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The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys.
Behav Pharmacol. 2007 Dec; 18(8):731-43.BP

Abstract

Development of N-methyl-D-aspartate (NMDA) antagonists for a variety of disorders has been hindered by their production of phencyclidine (PCP)-like psychological effects and abuse potential. There is, however, evidence to suggest that this problem might be mitigated by targeting NMDA receptors subtypes, in particular, those containing the NR2B subunit. To further test this hypothesis, the NR2B selective antagonist CP-101 606 (traxoprodil) was evaluated in two animal models: drug discrimination, a model of the subjective effects of drugs in humans, and self-administration, which evaluates the reinforcing properties of the drug. In the first study, CP-101 606(3-300 microg/kg/infusion) was tested for intravenous self-administration in rhesus monkeys experienced in PCP (5.6 microg/kg/infusion, intravenously) self-administration. In the second study, CP-101 606 was tested for production of PCP-like discriminative stimulus effects in rats (3-56 mg/kg, intraperitoneally) and rhesus monkeys (0.3-5.6 mg/kg intravenously). Evidence was obtained for reinforcing effects of at least one dose of CP-101 606 in all four monkeys. In rats, CP-101 606 produced more than 80% mean PCP-lever selection (2.0 mg/kg, intraperitoneally) but, unlike PCP itself, the dose producing the highest level of substitution was accompanied by more than 50% suppression of response rates. In monkeys, CP-101 606 produced more than 90% PCP-lever selection (0.1 mg/kg intramuscularly) in three of four animals at doses that did not significantly decrease rates of responding. The data show that CP-101 606 has some PCP-like discriminative stimulus effects in rats and monkeys and functions as a positive reinforcer in monkeys. These results suggest that inhibition of NR2B subunit containing NMDA receptors plays a role in the production of the subjective effects and abuse potential associated with many subtype-nonselective NMDA receptor antagonists such as PCP.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298-0613, USA. Klnichol@hsc.vcu.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17989511

Citation

Nicholson, Katherine L., et al. "The Phencyclidine-like Discriminative Stimulus Effects and Reinforcing Properties of the NR2B-selective N-methyl-D-aspartate Antagonist CP-101 606 in Rats and Rhesus Monkeys." Behavioural Pharmacology, vol. 18, no. 8, 2007, pp. 731-43.
Nicholson KL, Mansbach RS, Menniti FS, et al. The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys. Behav Pharmacol. 2007;18(8):731-43.
Nicholson, K. L., Mansbach, R. S., Menniti, F. S., & Balster, R. L. (2007). The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys. Behavioural Pharmacology, 18(8), 731-43.
Nicholson KL, et al. The Phencyclidine-like Discriminative Stimulus Effects and Reinforcing Properties of the NR2B-selective N-methyl-D-aspartate Antagonist CP-101 606 in Rats and Rhesus Monkeys. Behav Pharmacol. 2007;18(8):731-43. PubMed PMID: 17989511.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The phencyclidine-like discriminative stimulus effects and reinforcing properties of the NR2B-selective N-methyl-D-aspartate antagonist CP-101 606 in rats and rhesus monkeys. AU - Nicholson,Katherine L, AU - Mansbach,Robert S, AU - Menniti,Frank S, AU - Balster,Robert L, PY - 2007/11/9/pubmed PY - 2008/1/25/medline PY - 2007/11/9/entrez SP - 731 EP - 43 JF - Behavioural pharmacology JO - Behav Pharmacol VL - 18 IS - 8 N2 - Development of N-methyl-D-aspartate (NMDA) antagonists for a variety of disorders has been hindered by their production of phencyclidine (PCP)-like psychological effects and abuse potential. There is, however, evidence to suggest that this problem might be mitigated by targeting NMDA receptors subtypes, in particular, those containing the NR2B subunit. To further test this hypothesis, the NR2B selective antagonist CP-101 606 (traxoprodil) was evaluated in two animal models: drug discrimination, a model of the subjective effects of drugs in humans, and self-administration, which evaluates the reinforcing properties of the drug. In the first study, CP-101 606(3-300 microg/kg/infusion) was tested for intravenous self-administration in rhesus monkeys experienced in PCP (5.6 microg/kg/infusion, intravenously) self-administration. In the second study, CP-101 606 was tested for production of PCP-like discriminative stimulus effects in rats (3-56 mg/kg, intraperitoneally) and rhesus monkeys (0.3-5.6 mg/kg intravenously). Evidence was obtained for reinforcing effects of at least one dose of CP-101 606 in all four monkeys. In rats, CP-101 606 produced more than 80% mean PCP-lever selection (2.0 mg/kg, intraperitoneally) but, unlike PCP itself, the dose producing the highest level of substitution was accompanied by more than 50% suppression of response rates. In monkeys, CP-101 606 produced more than 90% PCP-lever selection (0.1 mg/kg intramuscularly) in three of four animals at doses that did not significantly decrease rates of responding. The data show that CP-101 606 has some PCP-like discriminative stimulus effects in rats and monkeys and functions as a positive reinforcer in monkeys. These results suggest that inhibition of NR2B subunit containing NMDA receptors plays a role in the production of the subjective effects and abuse potential associated with many subtype-nonselective NMDA receptor antagonists such as PCP. SN - 0955-8810 UR - https://www.unboundmedicine.com/medline/citation/17989511/The_phencyclidine_like_discriminative_stimulus_effects_and_reinforcing_properties_of_the_NR2B_selective_N_methyl_D_aspartate_antagonist_CP_101_606_in_rats_and_rhesus_monkeys_ L2 - http://dx.doi.org/10.1097/FBP.0b013e3282f14ed6 DB - PRIME DP - Unbound Medicine ER -