Alpha 1- noradrenergic receptor signalling in the dorsal raphe nucleus is critical for panic -like behaviour and defensive antinociception elicited by GABAergic disinhibition in dorsomedial, lateral and dorsal premammillary hypothalamic nuclei

Abstract

Hypothalamic nuclei are essential for the organisation of fear-induced defensive behaviours oriented to safe places, followed by unconditioned fear-induced antinociception, whereas midbrain tectum structures are associated with non-oriented escape responses. This study aimed to investigate the involvement of the noradrenergic system in both defensive behaviour and fear-induced antinociception. Wistar rats were pre-treated with microinjections of either physiological saline (0.2 µL) or the alpha1-noradrenergic selective antagonist WB4101 (5.0 µg/0.2 µL) into the dorsal raphe nucleus (DRN). After ten minutes, animals received a second microinjection of either physiological saline or bicuculline methiodide (40 ng/200 nL) into one of the following hypothalamic nuclei: dorsomedial (DMH), lateral (LH), or dorsal premammillary (PMd). Fear-induced behaviours were recorded in a circular open-field arena, and nociceptive thresholds were assessed using the tail-flick test for up to 60 min. Microinjections of WB4101 into the DRN resulted in a significant reduction in the frequency and duration of alertness, flat back approach, defensive immobility, and escape behaviours evoked by disinhibition of gamma-aminobutyric acid type A (GABA_A) receptors in the hypothalamic nuclei. Furthermore, a significant reduction in defensive antinociception was observed from 0 to 30 min following the end of hypothalamically orchestrated escape behaviours. These findings suggest that alpha1-noradrenergic receptors in the DRN modulate both defensive behaviour and unconditioned fear-induced antinociception elicited by impaired GABAergic neurotransmission in the hypothalamus.

Keywords: Alpha(1)-noradrenergic receptor; Dorsal raphe nucleus; Hypothalamus; Norepinephrinergic neurotransmission; Unconditioned fear-induced antinociception.