D-AP5

N-Methyl-D-aspartate receptor antagonist d-AP5 prevents pertussis toxin-induced alterations in rat spinal cords by inhibiting increase in concentrations of spinal CSF excitatory amino acids and downregulation of glutamate transporters.[Pubmed:19463918]

Brain Res Bull. 2009 Aug 28;80(1-2):69-74.

Recently, we found that intrathecal (i.t.) pertussis toxin (PTX) injection produces thermal hyperalgesia and is associated with increasing concentrations of excitatory amino acids (EAAs) in spinal cerebrospinal fluid (CSF) dialysates; a reduction in the antinociceptive effects of morphine and glutamate transporters (GTs) was also observed. The reduction in the morphine-induced analgesic effects is directly related to increased extracellular EAA levels, which are maintained by GTs at physiological levels. In this study, we aimed to examine the role of GT isoforms in thermal hyperalgesia, determine the EAA concentrations in CSF dialysates, and elucidate the role of N-methyl-d-aspartate (NMDA) receptors in PTX-induced reduction in the antinociceptive effects of morphine. Two i.t. catheters and one microdialysis probe were inserted into male Wistar rats: one catheter was used for PTX (1 microg) and morphine (10 microg) injection and the other was connected to an osmotic pump for NMDA receptor antagonist d-2-amino-5-phosphonopentanoic acid (D-AP5; 2 microg/h for 4 days) continuous infusion. The microdialysis probe was used to collect CSF dialysates for EAA measurements by high-performance liquid chromatography. Intrathecal morphine failed to produce antinociceptive effects in PTX-treated rats, and D-AP5 coinfusion prevented the PTX-induced reduction in the antinociceptive effect and associated downregulation of the GTs. We conclude that NMDA receptor suppression inhibits EAA excitation and reduces the morphine-induced antinociception in PTX-treated rats.

Effects of pre or posttraining dorsal hippocampus D-AP5 injection on fear conditioning to tone, background, and foreground context.[Pubmed:18727044]

Hippocampus. 2008;18(11):1089-93.

NMDA receptor antagonist D-AP5 was injected into the dorsal hippocampus of Wistar rats before or immediately after the training session in fear conditioning. Training was conducted both with signaled (background context) or unsignaled (foreground context) footshocks. Contextual fear conditioning was assessed 24 h later and tone fear conditioning 48 h after training (only in the signaled footshock condition). Pretraining injections impaired conditioned fear to contextual features, both in background and foreground configurations, whereas tone fear conditioning was left intact. Posttraining injections were ineffective in all cases. We conclude that dorsal hippocampal NMDA receptors are required for contextual fear acquisition independently of context saliency and that they are not required to early consolidation processes.

Effects of intra-hippocampal D-AP5 injections on one trial passive avoidance learning in adult laying hens (Gallus gallus domesticus).[Pubmed:19112472]

Acta Neurobiol Exp (Wars). 2008;68(4):494-501.

Domestic chickens are an established model organism for studies on learning and memory. Commonly, the chicks are used as subjects in several different learning tests, including one trial learning tests. However, for adult laying hens no such one trial learning tests have been established. In particular, there is no test established which focuses on the role of the hippocampus, a brain region, which is often critically involved in learning and memory consolidation. In this study we investigated the inhibitory effects of intra-hippocampal D-AP5 injections on a specific one trial passive avoidance learning test in adult laying hens (Gallus gallus domesticus). We used a step down avoidance learning paradigm (SDA) which is frequently used in rodents. Intra-hippocampal injections of D-AP5 impaired the learning abilities of adult laying hens compared to sham-injected control subjects. Thus, the experiments revealed that the hippocampus is critically involved in learning the inhibitory SDA task. Our results further indicate that the step down avoidance paradigm is suitable to examine learning and memory processes in adult laying hens.

N-methyl-d-aspartate receptors, learning and memory: chronic intraventricular infusion of the NMDA receptor antagonist d-AP5 interacts directly with the neural mechanisms of spatial learning.[Pubmed:23311352]

Eur J Neurosci. 2013 Mar;37(5):700-17.

Three experiments were conducted to contrast the hypothesis that hippocampal N-methyl-d-aspartate (NMDA) receptors participate directly in the mechanisms of hippocampus-dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug-induced neuropathological and/or sensorimotor disturbances. In experiment 1, rats given a chronic i.c.v. infusion of D-AP5 (30 mm) at 0.5 muL/h were selectively impaired, relative to aCSF-infused animals, in place but not cued navigation learning when they were trained during the 14-day drug infusion period, but were unimpaired on both tasks if trained 11 days after the minipumps were exhausted. D-AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in D-AP5-treated rats whether killed during or after chronic drug infusion. In experiment 2, a deficit in spatial learning was also apparent in D-AP5-treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of D-AP5 in selected brain areas. In Experiment 3, rats treated with D-AP5 showed a delay-dependent deficit in spatial memory in the delayed matching-to-place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning.

