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Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-D-aspartate channel blocker memantine.
Behav Pharmacol. 1998 May; 9(3):231-43.BP

Abstract

Memantine (MEM) is currently in clinical use in Europe for the treatment of various neurological disorders. It is a low-affinity channel blocker of N-methyl-D-aspartate (NMDA) receptors whose voltage-dependent, rapid binding kinetics are believed to limit its phencyclidine (PCP)-like side effects. MEM, and its analog amantadine (AMA), which has also been demonstrated to have some NMDA antagonist activity, were evaluated for PCP-like behavioral effects. The discriminative stimulus properties of MEM and AMA were tested in monkeys and rats trained to discriminate PCP from saline using a standard two-lever drug discrimination paradigm under a fixed ratio (FR) schedule of food reinforcement. In rats, MEM resulted in a dose-dependent substitution for PCP; however, full substitution occurred only at response rate suppressing doses. AMA failed to substitute for PCP at any dose tested. For MEM, all four monkeys showed complete substitution for PCP at doses which did not greatly decrease rates of responding. Conversely, AMA occasioned little or no responding on the PCP-associated level in any of the subjects. Intravenous self-administration of MEM and AMA was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. MEM served as a reinforcer in all subjects at one or more doses tested. For two of the subjects, at least one dose of AMA maintained rates of self-administration above those for saline. For both MEM and AMA, maximal response rates were considerably lower than with PCP self-administration and both drugs were much less potent in monkeys than would be predicted from rodent studies. The data show that MEM shares discriminative stimulus effects with PCP under these testing conditions, whereas the chemically similar compound AMA does not. MEM also serves as a positive reinforcer in rhesus monkeys, whereas AMA can serve as a weak reinforcer in only some subjects. Both AMA and MEM are reported to function as NMDA antagonists, yet clear differences exist in their behavioral effects with MEM acting more like a PCP-like antagonist. In addition, despite the rapid channel kinetics of MEM's NMDA receptor blockade, it may have some PCP-like abuse potential in humans at doses above the normal therapeutic levels.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0310, USA.No 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

9832937

Citation

Nicholson, K L., et al. "Evaluation of the Reinforcing and Discriminative Stimulus Properties of the Low-affinity N-methyl-D-aspartate Channel Blocker Memantine." Behavioural Pharmacology, vol. 9, no. 3, 1998, pp. 231-43.
Nicholson KL, Jones HE, Balster RL. Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-D-aspartate channel blocker memantine. Behav Pharmacol. 1998;9(3):231-43.
Nicholson, K. L., Jones, H. E., & Balster, R. L. (1998). Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-D-aspartate channel blocker memantine. Behavioural Pharmacology, 9(3), 231-43.
Nicholson KL, Jones HE, Balster RL. Evaluation of the Reinforcing and Discriminative Stimulus Properties of the Low-affinity N-methyl-D-aspartate Channel Blocker Memantine. Behav Pharmacol. 1998;9(3):231-43. PubMed PMID: 9832937.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-D-aspartate channel blocker memantine. AU - Nicholson,K L, AU - Jones,H E, AU - Balster,R L, PY - 1998/12/2/pubmed PY - 1998/12/2/medline PY - 1998/12/2/entrez SP - 231 EP - 43 JF - Behavioural pharmacology JO - Behav Pharmacol VL - 9 IS - 3 N2 - Memantine (MEM) is currently in clinical use in Europe for the treatment of various neurological disorders. It is a low-affinity channel blocker of N-methyl-D-aspartate (NMDA) receptors whose voltage-dependent, rapid binding kinetics are believed to limit its phencyclidine (PCP)-like side effects. MEM, and its analog amantadine (AMA), which has also been demonstrated to have some NMDA antagonist activity, were evaluated for PCP-like behavioral effects. The discriminative stimulus properties of MEM and AMA were tested in monkeys and rats trained to discriminate PCP from saline using a standard two-lever drug discrimination paradigm under a fixed ratio (FR) schedule of food reinforcement. In rats, MEM resulted in a dose-dependent substitution for PCP; however, full substitution occurred only at response rate suppressing doses. AMA failed to substitute for PCP at any dose tested. For MEM, all four monkeys showed complete substitution for PCP at doses which did not greatly decrease rates of responding. Conversely, AMA occasioned little or no responding on the PCP-associated level in any of the subjects. Intravenous self-administration of MEM and AMA was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. MEM served as a reinforcer in all subjects at one or more doses tested. For two of the subjects, at least one dose of AMA maintained rates of self-administration above those for saline. For both MEM and AMA, maximal response rates were considerably lower than with PCP self-administration and both drugs were much less potent in monkeys than would be predicted from rodent studies. The data show that MEM shares discriminative stimulus effects with PCP under these testing conditions, whereas the chemically similar compound AMA does not. MEM also serves as a positive reinforcer in rhesus monkeys, whereas AMA can serve as a weak reinforcer in only some subjects. Both AMA and MEM are reported to function as NMDA antagonists, yet clear differences exist in their behavioral effects with MEM acting more like a PCP-like antagonist. In addition, despite the rapid channel kinetics of MEM's NMDA receptor blockade, it may have some PCP-like abuse potential in humans at doses above the normal therapeutic levels. SN - 0955-8810 UR - https://www.unboundmedicine.com/medline/citation/9832937/Evaluation_of_the_reinforcing_and_discriminative_stimulus_properties_of_the_low_affinity_N_methyl_D_aspartate_channel_blocker_memantine_ L2 - https://www.lens.org/lens/search?q=citation_id:9832937 DB - PRIME DP - Unbound Medicine ER -