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This study investigated whether D,L-cis-2,3-Pyrrolidine dicarboxylate (D,L-cis-2,3-PDC), a new glutamate analogue, alters glutamate binding to cerebral plasma membranes and whether N-methyl-D-aspartate (NMDA) receptors are involved in the convulsant effect of this compound. D,L-cis-2,3-PDC reduced sodium-independent [3H]-L-glutamate binding to lysed membrane preparations from adult rat cortex and had no effect on sodium-dependent glutamate binding. Intracerebroventricular administration of D,L-cis-2,3-PDC (7.5-25 nmol/5 microl) induced generalized tonic-clonic convulsions in mice in a dose-dependent manner. The coadministration of MK-801 (7 nmol/2.5 microl), with D,L-cis-2,3-PDC (16.5 nmol/2.5 microl), fully protected the animals against D,L-cis-2,3-PDC-induced convulsions, while the coadministration of DNQX (10 nmol/2.5 microl) increased the latency to convulsions but did not alter the percentage of animals that had convulsions. These results suggest that D,L-cis-2,3-PDC-induced effects are mediated predominantly by NMDA receptors.

The results of a previous study in rats indicated that spiradoline has pharmacologically selective discriminative effects that are mediated by kappa-opioid receptors. However, the training dose, 3.0 mg/kg, increased response latencies, suggesting that it was relatively high. The current study was performed to characterize further the discriminative effects of spiradoline by using a lower training dose, 1.0 mg/kg, and testing a larger number of drugs for generalization with spiradoline. Rats were trained in a discrete-trial avoidance/escape procedure to discriminate 1.0 mg/kg spiradoline, SC, from saline in an average of 19.7 sessions; response latencies after saline and spiradoline were not different from each other. The rats generalized dose dependently and completely to other kappa-opioid agonists that have relatively high efficacy: ethylketocyclazocine, U69,593, and U50,488. They generalized partially to ketocyclazocine, (-)-N-allylnormetazocine, and DuP 747, and not at all to cyclazocine, butorphanol, nalorphine, and pentazocine, discriminable opioids that have relatively low efficacy at kappa-opioid receptors, or to morphine and dextromethorphan, discriminable drugs that do not act at kappa-opioid receptors. The discriminative effects of spiradoline were unaffected by the mu-opioid antagonist beta-funaltrexamine, but were blocked completely for at least 4 weeks by the kappa-opioid antagonist nor-binaltorphimine. Thus, spiradoline-like stimulus control of behavior remains kappa-opioid selective, and continues to have a high efficacy requirement even at a training dose that does not impair performance.

Spiradoline (U62066E) a racemic mixture of the two enantiomers U63639(+) and U63640(-), appears to have kappa opioid receptor activity, but the contribution of each enantiomer toward this activity is still in question. To determine the activity of each enantiomer in comparison to the racemic mixture, the three forms were tested in the cold-water tail-flick (CWTF) assay in male Sprague-Dawley rats. Antinociception by spiradoline was completely antagonized by naloxone 0.50 mg/kg, a dose five times that required to antagonize antinociception by fentanyl in this same assay. In a second series of tests, fentanyl-induced antinociception was markedly reduced, while spiradoline-induced antinociception was essentially unchanged. in methadone-tolerant animals. Of the enantiomers, only U63640 produced antinociception, whereas U63639 failed to affect the nociceptive response. Additionally, spiradoline failed to produce antinociception in animals pretreated with norbinaltorphimine (kappa receptor specific), but antinociception was not affected in animals pretreated with beta-funaltrexamine (mu receptor specific). These results show that spiradoline is a full antinociceptive agonist in the CWTF assay and that the effects of the drug are mediated through kappa opioid receptors.

The influences of the kappa-opiate agonist U50,488H (U50; 4 mg/kg IP), the neuroleptic haloperidol (HAL; 0.3 mg/kg IP), and MK-801 (0.2 mg/kg IP), a noncompetitive antagonist for NMDA receptors, were compared on the effects of nine days of d-amphetamine (AMPH) treatment (3 mg/kg IP) on food and water intake and urine output. AMPH prevented feeding stimulation produced by U50 during the first 2 h, whereas U50 inhibited the hyperphagic phase that rats showed between 2 and 5 h after AMPH administration. Tolerance did not develop to the first 2-h suppression of feeding; in contrast, the late hyperphagic phase slowly recovered across the nine days of treatment. Combined administration of the two drugs barely affected water intake but considerably increased urine output. Unlike U50, HAL left the late hyperphagic response to AMPH unchanged and delayed the development of hyperdipsia. In our study MK-801 had one effect only: It significantly reduced amphetamine diuresis. These results suggest that by inhibiting the late hyperphagic response U50 enhances the anorectic effects of AMPH, but that dopamine probably has no direct role in this interaction.

Morphine-induced antinociception was prevented by pretreatment with ginseng total saponins in the tail-pinch and tail-flick tests carried out in mice. The antinociceptive effect of U-50,488H, a selective kappa-opioid receptor agonist, was prevented by naloxone, a nonselective opioid receptor antagonist, in the tail-pinch but not in the tail-flick test. However, U-50,488H-induced antinociception was prevented by ginseng total saponins in the tail-flick but not in the tail-pinch test. These results indicate that nonopioid mechanisms are involved in the antagonism of U-50,488H-induced antinociception by ginseng total saponins. In addition, the antagonism of U-50,488H-induced antinociception in mice pretreated with ginseng total saponins was abolished by pretreatment with a serotonin precursor, 5-hydroxytryptophan, but not by a noradrenaline precursor, L-dihydroxyphenylalanine, in the tail-flick test. Therefore, it appears that the antagonism of U-50,488H-induced antinociception by ginseng total saponins is dependent on serotonergic mechanisms.

In a previous study, we found that the kappa opioid agonist U50,488H (U50) suppresses both appetitive and consummatory components of drinking behavior in rats trained to negotiate water in a straight runway. U50 also activates diuresis. Kappa opioid mechanisms could therefore play a dissipative role in the body's water balance. Since naloxone inhibits diuresis, but not hypodipsia produced by U50, these effects are probably mediated also by nonopioid mechanisms. In rats trained to negotiate water in a straight runway, we have studied the influence on the hypodipsic effects of U50 of the selective alpha-1 adrenoceptor antagonist dapiprazol (DAP), which we found to inhibit U50-mediated diuresis. When given alone, DAP (3 and 6 mg/kg IP) influenced neither running for water nor water intake; neither did it prevent the suppression of water intake produced by U50 (8 mg/kg IP) across the test. However, it did antagonize the U50-mediated slowing of running for water. Alpha-1 adrenoceptors thus appear to play a role in U50's effects on diuresis and the appetitive, but not consummatory, aspects of drinking.

The amnesia induced by cycloheximide (CXM) injected SC and by CXM or anisomycin injected ICV immediately after the training test was antagonized in combination with an opiate antagonist, naloxone (NLX). This antagonism occurred on both the passive avoidance- and escape-learning responses in a dose-dependent manner in mice. NLX alone (0.3-10.0 mg/kg) did not alter the performances of these tasks. Furthermore, the decrease in retention performance on shuttle avoidance in rats induced by CXM was also antagonized by NLX. Treatment with CXM and/or NLX did not affect spontaneous locomotor activity. The interaction of these drugs on the performance of the passive avoidance- and escape-learning and the shuttle avoidance tasks may be related to neurochemical memory processes. These results suggest that an opioid system may participate in the amnesic actions induced by protein synthesis inhibitors in these models.