Generalization of NMDA-Receptor Antagonists to the Discriminative Stimulus Effects of κ-Opioid Receptor Agonists U-50,488H, but Not TRK-820 in Rats

Abstract

Abstract. Generalizations of NMDA-receptor antagonists to the discriminative stimulus effects of κ-opioid receptor agonists in rats were examined. Phencyclidine, MK-801, and ketamine, noncompetitive NMDA-receptor antagonists, generalized to the discriminative stimulus effects of U-50,488H, but not those of TRK-820, whereas (±)-3-(2-carbaxypiperazine-4-yl) propyl-1-phosphonic acid (CPP), a competitive NMDA-receptor antagonist, and ifenprodil, an NR1 / NR2B NMDA-receptor antagonist, did not, suggesting that non-competitive NMDA-receptor antagonists possess U-50,488H-like discriminative stimulus effects in rats. Since U-50,488H and phencyclidine both induce aversive effects, our findings indicate that the cue of the discriminative stimulus effects of U-50,488H and non-competitive NMDA-receptor antagonists may be associated with their aversive effects.Keywords: drug discrimination, κ-opioid receptor agonist, NMDA-receptor antagonist It is generally accepted that discriminative stimulus effects of drugs in animals serve as a model for the subjective effects in humans (1). Furthermore, drug discrimination procedures have been shown to be useful for distinguishing drug effects mediated by κ-opioid receptors from those mediated by other receptors and for characterizing and quantifying such drug-receptor interactions (2 -4). We recently demonstrated that the patterns of generalization of κ-opioid receptor agonists to the discriminative stimulus effects of other κ-opioid receptor agonists, U-50,488H and TRK-820, were somewhat different (5). Furthermore, the potency order of κ-opioid receptor agonists to the discriminative stimulus effects of U-50,488H were parallel to the potency of their aversive effects, suggesting that the cue of the discriminative stimulus effects of U-50,488H is related to aversive effects in rats (5).Previous reports showed that phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist, exerts the discriminative stimulus effects in monkeys and rats. κ-Opioid receptor agonists or PCP induce place aversion using place conditioning paradigms (6). The goal of the present study was to compare the possible similarities in the discriminative stimulus effects of two different types of κ-opioid receptor agonists, U-50,488H and TRK-820, and NMDA-receptor antagonists. Therefore, we examined the generalization of NMDA-receptor antagonists such as PCP, MK-801, ketamine, ifenprodil, and (±)-3-(2-carbaxypiperazine-4-yl)propyl-1-phosphonic acid (CPP) to the discriminative stimulus effects of κ-opioid-receptor agonists in rats.Sixteen male Fischer 344 rats (Charles River Japan Inc., Atsugi) were maintained at 220 -230 g (80% freefeeding weight). Water was available ad libitum for all of the rats in their home cages. The rats were housed in individual cages at a room temperature of 22 ± 1°C with a 12-h light-dark cycle (light on 8:00 a.m. to 8:00 p.m.).

The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

“…Furthermore, Killinger et al [409] demonstrated that the discriminative stimulus effects of salvinorin A do not generalize to LSD, another 5-HT receptor agonist. Others have reported that non-competitive NMDA receptor antagonists (ketamine, PCP, MK-801), but not competitive antagonists, generalize to the discriminative stimulus effects of U50,488, but not the KOR agonist TRK-820 [410]. Collectively, these findings suggest that psychomimetic effects produced by salvinorin A differ from those produced by classical hallucinogens.…”

Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats

“…It also increases DA efflux in the NAc (Hancock and Stamford 1999), an effect often associated with reward and pleasure (Wise 2008). There is evidence in rats that ketamine and other non-competitive NMDA receptor antagonists (e.g., MK-801, phencyclidine) substitute for the KOR agonist U50,488 in drug discrimination tests (Mori et al 2006), suggesting similar discriminative stimulus properties in this species. It is conceivable that the drug discrimination test and the 5CSRTT are both most sensitive to the dissociative effects of these drugs in rats.…”

Activation of extracellular signal‐regulated kinase is critical for the discriminative stimulus effects induced by U‐50,488H

“…We previously demonstrated that the discriminative stimulus effects of the κ‐opioid receptor agonist U‐50,488H are associated with its aversive effects in rats (Mori et al, 2004). Moreover, we also reported that κ‐opioid receptor agonists, NMDA receptor antagonists and DA D 3 receptor agonists might possess similar discriminative stimulus effects in rats (Mori et al, 2006, Yoshizawa et al, 2010). Drug discrimination procedures have been shown to be useful for distinguishing drug effects mediated by κ‐opioid receptors from those mediated by other receptors and for characterizing and quantifying such drug‐receptor interactions (Teal and Holtzman, 1980; White and Holtzman, 1983), while its molecular signaling mechanism has not yet been characterized.…”

“…These data suggest that the κ‐opioid receptor is critical for the production of the U‐50,488H‐induced discriminative stimulus effect, as expected. We previously demonstrated that κ‐opioid receptor agonists, NMDA receptor antagonists and DA D 3 receptor agonists might possess similar discriminative stimulus effects in rats (Mori et al, 2006, Yoshizawa et al, 2010). However, we found in this study that the discriminative stimulus effects of U‐50,488H did not affect the mRNA expression of DA receptors and NMDA receptor subunits.…”