Research reportComparison of the effects of aging on 5-HT7 and 5-HT1A receptors in discrete regions of the circadian timing system in hamsters
Introduction
Many aspects of circadian function change with age. The amplitude of circadian rhythms often decreases during aging, and the phase relationship of rhythms to the environmental time signals also changes 10, 25, 31. Synchrony of circadian rhythms in various functions (e.g., body temperature, activity, and drinking) within an individual may be lost [25]. Furthermore, the aged circadian pacemaker is less responsive to many time cues, especially so-called `non-photic' time cues such as exposure to dark pulses and injections of the benzodiazepam, triazolam [34]. This decreased circadian responsiveness to time cues with aging has important implications for humans, because it suggests that jet lag and rotating work schedules may present a greater challenge for the middle-aged and elderly than for the young adult population.
Laboratory studies have shown that non-photic time cues, such as triazolam injections or exposure to dark pulses, presented during the midsubjective day, stimulate robust phase advances in young adult but not in middle-aged or old hamsters 5, 32, 33, 34. Although lesion studies suggest that two neural systems, NPY neurons and serotonin neurons, mediate the effects of non-photic time cues 2, 8, 18, to date only the latter has been implicated in the age-related loss of sensitivity to non-photic time cues. Studies have shown that systemic administration of the serotonergic agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) mimics non-photic phase shifts in young adult hamsters but is ineffective in old hamsters [19].
The sites and mechanism of action of serotonin for causing non-photic phase shifts of circadian rhythms are not yet completely understood. Two important components of the circadian timing system, the suprachiasmatic nucleus (SCN) and the intergeniculate leaflet (IGL) of the lateral geniculate nucleus (LGN), are possible sites of action of serotonergic induction of phase shifts. Both the SCN and the IGL are innervated by serotonergic neurons located in the midbrain raphe nuclei, i.e., by the median raphe nucleus (MRN) and the dorsal raphe nucleus (DRN), respectively [14]. The SCN is a necessary pacemaker for the generation of overt circadian rhythms, such as circadian rhythms in locomotor activity, drinking behavior, melatonin synthesis and circulating levels of ACTH [13]. The IGL, which sends NPY-ergic projections to the SCN [16], is necessary for non-photic phase shifts 8, 9.
Investigations of the sites and mechanisms of action of serotonin in resetting the circadian pacemaker have been conducted in vitro and in vivo. In vitro studies, in which serotonergic agonists such as 8-OH-DPAT reset the SCN neuronal activity rhythm, demonstrated that the SCN or surrounding tissue can respond directly to the phase-shifting effects of these agents 11, 12, 20, 21, 27. Furthermore, pharmacological studies suggested that the serotonin7 (5-HT7) receptor subtype mediates the serotonergic phase-shift in the SCN in vitro [11]. In contrast to these in vitro studies, the first reported in vivo study of the site of circadian action of 8-OH-DPAT, showed that the MRN and DRN, but not the SCN or the IGL, were sufficient target sites [15]. More recently, bilateral microinjections of 8-OH-DPAT into the SCN or the IGL have been shown to induce small phase shifts [1]. Thus, the SCN, IGL, MRN and DRN may all be sufficient sites of action for the phase-shifting effect of 8-OH-DPAT in vivo. Furthermore, although the site of action of the phase-shifting effect of 8-OH-DPAT in vivo has been investigated, the subtype of serotonin receptor mediating this effect of 8-OH-DPAT in vivo has not been studied. Because 8-OH-DPAT activates the serotonin1A (5-HT1A) receptors as well as the 5-HT7 receptors [11], it is possible that either receptor population might mediate the phase-shifting effects of this drug.
One possible mechanism causing the age-related loss of sensitivity to the circadian phase-resetting effect of 8-OH-DPAT could be a decrease of serotonin receptors in some region(s) of the circadian timing system during aging. Therefore, we hypothesized that aging decreases the 5-HT7 receptors and/or the 5-HT1A receptors. Because the SCN, IGL, MRN and DRN have each been implicated as potential target sites for the phase-shifting effect of 8-OH-DPAT 1, 15, all of these regions were examined. Syrian hamsters were used as the experimental animals because they have been the subjects of many studies concerning aging and the circadian timing system, including studies of the role of serotonin 17, 19.
