EFFERENT MECHANISMS OF DEFENSE RESPONSE FROM THE HYPOTHALAMUS

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The perifornical area of the hypothalamus has been known as the center for defense response, or "fight or flight" response, which is characterized by concomitant rise in arterial blood pressure (AP), heart rate (HR), and respiratory frequency (Rf). We examined whether orexin, a recently identified hypothalamic neuropeptide, contributes to the defense response and basal cardiovascular regulation using orexin knockout mice. Microinjection of a GABA-A receptor antagonist, bicuculline methiodide, to the perifornical area in urethane-anesthetized wild-type mice elicited dose-dependent increases in AP, HR, and Rf. Although similar changes were observed in orexin knockout mice, intensities were smaller and duration was shorter than those in wild-type mice.Moreover, in an awake and freely moving condition, telemeter-indwelling orexin knockout mice showed diminished cardiovascular and behavioral responses to emotional stress in the resident-intruder test. We also found that basal AP in orexin knockout mice was significantly lower by 〜20 mmHg in both anesthetized and awake conditions. Alpha-adrenergic blockade with prazosin or ganglion blockade with hexamethonium cancelled the difference in basal AP. HR and cardiac contractile parameters by echocardiography did not differ between the two strains of mice. These results indicate lower sympathetic vasoconstrictor tone in knockout mice. The present study suggests that orexin-containing neurons in the perifornical area play a crucial role as one of the efferent pathways of defense response and also operate as a regulator of AP at basal condition by activating sympathetic outflow.