bibo-3457 and Bradycardia

Neuropeptide Y (NPY) is involved in the regulation of emotionality including fear and anxiety, which modulate autonomic control of cardiovascular function. We therefore investigated the central effects of porcine NPY, selective Y1, Y2 and Y5 receptor agonists and a Y1 receptor antagonist on heart rate (HR) and HR variability in freely moving mice using auditory fear conditioning. Intracerebroventricular (i.c.v.) injections were applied 15 min before the tone-dependent memory test. NPY dose-dependently induced bradycardia associated with decreased HR variability, and blunted the stress-induced tachycardic response. The selective Y1 receptor antagonist BIBO 3304 blocked the NPY- and Y1-receptor agonist-induced suppression of conditioned tachycardia without affecting basal HR. The tachycardia elicited by both conditioned and unconditioned stressor was effectively attenuated by the Y1 receptor agonist. These results suggest a specific contribution of Y1, but not Y2 and Y5 receptors, to modulation of emotional responses most likely unrelated to impairment or modulation of memory. The NPY-induced bradycardia is attributed to not yet characterized NPY receptor subtypes other than Y1, Y2 and Y5, or a complex receptor interaction. In conclusion, NPY mediates central inhibition of sympathetic outflow, potentially coupled with attenuation of parasympathetic tone, i.e., mechanisms that may be associated with the reported anxiolytic action.

Topics: Animals; Arginine; Auditory Perception; Bradycardia; Conditioning, Psychological; Cues; Fear; Heart Rate; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Receptors, Neuropeptide Y; Swine