Section snippets
Animals and tissue preparation
Male Syrian hamsters obtained from Harlan Sprague–Dawley (SYR-HSD) were maintained in our laboratory under a 14 L:10 D photoperiod (lights on at 0600 h) for at least 1–2 weeks. Various ages were studied (Experiment 1: 3, 12 or 15 months old; Experiment 2: 3–4 months and 17–19 months) based on previous findings that Syrian hamsters exhibit changes in 5-HT1B receptors by 12–14 months of age [3]and loss of sensitivity to 8-OH-DPAT by 18 months of age [19]. The hamsters were sacrificed during the
Experiment 1
In this experiment, specific []8-OH-DPAT binding to the 5-HT7 and 5-HT1A receptors was quantified in three groups of hamsters: 3, 12, and 15 months of age. Both receptor subtypes were identified in all of the neuroanatomical components of the circadian timing system which were examined (i.e., the SCN, IGL, MRN and DRN) (Fig. 1). Concerning the IGL, both receptor subtypes were not restricted to this narrow band of tissue, but also appeared to be present in the surrounding LGN. In all regions,
Discussion
The most important result of this study is the finding that aging induces a marked decrease in specific binding of []8-OH-DPAT to the 5-HT7 receptors in the DRN during the midsubjective day. This age-related loss of specific binding of []8-OH-DPAT to the 5-HT7 receptors in the DRN was only observed in hamsters that were 17–19 months of age, the same age at which hamsters exhibit a reduced sensitivity to the phase-shifting effect of 8-OH-DPAT [19]. None of the other regions examined (i.e.,
Acknowledgements
Supported by NIH Grant AG-13418.
References (36)
- et al.
Specific destruction of the serotonergic afferents to the suprachiasmatic nuclei prevents triazolam-induced phase advances of hamster activity rhythms
Behav. Brain Res.
(1994) - et al.
Investigations of the regulation of specific 2-[]iodomelatonin binding sites in Siberian hamsters by endogenous and exogenous melatonin
Brain Res.
(1993) - et al.
Intergeniculate leaflet lesions and behaviorally-induced shifts of circadian rhythms
Brain Res.
(1994) - et al.
A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms
Neuron
(1993) - et al.
Serotonergic regulation of circadian rhythms in Syrian hamsters
Neuroscience
(1997) - et al.
A serotonin neurotoxin attenuates the phase-shifting effects of triazolam on the circadian clock in hamsters
Brain Res.
(1995) - et al.
A serotonin agonist phase-shifts the circadian clock in the suprachiasmatic nuclei in vitro
Brain Res.
(1990) - et al.
Serotonin receptor gene expression in the rat suprachiasmatic nuclei
Brain Res.
(1993) - et al.
Phase-resetting effect of 8-OH-DPAT, a serotonin 1A receptor agonist, on the circadian rhythm of firing rate in the rat suprachiasmatic nuclei in vitro
Brain Res.
(1992) - et al.
Destruction of the hamster serotonergic system by 5,7-DHT: effects on circadian rhythm phase, entrainment and response to triazolam
Brain Res.
(1990)
Serotonergic antagonists impair arousal-induced phase shifts of the circadian system of the Syrian hamster
Brain Res.
Effects of age on the circadian system
Neurosci. Biobehav. Rev.
Aging alters the entraining effects of an activity-inducing stimulus on the circadian clock
Brain Res.
5-HT7 receptors mediate serotonergic effects on light-sensitive suprachiasmatic nucleus neurons
Brain Res.
Roles of suprachiasmatic nuclei and intergeniculate leaflets in mediating the phase-shifting effects of a serotonergic agonist and their photic modulation during the subjective day
J. Biol. Rhythms
The effect of aging on serotonin1B receptors in the suprachiasmatic nuclei and other brain regions
Soc. Neurosc. Abstr.
Dark pulses affect the circadian rhythm of activity in hamsters kept in constant light
Am. J. Physiol.
A receptor autoradiographic and in situ hybridization analysis of the distribution of the 5-HT7 receptor in rat brain
Br. J. Pharmacol.
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