Abstract
The present study assessed the ability of various site-selective N-methyl-d-aspartate (NMDA) receptor antagonists to affect the discriminative stimulus properties of naloxone in morphine-dependent rats. Adult male Wistar rats were trained to discriminate 0.1 mg/kg of s.c. naloxone from saline using a Y-maze shock-avoidance procedure. Naloxone-appropriate responding was exhibited as a function of naloxone dose (0.01–1.0 mg/kg, ED50 = 0.03 mg/kg) and was also observed when morphine treatment temporarily was discontinued (8–96 hr, peak at 24 hr). Discriminative stimulus effects of naloxone (0.1–3.0 mg/kg) were antagonized by morphine (10–100 mg/kg). Ligands of peripheral opioid receptors failed to either substitute for naloxone (methylnaloxone, 0.1–3.0 mg/kg) or attenuate naloxone’s stimulus effects (loperamide, 1–30 mg/kg). In rats treated with the training dose of naloxone, administration of dizocilpine (0.03–0.3 mg/kg) andd-CPPene (1–10 mg/kg) decreased levels of naloxone-appropriate responding, whereas memantine (1–30 mg/kg), ACEA-1021 (10 and 50 mg/kg) and eliprodil (3–30 mg/kg) seemed to have little or no effects. Meanwhile, all NMDA receptor antagonists produced a decrease in the occurrence of two or more of the following opioid withdrawal signs: weight loss, forelimb tremor, ptosis, diarrhea and “wet-dog”-like shaking. Additionally, dizocilpine (0.1 mg/kg),d-CPPene (5.6 mg/kg) and ACEA-1021 (50 mg/kg) but not memantine (10 mg/kg) or eliprodil (30 mg/kg) significantly reduced the naloxone-appropriate escape area selection when administered during the period of suspended morphine treatment 24 hr after the last morphine injection. Thus, NMDA receptor antagonists appear to inhibit the discriminative stimulus effects of both naloxone-precipitated and spontaneous morphine withdrawal, and this ability depends on the type of antagonist applied.
Footnotes
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Send reprint requests to: Dr. Anton Y. Bespalov, Laboratory of Behavioral Pharmacology, Institute of Pharmacology, Pavlov Medical University, 6/8 Lev Tolstoy St., St. Petersburg 197089, Russia. E-mail:abespalov{at}spmu.rssi.ru
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↵1 This work was supported in part by Fogarty International Research Collaboration Award 1-R03TW00714–01.
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↵2 A preliminary report of some of these data was presented at the 10th ECNP Congress, Vienna, Austria, September 13–17, 1997.
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- EAA
- excitatory amino acid
- PCP
- phencyclidine
- dizocilpine (MK-801)
- (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine maleate
- d-CPPene (SDZ EAA 494)
- 3-(2-carboxypiperazin- 4-yl)-1-propenyl-1-phosphonic acid
- memantine
- 3,5-dimethyladamantan-1-amine
- ACEA-1021 (licostinel)
- 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione
- Received December 4, 1997.
- Accepted April 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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