Differential effects of hypocretins on noise-alone versus potentiated startle responses

Hypocretins are recently discovered neuropeptides, synthesized exclusively in the hypothalamus with excitatory efferents to noradrenergic, serotonergic, and GABAergic (gamma-aminobutyric acid) neurons. Hypocretins also increase corticotropin releasing hormone (CRH) secretion. These actions suggest a possible role for hypocretins in the neurobiology of anxiety, fear, or startle mechanisms. We examined the effects of intracerebroventricular (ICV) administration of hypocretin-A and hypocretin-B on behavior in the Startle Potentiated Startle (SPS) paradigm, a repeated measures, non-shock animal model for studying the classically conditioned enhancement of acoustic startle in the rat. SPS has been used to study effects of anxiolytic treatments. Male Sprague-Dawley rats were tested using the SPS paradigm for 3 days (M-W-F). Following training, rats were anesthetized and 26 gauge stainless cannulae were permanently implanted into the lateral ventricle for intracerebroventricular (ICV) infusions. Following 6-9 days of recovery period, the M-W-F SPS testing was resumed. ICV infusion of both Hypocretin-A (1 and 3 nM) and Hypocretin-B (3 and 10 nM) produced significant reduction in Noise Alone Startle amplitude compared to pre-infusion baseline, whereas infusion with vehicle did not affect Noise Alone Startle. The effect of Hypocretin-B was brief (first 10 min post-infusion), whereas the effect of Hypocretin-A persisted across much of the 50 min post-infusion period. Neither Hypocretin-A nor Hypocretin-B significantly altered the magnitude of the SPS response. Contrary to our expectations, hypocretins seems to possess anxiolytic rather than pro-anxiogenic properties, as indicated by decrease in Noise Alone Startle.