Browsing by Author "Antle, Michael C"

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    Activation of M1/4 receptors phase advances the hamster circadian clock during the day
    (Elsevier, 2016-05-16) Basu, Priyoneel; Wensel, Adrienne L; McKibbon, Reid; Lefebvre, Nicole; Antle, Michael C
    The mammalian circadian clock in the suprachiasmatic nucleus (SCN) can be reset by the cholinergic agonist carbachol. In hamsters, intraSCN carbachol produces phase advances during the day. This phenomenon has previously been attributed to the muscarinic receptors, as carbachol-induced phase shifts are blocked by pretreatment with the muscarinic antagonist atropine. The SCN contains all five muscarinic receptors, leaving open the question as to which muscarinic receptors mediate these shifts. Here we test two selective muscarinic agonists, the M1/4 agonist McN-A-343 and the M2/3 agonist bethanechol, in addition to the non-selective cholinergic agonist carbachol. Consistent with previous reports, carbachol produced significant phase advances when injected to the SCN during the mid-subjective day. At the doses used here, McN-A-343, but not bethanechol, also produced significant phase shifts when injected to the SCN during the mid-subjective day. Phase shifts to McN-A-343 were as large as those produced by carbachol, suggesting that activation of the M1/4 receptors alone can fully account for the daytime phase advances produced by cholinergic agonists. Given acetylcholine’s role in arousal, and the similarity between phase advances to carbachol/McN-A-343 and to exercise and arousal manipulations, it is possible that acetylcholine may contribute to non-photic resetting of the circadian clock.
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    Chronic BMY7378 treatment alters behavioral circadian rhythms
    (Wiley, 2017-10-17) Vijaya Shankara, Jhenkruthie; Orr, Angélique; Mychasiuk, Richelle; Antle, Michael C
    The mammalian circadian clock is synchronized to the day:night cycle by light. Serotonin modulates the circadian effects of light, with agonists inhibiting response to light and antagonists enhancing responses to light. A special class of serotonergic compounds, the mixed 5-HT1A agonist/antagonists, potentiate light-induced phase advances by up to 400% when administered acutely. In this study, we examine the effects of one of these mixed 5-HT1A agonist/antagonists, BMY7378, when administered chronically. Thirty adult male hamsters were administered either vehicle or BMY7378 via surgically implanted osmotic minipumps over a period of 28 days. In a light:dark cycle, chronic BMY7378 advanced the phase angle of entrainment, prolonged the duration of the active phase, and attenuated the amplitude of the wheel running rhythm during the early night. In constant darkness, chronic treatment with BMY7378 significantly attenuated light-induced phase advances, but had no significant effect on light-induced phase delays. Non-photic phase shifts to daytime administration of a 5-HT1A/7 agonist were also attenuated by chronic BMY7378 treatment. qRT-PCR analysis revealed that chronic BMY7378 treatment upregulated mRNA for 5-HT1A and 5-HT1B receptors in the hypothalamus, and downregulated mRNA for 5-HT1A and monoamine oxidase-A in the brainstem. These results highlight adaptive changes of serotonin receptors in the brain to chronic treatment with BMY7378, and link such up- and down-regulation to changes in important circadian parameters. Such long-term changes to the circadian system should be considered when patients are treated chronically with drugs that alter serotonergic function.
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    Phase shifts to light are altered by antagonists to neuropeptide receptors
    (Elsevier, 2016-07-07) Chan, Ryan K; Sterniczuk, Roxanne; Enkhbold, Yaruuna; Jeffers, Ryan T; Basu, Priyoneel; Duong, Bryan; Chow, Sue-Len; Smith, Victoria M; Antle, Michael C
    The mammalian circadian clock in the suprachiasmatic nucleus (SCN) is a heterogeneous structure. Two key populations of cells that receive retinal input and are believed to participate in circadian responses to light are cells that contain vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP). VIP acts primarily through the VPAC2 receptor while GRP works primarily through the BB2 receptor. Both VIP and GRP phase shift the circadian clock in a manner similar to light when applied to the SCN, both in vivo and in vitro, indicating that they are sufficient to elicit photic-like phase shifts. However, it is not known if they are necessary signals for light to elicit phase shifts. Here we test the hypothesis that GRP and VIP are necessary signaling components for photic phase shifting the hamster circadian clock by testing two antagonists for each of these neuropeptides. The BB2 antagonist PD176252 had no effect on light-induced delays on its own, while the BB2 antagonist RC-3095 had the unexpected effect of significantly potentiating both phase delays and advances. Neither of the VIP antagonists ([D-p-Cl-Phe6, Leu17]-VIP, or PG99-465) altered phase shifting responses to light on its own. When the BB2 antagonist PD176252 and the VPAC2 antagonist PG99-465 were delivered together to the SCN, phase delays were significantly attenuated. These results indicate that photic phase shifting requires participation of either VIP or GRP, and only when signaling in both pathways is inhibited are phase shifts to light impaired. Additionally, the unexpected potentiation of light induced phase shifts by RC-3095 should be investigated further for potential chronobiotic applications.
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    Serotonergic enhancement of circadian responses to light: Role of the raphe and intergeniculate leaflet
    (Wiley, 2015-11) Smith, Victoria M; Jeffers, Ryan T; Antle, Michael C
    Light serves as the primary stimulus that synchronizes the circadian clock in the suprachiasmatic nucleus (SCN) to the external day-night cycle. Appropriately timed light exposure can reset the phase of the circadian clock. Some serotonergic drugs that bind to the 5-HT1A receptor can enhance phase shifts to light. The mechanism by which this potentiation occurs is not well understood. In this study we examine where in the hamster brain one of these drugs, BMY7378, might be working. Systemic (5 mg/kg), intradorsal raphe and intra-median raphe (both 15.6 nmol in 0.5 μl), but not intra-SCN (7.8 nmol or 15.6 nmol in 0.5 μl) injections of BMY7378 significantly potentiated phase shifts to light. Potentiation of photic shifts persisted when serotonergic innervation of the SCN was lesioned with infusions of the serotonin neurotoxin 5,7-dihydroxytryptamine into the SCN. Light-induced c-Fos expression in the rostral and caudal intergeniculate leaflet (IGL) was attenuated with systemic BMY7378, suggesting that the IGL may be involved in this response. Both complete IGL lesions and depletion of serotonergic innervation of the IGL prevented systemic BMY7378 from potentiating photic phase shifts. Together these findings suggest that the mechanism by which BMY7378 enhances photic responses is by changing the activity of the raphe nuclei to influence how the IGL responds to light, which subsequently influences the SCN as one of its downstream targets. Identification of the network that underlies this potentiation could lead to the development of useful therapeutic interventions for treating sleep and circadian disorders