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Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys.
Psychopharmacology (Berl). 1999 Sep 01; 146(1):49-59.P

Abstract

RATIONALE

Dextromethorphan (DXM) and its metabolite, dextrorphan (DXO) have neuroprotective and anticonvulsant properties through their activity as N-methyl-D-aspartate (NMDA) receptor channel blockers. Based on this receptor activity, coupled with reports of DXM abuse, both were evaluated for abuse potential and phencyclidine (PCP)-like behavioral effects in two animal models.

OBJECTIVES AND METHODS

The discriminative stimulus properties of DXO and DXM were tested in rats (3-56 mg/kg DXM, i.p. and 2.2-40.9 mg/kg DXO, i.p.) and rhesus monkeys (0.3-10 mg/kg DXM, i.m. and 0.25-8.0 mg/kg DXO, i. m.) trained to discriminate PCP from saline using a standard two-lever drug-discrimination paradigm under a fixed-ratio (FR) schedule of food reinforcement. In a second set of experiments, i.v. self-administration of DXO (10-100 microg/kg/infusion) and DXM (10-1000 microg/kg/infusion) were tested under a FR schedule of reinforcement in monkeys trained to lever press for infusions of PCP during daily 1-h sessions.

RESULTS

In rats, both DXM and DXO produced a dose-dependent substitution for PCP. When tested in monkeys, DXM yielded partial (1 monkey) and full (2 monkeys) substitution for PCP, while DXO substituted fully for PCP in all four subjects tested. In the self-administration study, in five of the six subjects, at least one dose of DXM served as a positive reinforcer, maintaining infusion rates above those for saline. For DXO, at least one dose maintained infusion numbers well above mean saline infusion numbers in all subjects.

CONCLUSIONS

Taken together, these data show that DXM has some PCP-like effects in rats and monkeys, but that they are more reliably produced by its metabolite, DXO. Thus, high doses of DXM may have some PCP-like abuse potential in humans but this potential may be associated with, or enhanced by, metabolism of DXM to DXO.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Medical College of Virginia, Box 980310, Virginia Commonwealth University, Richmond, VA 23298-0310, USA,No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

10485964

Citation

Nicholson, K L., et al. "Evaluation of the Reinforcing Properties and Phencyclidine-like Discriminative Stimulus Effects of Dextromethorphan and Dextrorphan in Rats and Rhesus Monkeys." Psychopharmacology, vol. 146, no. 1, 1999, pp. 49-59.
Nicholson KL, Hayes BA, Balster RL. Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys. Psychopharmacology (Berl). 1999;146(1):49-59.
Nicholson, K. L., Hayes, B. A., & Balster, R. L. (1999). Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys. Psychopharmacology, 146(1), 49-59.
Nicholson KL, Hayes BA, Balster RL. Evaluation of the Reinforcing Properties and Phencyclidine-like Discriminative Stimulus Effects of Dextromethorphan and Dextrorphan in Rats and Rhesus Monkeys. Psychopharmacology (Berl). 1999 Sep 1;146(1):49-59. PubMed PMID: 10485964.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys. AU - Nicholson,K L, AU - Hayes,B A, AU - Balster,R L, PY - 1999/9/15/pubmed PY - 1999/9/15/medline PY - 1999/9/15/entrez SP - 49 EP - 59 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 146 IS - 1 N2 - RATIONALE: Dextromethorphan (DXM) and its metabolite, dextrorphan (DXO) have neuroprotective and anticonvulsant properties through their activity as N-methyl-D-aspartate (NMDA) receptor channel blockers. Based on this receptor activity, coupled with reports of DXM abuse, both were evaluated for abuse potential and phencyclidine (PCP)-like behavioral effects in two animal models. OBJECTIVES AND METHODS: The discriminative stimulus properties of DXO and DXM were tested in rats (3-56 mg/kg DXM, i.p. and 2.2-40.9 mg/kg DXO, i.p.) and rhesus monkeys (0.3-10 mg/kg DXM, i.m. and 0.25-8.0 mg/kg DXO, i. m.) trained to discriminate PCP from saline using a standard two-lever drug-discrimination paradigm under a fixed-ratio (FR) schedule of food reinforcement. In a second set of experiments, i.v. self-administration of DXO (10-100 microg/kg/infusion) and DXM (10-1000 microg/kg/infusion) were tested under a FR schedule of reinforcement in monkeys trained to lever press for infusions of PCP during daily 1-h sessions. RESULTS: In rats, both DXM and DXO produced a dose-dependent substitution for PCP. When tested in monkeys, DXM yielded partial (1 monkey) and full (2 monkeys) substitution for PCP, while DXO substituted fully for PCP in all four subjects tested. In the self-administration study, in five of the six subjects, at least one dose of DXM served as a positive reinforcer, maintaining infusion rates above those for saline. For DXO, at least one dose maintained infusion numbers well above mean saline infusion numbers in all subjects. CONCLUSIONS: Taken together, these data show that DXM has some PCP-like effects in rats and monkeys, but that they are more reliably produced by its metabolite, DXO. Thus, high doses of DXM may have some PCP-like abuse potential in humans but this potential may be associated with, or enhanced by, metabolism of DXM to DXO. SN - 0033-3158 UR - https://www.unboundmedicine.com/medline/citation/10485964/Evaluation_of_the_reinforcing_properties_and_phencyclidine_like_discriminative_stimulus_effects_of_dextromethorphan_and_dextrorphan_in_rats_and_rhesus_monkeys_ L2 - https://dx.doi.org/10.1007/s002130051087 DB - PRIME DP - Unbound Medicine ER -