piperidines and 4-(2--pyridyldithio)benzyldiazoacetate

Topics: Animals; Diazonium Compounds; Female; Long-Term Synaptic Depression; Phenols; Piperidines; Pyridines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Presynaptic; Sulfonamides; Vestibular Nuclei

Thin basal dendrites can strongly influence neuronal output via generation of dendritic spikes. It was recently postulated that glial processes actively support dendritic spikes by either ceasing glutamate uptake or by actively releasing glutamate and adenosine triphosphate (ATP). We used calcium imaging to study the role of NR2C/D-containing N-methyl-d-aspartate (NMDA) receptors and adenosine A1 receptors in the generation of dendritic NMDA spikes and plateau potentials in basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. We found that NR2C/D glutamate receptor subunits contribute to the amplitude of synaptically evoked NMDA spikes. Dendritic calcium signals associated with glutamate-evoked dendritic plateau potentials were significantly shortened upon application of the NR2C/D receptor antagonist PPDA, suggesting that NR2C/D receptors prolong the duration of calcium influx during dendritic spiking. In contrast to NR2C/D receptors, adenosine A1 receptors act to abbreviate dendritic and somatic signals via the activation of dendritic K(+) current. This current is characterized as a slow-activating outward-rectifying voltage- and adenosine-gated current, insensitive to 4-aminopyridine but sensitive to TEA. Our data support the hypothesis that the release of glutamate and ATP from neurons or glia contribute to initiation, maintenance and termination of local dendritic glutamate-mediated regenerative potentials.

Topics: Animals; Dendrites; Diazonium Compounds; Glutamic Acid; Mice; N-Methylaspartate; Piperidines; Prefrontal Cortex; Pyramidal Cells; Pyridines; Receptor, Adenosine A1; Receptors, N-Methyl-D-Aspartate; Synaptic Potentials

Amyloid β-protein (Aβ) in the brain of Alzheimer's disease (AD) potently inhibits the synaptic plasticity subsequently causing the cognitive deficits. Long-term potentiation (LTP) of synaptic transmission is thought to be an important cellular mechanism underlying memory formation. Different NR2 subunits are involved in NMDA receptor-dependent LTP. In the present study, we investigated the roles of NR2B and NR2D-containing NMDAR on Aβ(1-42)-induced LTP deficits in the hippocampal slices of rats by using selective NMDAR antagonists. First, we found that Aβ(1-42) significantly inhibited the LTP in the dentate gyrus of slices as reported before. Following that the Aβ(1-42)-induced LTP inhibition was prevented by the pre-perfusion of the specific NR2B-containing NMDAR antagonists ifenprodil (approximately >200-fold selectivity for NR2B) and Ro25-6981 (>3,000-fold selectivity for NR2B), as well as PPDA, a specific NR2D receptor antagonist. Meanwhile, the antagonists on their own had no or only partial effects on the normal LTP in the same dose condition. These findings not only support the effects of NR2B and NR2D subunits on Aβ(1-42)-induced LTP deficits, but also imply that preferentially targeting NR2B- and NR2D-containing NMDARs may provide an effective means to prevent cognitive deficits in the early AD.

Topics: Amyloid beta-Peptides; Animals; Dentate Gyrus; Diazonium Compounds; Excitatory Amino Acid Antagonists; Long-Term Potentiation; Male; Peptide Fragments; Piperidines; Pyridines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

We investigated the role of the central NMDA receptor NR2 subunits in the modulation of nociceptive behavior and p-p38 MAPK expression in a rat model with compression of the trigeminal nerve root. To address this possibility, changes in air-puff thresholds and pin-prick scores were determined following an intracisternal administration of NR2 subunit antagonists. We also examined effects of NR2 subunit antagonists on the p-p38 MAPK expression.. Experiments were carried out using male Sprague-Dawley rats weighing (200-230 g). Compression of the trigeminal nerve root was performed under pentobarbital sodium (40 mg/kg) anesthesia. Compression of the trigeminal nerve root produced distinct nociceptive behavior such as mechanical allodynia and hyperalgesia. Intracisternal administration of 10 or 20 μg of D-AP5 significantly increased the air-puff threshold and decreased the pin-prick scores in a dose-dependent manner. The intracisternal administration of PPPA (1, 10 μg), or PPDA (5, 10 μg) increased the air-puff threshold and decreased the pin-prick scores ipsilateral as well as contralateral to the compression of the trigeminal root. Compression of the trigeminal nerve root upregulated the expression of p-p38 MAPK in the ipsilateral medullary dorsal horn which was diminished by D-AP5, PPPA, PPDA, but not Ro25-6981.. Our findings suggest that central NMDA receptor NR2 subunits play an important role in the central processing of trigeminal neuralgia-like nociception in rats with compression of the trigeminal nerve root. Our data further indicate that the targeted blockade of NR2 subunits is a potentially important new treatments strategy for trigeminal neuralgia-like nociception.

Topics: Animals; Behavior, Animal; Diazonium Compounds; Drug Administration Routes; Male; Motor Activity; Nociceptors; p38 Mitogen-Activated Protein Kinases; Phenols; Phosphorylation; Piperidines; Pyridines; Radiculopathy; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Nerve Roots; Trigeminal Nerve; Up-Regulation