CP-101,606, an NR2B subunit selective NMDA receptor antagonist, inhibits NMDA and injury induced c-fos expression and cortical spreading depression in rodents.

(1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606) is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors containing the NR2B subunit. This compound was used to investigate the role of NR2B containing receptors in three responses to NMDA receptor activation in vivo. In mouse, CP-101,606 completely inhibited increases in fos-like immunoreactivity in dentate gyrus caused by a subconvulsant intraperitoneal dose of NMDA. In rat, the compound completely blocked cortical c-fos mRNA induction following focal injury in parietal cortex and the initiation and propagation of electrically induced cortical spreading depression. Inhibition of these responses by CP-101,606 indicates that c-fos induction and cortical spreading depression are dependent on activation of NMDA receptors containing the NR2B subunit. Since NMDA receptor dependent c-fos induction and cortical spreading depression may contribute to neuron loss after focal CNS injury, inhibition of these responses by CP-101,606 may contribute to the neuroprotective efficacy of the compound.

3-Dimensional anatomic relationship of serotonergic and muscarinic receptor binding in the pontine reticular formation of the human infant brainstem.

Cholinergic and serotonergic neurons of the rostral pontine reticular formation have been implicated by animal studies in the modulation of sleep and waking. To define better the spatial relationships between muscarinic and serotonergic receptor binding in the rostral human brainstem, we used 3-dimensional computer reconstructions of serial autoradiographs generated with radioligands to muscarinic and serotonergic receptors. Receptor binding was assessed in a series of 9 human infants, and 3-dimensional reconstructions were performed in a representative infant at 53 postconceptional weeks. The computer reconstructions demonstrated a 3-dimensional distinct pattern in the rostral pontine reticular formation, with high (3H)lysergic acid diethylamide binding to serotonin receptors in the median raphe nucleus flanked by paramedian bands of high (3H)quinuclidinyl benzilate binding to muscarinic cholinergic receptors in the medial nucleus pontis oralis. Based upon comparisons to animal data, we suggest that the muscarinic-serotonergic pattern of receptor binding in the rostral pontine reticular formation represents part of the neurochemical organization of the circuitry involved in the modulation of rapid eye movement (REM) sleep in humans.

Tritiated-naloxone binding to brainstem opioid receptors in the sudden infant death syndrome.

The sudden infant death syndrome (SIDS) is defined as the sudden death of an infant under 1 year of age that remains unexplained after a thorough case investigation, including a complete autopsy. We hypothesized that SIDS is associated with altered 3H - naloxone binding to opioid receptors in brainstem nuclei related to respiratory and autonomic control. We analyzed 3H - naloxone binding in 21 regions in SIDS and control brainstems using quantitative tissue receptor autoradiography. Three groups were analyzed: SIDS (n = 45); acute controls (n = 14); and a chronic group with oxygenation disorders (n = 15). Opioid binding was heavily concentrated in the caudal nucleus of the solitary tract, nucleus parabrachialis medialis, spinal trigeminal nucleus, inferior olive, and interpeduncular nucleus in all cases analyzed (n = 74). The arcuate nucleus on the ventral medullary surface contained negligible binding in all cases (n = 74), and therefore binding was not measurable at this site. We found no significant differences among the three groups in the age-adjusted mean 3H - naloxone binding in 21 brainstem sites analyzed. The only differences we have found to date between SIDS and acute controls are decreases in 3H - quinuclidinyl benzilate binding to muscarinic cholinergic receptors and in 3H - kainate binding to kainate receptors in the arcuate nucleus in alternate sections of this same data set. The present study suggests that there is not a defect in opioid receptor binding in cardiorespiratory nuclei in SIDS brainstems.