Histamine Phase Shifts the Hamster Circadian Pacemaker via an NMDA Dependent Mechanism

Abstract

The SCN acts as the central pacemaker for circadian rhythms in mammals. Histamine has been shown to affect circadian rhythms both in vivo and in vitro. We investigated the mechanism by which histamine phase shifts circadian rhythms in vitro. Hypothalamic slices containing the SCN were prepared from golden hamsters, and spontaneous firing rates of individual cells were recorded on the second day in vitro. Application of histamine (1 microM-10 mM) at the extrapolated time of 2 h after lights off (ZT 14) on day 1 in vitro delayed the time of peak firing in a dose-dependent manner. Pre-exposure to the N-methyl-D-aspartate (NMDA) receptor antagonist (+/-)-2-amino-5-phosphonopentanoic acid (AP-5; 100 microM-1 mM) 5 min before histamine (1 microM) was applied to the slice blocked the phase-delaying effects of histamine. Application of the H1 blocker mepryamine (100 nM) or the H2 blocker cimetidine (10 microM) followed by histamine had no effect on the phase delay induced by histamine. In whole cell recordings from acutely dissociated neurons of hamster SCN, histamine (50 microM) was shown to potentiate NMDA-evoked currents by 52 +/- 12%. These experiments demonstrate that histamine phase shifts of the circadian clock are dependent on NMDA receptor activation and that histamine can directly potentiate NMDA currents in SCN neurons. Histamine may alter circadian clock function by acting directly on NMDA receptors, possibly via binding to the polyamine site.

Histamine Potentiates N-Methyl-d-aspartate Receptors by Interacting with an Allosteric Site Distinct from the Polyamine Binding Site

“…However, histamine was 10-fold less potent in synaptosomes (EC 50 ϭ 99 Ϯ 17 M; Table 1), which may result from differences between presynaptic adult versus postsynaptic embryonic NMDARs. Moreover, as shown previously (Vorobjev et al, 1993;Zwart et al, 1996;Meyer et al, 1998), some neurons did not respond to histamine, and their presence in synaptosomes might underestimate the potency of histamine. The magnitude of the histamine-induced potentiation of NMDARs considerably varied among systems.…”

“…Among them, histamine facilitated the NMDA-induced depolarization of projection neurons in cortical slices (Payne and Neuman, 1997). Phase shifts of the circadian clock induced by histamine in slices of the hamster suprachiasmatic nucleus were NMDA-dependent (Meyer et al, 1998). Histamine might also act through NMDARs to facilitate the induction of long-term potentiation (Brown et al, 1995) and to cause long-lasting increases of excitability (Selbach et al, 1997) in the CA1 region of rat hippocampal slices.…”

N-methyl-D-aspartate receptor subunit NR2B is widely expressed throughout the rat diencephalon: An immunohistochemical study

“…Our data suggest that NR2B is likely a component of at least some NMDA-Rs involved in mediating the photic entrainment of SCH neurons. This is also indirectly suggested by the report that HA phase shifts the circadian pacemaker in hamsters by a mechanism that may involve direct actions at NMDA-Rs (Meyer et al, 1998). A direct action of HA at NMDA-Rs may be an indicator of NR2B presence in these cells (Williams, 1994;Sharonova et al, 1996).…”

Circadian clock resetting in the mouse changes with age

“…HA can reset the circadian clock in both rats and hamsters (Harrington et al 2000). In hamsters, these shifts are dependent on NMDA receptor activation, and HA can potentiate NMDA currents within the hamster SCN (Meyer et al 1998).…”