cp-101-606 and 5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1-4-dihydroquinoxaline-2-3-dione

N-methyl-D-aspartate (NMDA) receptors play crucial roles in learning and memory, but the role of each NMDA receptor subtype in a specific cognitive process is unclear. Non-selective blockers of NMDA receptor are used to model the cognitive impairment in schizophrenia and Alzheimer's disease. Counter-intuitively selective NR2A and 2B NMDA receptor antagonists are thought to have pro-cognitive properties. These seemingly contrasting findings might in part be the result of different compounds and behavioral measures used across studies.. We compared the effect of NVP-AAM077 (NR2A antagonist), CP 101-606 (NR2B antagonist), and MK-801 (non-selective antagonist) in a series of touch screen tasks that can be used to measure spatial cognition and cognitive flexibility.. NVP-AAM077, CP 101-606, and MK-801 were administered prior to testing, in adult male Lister-hooded rats trained in tasks of location discrimination, paired associate learning (PAL), and trial unique non-match to location (TUNL).. Results showed that MK-801 impaired performance on all the tasks. In contrast, CP 101-606 only impaired reversal learning in location discrimination and had minimal effect on working memory in TUNL and caused a modest improvement in accuracy in PAL and acquisition of a spatial discrimination. NVP-AAM077 had little effect on performance across tasks, although these data allude to a potential enhancement of acquisition of a spatial location and impairments in spatial reversal learning in a separation-dependent manner.. These data demonstrated that non-selective NMDA antagonism will disrupt numerous aspects of cognitive function. However, selective antagonism is capable of impairing or enhancing cognitive function in a task-dependent fashion.

Topics: Animals; Association Learning; Cognition; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Piperidines; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate; Spatial Memory

Within the amygdala, most N-methyl-D-aspartic acid (NMDA) receptors consist of NR1 subunits in combination with either NR2A or NR2B subunits. Because the particular subunit composition greatly influences the receptors' properties, we investigated the contribution of both subtypes to fear conditioning and expression. To do so, we infused the NR1/NR2B receptor antagonist CP101,606 (0.5, 1.5, or 4.5 microg/amygdala) or the NR1/NR2A-preferring antagonist NVP-AAM077 (0.075, 0.25, 0.75, or 2.5 microg/amygdala) into the amygdala prior to either fear conditioning (i.e., light-shock pairings) or fear-potentiated startle testing. CP101,606 nonmonotonically disrupted fear conditioning but did not disrupt fear expression. NVP-AAM077 dose-dependently disrupted fear conditioning as well as fear expression. The results suggest that amygdala NR1/NR2B receptors play a special role in fear memory formation, whereas NR1/NR2A receptors participate more generally in synaptic transmission.

Topics: Amygdala; Animals; Conditioning, Psychological; Dose-Response Relationship, Drug; Fear; Male; Piperidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Reflex, Startle

NMDA receptor (NMDAR) 2A (NR2A)- and NR2B-type NMDARs coexist in synapses of CA1 pyramidal cells. Recent studies using pharmacological blockade of NMDAR subtypes proposed that the NR2A type is responsible for inducing long-term potentiation (LTP), whereas the NR2B type induces long-term depression (LTD). This contrasts with the finding in genetically modified mice that NR2B-type NMDARs induce LTP when NR2A signaling is absent or impaired, although compensatory mechanisms might have contributed to this result. We therefore assessed the contribution of the two NMDAR subtypes to LTP in mouse hippocampal slices by different induction protocols and in the presence of NMDAR antagonists, including the NR2A-type blocker NVP-AAM077, for which an optimal concentration for subtype selectivity was determined on recombinant and native NMDARs. Partial blockade of NMDA EPSCs by 40%, either by preferentially antagonizing NR2A- or NR2B-type NMDARs or by the nonselective antagonist D-AP-5, did not impair LTP, demonstrating that hippocampal LTP induction can be generated by either NMDAR subtype.

Topics: Animals; Cell Line; Electric Stimulation; Excitatory Postsynaptic Potentials; Hippocampus; Humans; Kidney; Long-Term Potentiation; Mice; Organ Culture Techniques; Piperidines; Pyramidal Cells; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Transfection