Utilization of the resolved L-isomer of 2-amino-6-phosphonohexanoic acid (L-AP6) as a selective agonist for a quisqualate-sensitized site in hippocampal CA1 pyramidal neurons.[Pubmed:7953634]

Brain Res. 1994 Jun 27;649(1-2):203-7.

Brief exposure of rat hippocampal slices to quisqualic acid (QUIS) sensitizes neurons to depolarization by the alpha-amino-omega-phosphonate excitatory amino acid (EAA) analogues AP4, AP5 and AP6. These phosphonates interact with a novel QUIS-sensitized site. Whereas L-AP4 and D-AP5 cross-react with other EAA receptors, DL-AP6 has been shown to be relatively selective for the QUIS-sensitized site. This specificity of DL-AP6, in conjunction with the apparent preference of this site for L-isomers, suggested that the hitherto unavailable L-isomer of AP6 would be a potent and specific agonist. We report the resolution of the D- and L-enantiomers of AP6 by fractional crystallization of the L-lysine salt of DL-AP6. We also report the pharmacological responses of kainate/AMPA, NMDA, lateral perforant path L-AP4 receptors and the CA1 QUIS-sensitized site to D- and L-AP6, and compare these responses to the D- and L-isomers of AP3, AP4, AP5 and AP7. The D-isomers of AP4, AP5 and AP6 were 5-, 3- and 14-fold less potent for the QUIS-sensitized site than their respective L-isomers. While L-AP4 and L-AP5 cross-reacted with NMDA and L-AP4 receptors, L-AP6 was found to be highly potent and specific for the QUIS-sensitized site (IC50 = 40 microM). Its IC50 values for kainate/AMPA, NMDA and L-AP4 receptors were > 10, 3 and 0.8 mM, respectively. As with AP4 and AP5, sensitization to L-AP6 was reversed by L-alpha-aminoadipate.

Actions of D and L forms of 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate in the cat spinal cord.[Pubmed:6145492]

Brain Res. 1982 Mar 11;235(2):378-86.

The separate optical enantiomers of 2-amino-5-phosphonovalerate (APV) and 2-amino-4-phosphonobutyrate (APB) have been tested for their ability to modify amino acid-induced and synaptic excitation of cat spinal neurones. D-(-)-APV was a highly potent and selective antagonist of amino acid-induced and synaptic excitation. Polysynaptic excitation was more susceptible to antagonism by D-APV than was monosynaptic excitation. It was considered likely that the depression of synaptic excitation by D-APV was due to the blockade of an excitatory amino acid transmitter acting at N-methyl-D-aspartate (NMDA) receptors. L-(+)-APV showed a relatively weak amino acid and synaptic blocking activity, which was similar in character to that of D-APV, and which may have been due to a slight residuum of the D isomer in the sample of the L form used. D-(-)-APB was a weak and relatively non-selective antagonist of amino acid-induced responses. In contrast, L-(+)-APB either had no effect or, at higher concentrations, enhanced these responses. Both isomers depressed synaptic responses in a proportion of the cells tested, the L form being the more potent isomer in producing this effect. Monosynaptic and polysynaptic excitations were both susceptible to this type of action. The depression of synaptic excitation by D-APB may have been due in some cases to the blockade of an excitatory amino acid transmitter. However, it is unlikely that the synaptic depressant action of L-APB is due to this mechanism.

The effects of a series of omega-phosphonic alpha-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations.[Pubmed:7042024]

Br J Pharmacol. 1982 Jan;75(1):65-75.

1 The depressant actions on evoked electrical activity and the excitant amino acid antagonist properties of a range of omega-phosphonic alpha-carboxylic amino acids have been investigated in the isolated spinal cord preparations of the frog or immature rat. 2 When tested on dorsal root-evoked ventral root potentials, members of the homologous series from 2- amino-5-phosphonovaleric acid to 2-amino-8-phosphonooctanoic acid showed depressant actions which correlated with the ability of the substances to antagonize selectivity motoneuronal depolarizations induced by N-methyl-D-aspartate. 3 2-Amino-5-phosphonovalerate was the most potent substance of the series giving an apparent KD of 1.4 microM for the antagonism of responses to N-methyl-D-aspartate. 4 A comparison of the (+)- and (-)-forms of 2-amino-5-phosphonovalerate indicated that the N-methyl-D-aspartate antagonist activity and the neuronal depressant action of this substance were both due mainly to the (-)-isomer. 5 The (-)- and (+)-forms of 2-amino-4-phosphonobutyrate had different actions. The (-)-forms of this substance had a relatively weak and non-selective antagonist action on depolarizations induced by N-methyl-D-aspartate, quisqualate and kainate and a similarly weak depressant effect when tested on evoked electrical activity. The (+)-form was more potent than he (-)-form in depressing electrically evoked activity but did not antagonize responses to amino acid excitants. At concentrations higher than those required to depress electrically evoked activity, the (+)-form produced depolarization. This action was blocked by 2-amino-5-phosphonovalerate.