Rationale: The rat fear-potentiated startle (FPS) paradigm is a translational model of conditioned fear involving central amygdala pathways of the brain. Hypothalamic orexin neurons have input-output projections to the amygdala; they modulate vigilance and stress-related responses.
Objective: To investigate whether the transient pharmacological blockade of orexin receptors moderates the conditioned fear response.
Methods: F344 rats received acute oral treatment with the dual orexin receptor antagonist almorexant (30-300 mg/kg) or with one of the clinically effective anxiolytics diazepam (1-10 mg/kg), buspirone (10-100 mg/kg), fluoxetine (3-30 mg/kg), and sertraline (10-100 mg/kg). Drug effects on startle responses were assessed in both fear- and non-fear-conditioned rats; on forepaw grip and horizontal wire motor performance, and on elevated plus maze (EPM) behavior.
Results: Diazepam and almorexant both dose-dependently decreased FPS in the presence of the fear-conditioned stimulus (CS; light) more prominently than background startle in absence of the CS (dark). Diazepam induced myorelaxation and reduced startle responses in control non-fear-conditioned rats. Almorexant had no myorelaxant effects and left startle responses under light in non-fear-conditioned rats intact. On the EPM, diazepam showed anxiolytic-like effects, almorexant not. Buspirone demonstrated anxiolytic-like effects on FPS by simultaneously reducing CS-related startle and increasing no-CS-background startle. Fluoxetine did not affect FPS, whereas sertraline showed anxiogenic-like effects.
Conclusions: Almorexant reduced FPS, but did not affect EPM behavior. Almorexant's overall pattern of effects on FPS was comparable to but less pronounced than that of the anxiolytic benzodiazepine diazepam. The endogenous orexin system actively contributes to fear-conditioned startle reactions in the rat.