Altered emotional behavior in PACAP-type-I-receptor-deficient mice

PAC1 (pituitary adenylate cyclase activating polypeptide type I receptor) i s a G-protein-coupled receptor that binds the strongly conserved neuropepti de PACAP (pituitary adenylate cyclase activating polypeptide) with a thousa ndfold higher affinity than the related peptide VIP (vasoactive intestinal peptide). PAC1 shows strong expression in brain areas which have been impli cated in the emotional control of behavior, such as the amygdala, the hypot halamus, the locus coeruleus and the periaqueductal gray. To assess whether PAC1-mediated signaling has an impact on emotional behavior, we analysed t wo different mutant mouse lines with an ubiquitous or a forebrain-specific inactivation of PAC1 in several testing paradigms modelling general locomot or activity and anxiety-related behavior. We clearly demonstrate that mice with a ubiquitous but not with a forebrain-specific deletion of PAC I exhib it elevated locomotor activity and strongly reduced anxiety-like behavior. We could not observe any gross alteration in circadian rhythmicity nor any enhanced sensitivity towards ethanol in the mutant mice. We previously demo nstrated that PAC I plays a crucial role in contextual fear conditioning. T herefore the finding that PAC1-deficient mice exhibit reduced anxiety is qu ite exciting, since the receptor and hence, its ligand PACAP seem to be imp ortant for both, innate and learned fear. (C) 2001 Elsevier Science BY. All rights reserved.