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.