Chronic BMY7378 treatment alters behavioral circadian rhythms

Abstract

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-HT_1A 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-HT_1A 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-HT_1A/7 agonist were also attenuated by chronic BMY7378 treatment. qRT-PCR analysis revealed that chronic BMY7378 treatment upregulated mRNA for 5-HT_1A and 5-HT_1B receptors in the hypothalamus, and downregulated mRNA for 5-HT_1A 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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