Local repeated corticotropin-releasing factor infusion exacerbates anxiety- and fear-related behavior: differential involvement of the basolateral amygdala and medial prefrontal cortex

Abstract

Increased central corticotropin-releasing factor (CRF) signaling has been associated with various psychiatric symptoms, including anxiety, depression and psychosis. CRF signaling in both the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) has been implicated in anxiety-like behavior. In addition, repeated activation of CRF receptors within the BLA induces a chronic anxious state. Here we studied the effects of local repeated CRF infusion in the BLA and mPFC on different forms of anxiety, as assessed during light-enhanced startle (LES, general anxiety) and acquisition of fear-potentiated startle (FPS, cue-conditioned fear). In addition, as CRF has been implicated in sensorimotor gating, prepulse inhibition (PPI) was assessed to determine if local CRF infusion within the BLA or mPFC would interfere with the processing of sensory information. To this end, canulas were placed bilaterally in either the BLA or mPFC of Wistar rats. After recovery, animals were infused with h/rCRF (200 ng/side) or vehicle for five consecutive days. Long term effects of local CRF infusion on LES and acquisition of FPS were measured 4 and 10 days post-treatment, respectively. In addition, the acute (day 1), sub-chronic (day 5) and long-term (7 days post treatment) effects on PPI were measured in the same animals. A clear regional differentiation was found on the long lasting effect of CRF on anxiety-like behavior: infusion into the BLA only enhanced acquisition of FPS, whereas infusion into the mPFC only enhanced LES. Sub-chronic CRF infusion into the BLA, but not the mPFC, disrupted PPI. This disturbed PPI was normalized 7 days post-treatment. Together, the current study shows that local repeated CRF receptor activation in the BLA and mPFC is differentially involved in anxiety- and fear-related behavior. In addition, the BLA may be involved in CRF-induced sensorimotor gating deficits. The absence of a long-term effect on these PPI deficits suggests that lasting activation of CRF receptors is a prerequisite for CRF-mediated effects on sensorimotor gating. The long-term effects of repeated CRF infusion on LES and acquisition of FPS on the other hand, show that in case of anxiety-related processes repeated CRF infusion may have lasting effects.