Effects of modulation of NMDA neurotransmission on response rate and duration in a conflict procedure in rats
2区 · 医学
作者: Wiley, Jenny L. ; Compton, Amelia D. ; Holcomb, Jennifer D. ; McCallum, Sarah E. ; Varvel, Steven A. ; Porter, Joseph H. ; Balster, Robert L.
N-Methyl-D-aspartate (NMDA) antagonists and gamma-aminobutyric acid agonists share a number of common pharmacological properties, including motor and anticonvulsant effects. In the present study, site-selective NMDA antagonists were evaluated for potential anxiolytic efficacy and motor impairment in a modified Geller-Seifter conflict procedure, an animal model widely used to screen drugs for anxiolytic effects. Male Sprague-Dawley rats were trained to respond for food reward under a multiple FI 30 s (food only), FR 10 (food + shock) operant schedule. Consistent with the results of previous studies, the benzodiazepines chlordiazepoxide and diazepam selectively increased punished responding and increased response durations at higher doses. The competitive NMDA antagonist CGP 37,849 increased punished responding at some doses, though not selectively, and also increased response duration in both schedule components. The glycine-site modulators milacemide, ACEA 1011 and ACEA 1021, the NR2B-selective polyamine site antagonist eliprodil and NMDA did not produce anticonflict effects at any dose and had inconsistent effects on response durations. These results suggest that the anticonflict effects of NMDA antagonists are not as reliable as those of the benzodiazepines. Further research is needed to clarify the experimental conditions under which the anxiolytic potential of NMDA antagonists is most evident.
1996-06-01·Pharmacology, Biochemistry and Behavior4区 · 心理学
Differential sensitivity of mice bred for stress-induced analgesia to morphine and ACEA-1011 in the formalin test
4区 · 心理学
作者: Lutfy, Kabirullah ; Sadowski, Bogdan ; Marek, Przemyslaw ; Kwon, Ik-Sung ; Keana, John F. W. ; Weber, Eckard
The antinociceptive effect of morphine, an opioid receptor agonist, and ACEA-1011, a novel NMDA receptor/glycine site antagonist, was examined in the formalin test in mice selectively bred for high (HA) and low (LA) swim stress-induced analgesia (SSIA). A subcutaneous (SC) injection of formalin produced a biphasic nociceptive response in both lines. HA mice spent more time licking the injected paw than the LA mice in both phases of the formalin test. Morphine was equally potent in the early phase in both lines, but it was more potent in HA mice than in LA mice in the tonic late phase of the formalin test. Similarly, ACEA-1011 produced an equally potent antinociceptive effect in the early phase in both lines; however, the compound was more potent in LA mice than in HA mice in the tonic late phase of the formalin test. These data suggest that in HA mice antinociception in the tonic late phase of the formalin test is mediated largely by an opioid-mediated mechanism, whereas in the opioid-deficient LA line at least a nonopioid-mediated mechanism involving the NMDA receptor is also implicated.
1996-03-01·Molecular Pharmacology3区 · 医学
Antagonist pharmacology of kainate- and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-preferring receptors
3区 · 医学
作者: Wilding, Timothy J. ; Huettner, James E.
Whole-cell recordings were used to study the antagonist pharmacology of two subtypes of non-N-methyl-D-aspartate glutamate receptors: the kainate-preferring subtype expressed by rat dorsal root ganglion (DRG) neurons and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring subtype expressed by neurons from rat cerebral cortex. A series of quinoxaline derivatives were tested for the ability to distinguish between AMPA and kainate receptors, as determined by differential potency. Of the nine compounds studied, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX) showed the highest selectivity for AMPA-preferring receptors, whereas 5-chloro-7-trifluoromethyl-2,3-quinoxalinedione (ACEA-1011) showed the highest selectivity for the kainate-preferring subtype. NBQX blocked non-N-methyl-D-aspartate currents in cortical cells with a Kb of 0.3 mircroM, but in DRG neurons the Kb for NBQX was 3-fold higher (0.9 microM). ACEA-1011 also blocked the currents in DRG cells with a Kb of approximately 1 microM, but in cortical neurons the kb for this drug was 10-12 microM. Several the Kb for this drug was 10-12 micron. Several additional compounds were tested for selective potency, including 5-nitro-6,7,8,9-tetrahydrobenzo[G]indole-2,3-dione-3-oxime, gamma-D-glutamylaminomethylsulphonic acid, and derivatives of kynurenic acid and 1-benzazepine. 5-Nitro-6,7,8,9-tetrahydrobenzo- [G]indole-2,3-dione-3-oxime displayed the highest selectivity in this group, blocking kainate receptors with a Kb of 6 microM while inhibiting AMPA receptors with a Kb of >100 microM. The remaining antagonists showed <3-fold selectivity between AMPA and kainate receptor subtypes. Our results suggest that most competitive antagonists block native AMPA and kainate receptors with approximately similar potencies, which is in marked contrast to the substantial differences in potency that have been observed with receptor agonists.