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Effects of central orexin 1 receptor blockade on locus coeruleus neurons with lateral hypothalamic input

The locus coeruleus (LC) receives a major orexinergic input and is densely packed with orexin 1 receptors (OX1‐R). Here we examined the effects of central administration of an OX1‐R antagonist on lateral hypothalamic (LH) stimulation‐induced activation of LC neurons. All experiments were conducted using male Sprague Dawley rats under initial isoflurane (1.7–1.9%) anaesthesia followed by urethane (1.3–1.4 g/kg, i.v.). Electrical stimulation of the LH (0.5 Hz, twin 0.5 ms pulses, 3 ms interpulse interval, 300uA) evoked excitatory responses in all LC neurons studied (n = 24) as judged by construction of peri‐stimulus time histograms. LC neurons responded to LH stimulation with an onset latency of 6.5±0.4 ms and a peak latency of 15.3±0.8 ms. Intracerebroventricular administration of the OX1‐R antagonist SB334867A (10 nmol) but not vehicle inhibited LH stimulation‐induced activation of LC neurons by 58±14% (n = 6 neurons). Abolition of LH stimulation‐induced excitatory responses in LC neurons occasionally (n=3/6) revealed constant latency antidromic responses verified by positive collision tests. These findings indicate that the LC receives a robust excitatory input which is mediated, at least in part, by orexin acting at OX1‐Rs. Furthermore, some LC neurons that receive an orexinergic input also project to the LH region. Supported by the Austin Hospital Medical Research Foundation.