PCP-lever responding (ED50=23.48 mg/kg). The selective antagonist of NMDA receptors containing the NR1A/NR2B-subunits Ro 25-6981 (20 mg/kg; i.p.) resulted in a complete substitution (more than 80% of PCP-lever selection) for PCP (ED50=8.59 mg/kg). In contrast, the NR1A/NR2A NMDA receptor-preferring antagonist NVP-AAM077 (2-10 mg/kg; i.p.) failed to produce PCP-like discriminative stimuli. At high doses SDZ 220-581 (ED50=2.44), NVP-AAM077 (ED50=8.33) and SDZ EAB-515 (ED50=25.81) decreased the performance of the rats in this operant task. The ability of these NMDA receptor antagonists to disrupt the prepulse inhibition (PPI) of the startle response and to alter locomotor activity was also studied. PCP (0.5-2 mg/kg; s.c.), SDZ 220-581 (0.5-5 mg/kg; s.c.), SDZ EAB-515 (1-30 mg/kg; i.p.) and Ro 25-6981 (5-20 mg/kg; i.p.) disrupted PPI and at high doses produced hyperlocomotion. In contrast, NVP-AAM077 (5-20 mg/kg; i.p.) did not disrupt PPI and reduced locomotor activity. In conclusion, it appears that the NMDA receptor containing the NR2B, rather than the NR2A subunit, may play a major role in the PCP-like discriminative stimulus. In addition, sensory motor gating disturbances associated with NMDA antagonists do not seem to result from a blockade of NR1/NR2A-containing NMDA receptors.

Authors+Show Affiliations

Novartis Pharma AG, Nervous System Research, Basel, Switzerland. frederique.chaperon@pharma.novartis.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

14501261

Citation

Chaperon, F, et al. "Substitution for PCP, Disruption of Prepulse Inhibition and Hyperactivity Induced By N-methyl-D-aspartate Receptor Antagonists: Preferential Involvement of the NR2B Rather Than NR2A Subunit." Behavioural Pharmacology, vol. 14, no. 5-6, 2003, pp. 477-87.
Chaperon F, Müller W, Auberson YP, et al. Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N-methyl-D-aspartate receptor antagonists: preferential involvement of the NR2B rather than NR2A subunit. Behav Pharmacol. 2003;14(5-6):477-87.
Chaperon, F., Müller, W., Auberson, Y. P., Tricklebank, M. D., & Neijt, H. C. (2003). Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N-methyl-D-aspartate receptor antagonists: preferential involvement of the NR2B rather than NR2A subunit. Behavioural Pharmacology, 14(5-6), 477-87.
Chaperon F, et al. Substitution for PCP, Disruption of Prepulse Inhibition and Hyperactivity Induced By N-methyl-D-aspartate Receptor Antagonists: Preferential Involvement of the NR2B Rather Than NR2A Subunit. Behav Pharmacol. 2003;14(5-6):477-87. PubMed PMID: 14501261.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N-methyl-D-aspartate receptor antagonists: preferential involvement of the NR2B rather than NR2A subunit. AU - Chaperon,F, AU - Müller,W, AU - Auberson,Y P, AU - Tricklebank,M D, AU - Neijt,H C, PY - 2003/9/23/pubmed PY - 2004/1/14/medline PY - 2003/9/23/entrez SP - 477 EP - 87 JF - Behavioural pharmacology JO - Behav Pharmacol VL - 14 IS - 5-6 N2 - The non-competitive NMDA receptor antagonist phencyclidine (PCP) is known to produce a discriminative stimulus in rats. The first aim of the present study was to investigate which NMDA receptor subtype(s) is involved in this effect of PCP. Rats were trained to discriminate PCP (2 mg/kg; i.p.) from saline in a two lever operant task. The NMDA channel blocker, (+)MK-801 (0.1 mg/kg; i.p.) and the competitive NMDA receptor antagonist SDZ 220-581 (3 mg/kg; i.p.) produced 76% of PCP-lever selection (ED50=0.045 and 2 mg/kg, respectively), whereas their respective inactive enantiomers (-)MK-801 (0.025-0.1 mg/kg) and SDZ 221-653 (2-5 mg/kg) induced less than 30% of PCP-appropriate responding. Another competitive NMDA antagonist, SDZ EAB-515 (30 mg/kg; i.p.), induced 63% of PCP-lever responding (ED50=23.48 mg/kg). The selective antagonist of NMDA receptors containing the NR1A/NR2B-subunits Ro 25-6981 (20 mg/kg; i.p.) resulted in a complete substitution (more than 80% of PCP-lever selection) for PCP (ED50=8.59 mg/kg). In contrast, the NR1A/NR2A NMDA receptor-preferring antagonist NVP-AAM077 (2-10 mg/kg; i.p.) failed to produce PCP-like discriminative stimuli. At high doses SDZ 220-581 (ED50=2.44), NVP-AAM077 (ED50=8.33) and SDZ EAB-515 (ED50=25.81) decreased the performance of the rats in this operant task. The ability of these NMDA receptor antagonists to disrupt the prepulse inhibition (PPI) of the startle response and to alter locomotor activity was also studied. PCP (0.5-2 mg/kg; s.c.), SDZ 220-581 (0.5-5 mg/kg; s.c.), SDZ EAB-515 (1-30 mg/kg; i.p.) and Ro 25-6981 (5-20 mg/kg; i.p.) disrupted PPI and at high doses produced hyperlocomotion. In contrast, NVP-AAM077 (5-20 mg/kg; i.p.) did not disrupt PPI and reduced locomotor activity. In conclusion, it appears that the NMDA receptor containing the NR2B, rather than the NR2A subunit, may play a major role in the PCP-like discriminative stimulus. In addition, sensory motor gating disturbances associated with NMDA antagonists do not seem to result from a blockade of NR1/NR2A-containing NMDA receptors. SN - 0955-8810 UR - https://www.unboundmedicine.com/medline/citation/14501261/Substitution_for_PCP_disruption_of_prepulse_inhibition_and_hyperactivity_induced_by_N_methyl_D_aspartate_receptor_antagonists:_preferential_involvement_of_the_NR2B_rather_than_NR2A_subunit_ L2 - http://dx.doi.org/10.1097/01.fbp.0000091471.79060.ed DB - PRIME DP - Unbound Medicine ER -