Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression

Guscott, Martin R.; Bristow, Linda J.; Hadingham, Karen L.; Rosahl, Thomas W.; Beer, Margaret S.; Stanton, Josephine A.; Bromidge, Frances A.; Owens, Andrew; Huscroft, Ian T.; Myers, Janice; Rupniak, N. M. J.; Patel, Shil; Whiting, Paul J.; Hutson, Peter H.; Fone, Kevin C. F.; Biello, Stephany M.; Kulagowski, Janusz J.; McAllister, George

doi:10.1016/j.neuropharm.2004.11.015

Cited by 203 publications

(161 citation statements)

References 43 publications

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“…Still, even in hamsters there are actions of serotonin on the circadian system mediated at the level of the SCN (Weber et al 1998), and serotonin agonists reset the mouse SCN in vitro (Prosser 2003). The mechanism by which serotonin agonists reset the circadian clock in vitro is still unclear, and may involve the 5HT 1A , 5HT 5A and 5HT 7 receptor subtypes (Sprouse et al 2005;Guscott et al 2005). The agonist 8-OH-DPAT can act on both the 5HT 1A and 5HT 7 subtype.…”

Section: Discussionmentioning

confidence: 99%

“…With the exception of NPY, NMDA and DPAT which have shown to reset the mammalian circadian clock of the mouse in a manner similar to hamsters and/or rats (Guscott et al 2005;Soscia and Harrington 2004), the other transmitters have not been shown to be effective as resetting agents within the mouse SCN. Testing these agents in mice is particularly important as much circadian work now takes advantage of developed molecular tools only available in the mouse model.…”

Section: Discussionmentioning

confidence: 99%

“…Glutamate 10 −3 M microdrop (Biello et al 1997a Neurochemicals that phase shift in a pattern similar to behavioural stimuli: (Guscott et al 2005) Muscimol 10 μM bath (Tominaga et al 1994) Data analysis Initially the average firing rate of each cell recorded from one slice was plotted against the ZT of the recording. Slices without significant differences across firing rate data grouped into 1-h (ZT) bins (p<0.05; ANOVA) were not used for further analysis.…”

Section: Methodsmentioning

confidence: 99%

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Circadian clock resetting in the mouse changes with age

Biello

2009

AGE

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The most widely recognised consequence of normal age-related changes in biological timing is the sleep disruption that appears in old age and diminishes the quality of life. These sleep disorders are part of the normal ageing process and consist primarily of increased amounts of wakefulness and reduced amounts of deep sleep. Changes in the amplitude and timing of the sleep-wake cycle appear to represent, at least in part, a loss of effective circadian regulation of sleep. Understanding alterations in the characteristics of stimuli that help to consolidate internal rhythms will lead to recommendations to improve synchronisation in old age. Converging evidence from both human and animal studies indicate that senescence is associated with alterations in the neural structure thought to be primarily responsible for the generation of the circadian oscillation, the suprachiasmatic nuclei (SCN). Work has shown that there are changes in the anatomy, physiology and ability of the clock to reset in response to stimuli with age. Therefore it is possible that at least some of the observed age-related changes in sleep and circadian timing could be mediated at the level of the SCN. The SCN contain a circadian clock whose activity can be recorded in vitro for several days. We have tested the response of the circadian clock to a number of neurochemicals that reset the clock in a manner similar to light, including glutamate, N-methyl-D-aspartate (NMDA), gastrin-releasing peptide (GRP) and histamine (HA). In addition, we have also tested agents which phase shift in a pattern similar to behavioural 'non-photic' signals, including neuropeptide Y (NPY), serotonin (5HT) and gamma-aminobutyric acid (GABA). These were tested on the circadian clock in young and older mice (approximately 4 and 15 months old). We found deficits in the response to specific neurochemicals but not to others in our older mice. These results indicate that some changes seen in the responsiveness of the circadian clock to light with age may be mediated at the level of the SCN. Further, the responsiveness of the circadian clock with age is attenuated to some, but not all stimuli. This suggests that not all clock stimuli loose their effectiveness with age, and that it may be possible to compensate for deficits in clock performance by enhancing the strength of those stimulus pathways which are intact.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Circadian clock resetting in the mouse changes with age

Biello

2009

AGE

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“…The 5-HT 7 receptor subtype, the most recently cloned of the serotonin receptor subtypes, modulates many physiological and behavioral functions, including circadian rhythms (Ehlen et al, 2001;Duncan et al, 2004;, rapid eye movement (REM) sleep (Hagan et al, 2000;Thomas et al, 2003;Monti and Jantos, 2006), body temperature (Hedlund et al, 2003), learning and memory (Roberts et al, 2004), and behavior (Guscott et al, 2005;Hedlund et al, 2005). For example, administration of the 5-HT 7 receptor-selective antagonists, SB-269970-A or DR-4004, to hamsters blocks phase advances of circadian locomotor activity rhythms induced by the serotonergic agonists, 8-OH-DPAT or 5-carboxamidotryptamine, demonstrating that pharmacological activation of 5-HT 7 receptors stimulates circadian phase resetting (Ehlen et al, 2001;Duncan et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Also, administration of 5-HT 7 receptor-selective antagonists to guinea pigs or rats selectively decreases REM sleep, suggesting that endogenous serotonin acting at 5-HT 7 receptors exerts a tonic inhibition on REM sleep (Hagan et al, 2000;Thomas et al, 2003;Monti and Jantos, 2006). Furthermore, studies in mice have shown that deletion of the 5-HT 7 receptor gene impairs memory and learning (Roberts et al, 2004), reduces immobility in the Porsolt swim test, similar to antidepressants (Guscott et al, 2005;Hedlund et al, 2005), and inhibits hypothermia induced by 8-OH-DPAT (Hedlund et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Expression of 5-HT7 receptor mRNA in the hamster brain: Effect of aging and association with calbindin-D28K expression

Duncan

Franklin

2007

Brain Research

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Aging affects several processes modulated by the 5-HT 7 receptor subtype, including circadian rhythms, learning and memory, and depression. Previously, we showed that aging induces a decrease in the hamster dorsal raphe (DRN) in both 5-HT 7 receptor binding and circadian phase resetting responses to 8-OH-DPAT microinjection. To elucidate the mechanisms underlying the aging decrease in 5-HT 7 receptors, we investigated aging modulation of 5-HT 7 receptor mRNA expression in the DRN, brain regions afferent to the DRN, and brain regions regulating circadian rhythms or memory. In situ hybridization for 5-HT 7 receptor mRNA was performed on coronal sections prepared from the brains of young, middle-aged, and old male Syrian hamsters. 5-HT 7 receptor mRNA expression was quantified by densitometry of X-ray film autoradiograms. The results showed that aging did not significantly affect 5-HT 7 receptor mRNA expression in the DRN or most other brain regions examined, with the exception of the cingulate cortex and paraventricular thalamic nucleus. Within the suprachiasmatic nucleus, the site of the master circadian pacemaker in mammals, 5-HT 7 receptor mRNA expression was localized in a discrete subregion resembling the calbindin subnucleus previously described. A second experiment using adjacent tissue sections showed that 5-HT 7 receptor mRNA and calbindin mRNAs were concentrated in the same region of the SCN, and as well as in the same region of several other brain structures. The localization of 5-HT 7 receptors and calbindin mRNAs within the same regions suggests that proteins they encode may interact to modulate processes such as circadian timekeeping.

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