Histamine-1 receptor is not required as a downstream effector of orexin-2 receptor in maintenance of basal sleep/wake states.

AIM: The effect of orexin on wakefulness has been suggested to be largely mediated by activation of histaminergic neurones in the tuberomammillary nucleus (TMN) via orexin receptor-2 (OX(2)R). However, orexin receptors in other regions of the brain might also play important roles in maintenance of wakefulness. To dissect the role of the histaminergic system as a downstream mediator of the orexin system in the regulation of sleep/wake states without compensation by the orexin receptor-1 (OX(1)R) mediated pathways, we analysed the phenotype of Histamine-1 receptor (H(1)R) and OX(1)R double-deficient (H(1)R(-/-);OX(1)R(-/-)) mice. These mice lack OX(1)R-mediated pathways in addition to deficiency of H(1)R, which is thought to be the most important system in downstream of OX(2)R. METHODS: We used H(1)R deficient (H(1)R(-/-)) mice, H(1)R(-/-);OX(1)R(-/-) mice, OX(1)R and OX(2)R double-deficient (OX(1)R(-/-);OX(2)R(-/-)) mice, and wild type controls. Rapid eye movement (REM) sleep, non-REM (NREM) sleep and awake states were determined by polygraphic electroencephalographic/electromyographic recording. RESULTS: No abnormality in sleep/wake states was observed in H(1)R(-/-) mice, consistent with previous studies. H(1)R(-/-);OX(1)R(-/-) mice also showed a sleep/wake phenotype comparable to that of wild type mice, while OX(1)R(-/-); OX(2)R(-/-) mice showed severe fragmentation of sleep/wake states. CONCLUSION: Our observations showed that regulation of the sleep/wake states is completely achieved by OX(2)R-expressing neurones without involving H(1)R-mediated pathways. The maintenance of basal physiological sleep/wake states is fully achieved without both H(1) and OX(1) receptors. Downstream pathways of OX(2)R other than the histaminergic system might play an important role in the maintenance of sleep/wake states.

Father-to-mother-to-infant transmission of HIV-1: clonally transmitted isolate of infant mutates more rapidly than that of the mother and rapidly loses reactivity with neutralizing antibody.

The sequences of the V3 loop and surrounding regions of human immunodeficiency virus type-1 from a father-to-mother-to-infant trimmer were studied and the horizontal and vertical transmissions compared. The father's virus was variable for reactivity with neutralizing antibody and sequences of the V3 loop central core sequence. In contrast, the mother's viral sequences were much less diverse and reacted with a virus neutralizing antibody. The infant's viral sequences were also less diverse than those of the father, and N-glycosylation sites were conserved. By phylogenetic analysis, the major clone, of which V3-peptide reacted with the neutralizing antibody, was found to be transmitted from the mother to her infant; however, the mutated minor clones did not bind to the antibody. These findings suggest that both horizontal and vertical virus transmission were selective, and that the clonally transmitted virus in infants mutates more rapidly than viruses in the mother, to whom the virus was horizontally transmitted.