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

PAC1 (pituitary adenylate cyclase activating polypeptide type I receptor) is a G-protein-coupled receptor that binds the strongly conserved neuropeptide PACAP (pituitary adenylate cyclase activating polypeptide) with a thousandfold higher affinity than the related peptide VIP (vasoactive intestinal peptide). PAC1 shows strong expression in brain areas which have been implicated in the emotional control of behavior, such as the amygdala, the hypothalamus, the locus coeruleus and the periaqueductal gray. To assess whether PAC1-mediated signaling has an impact on emotional behavior, we analysed two different mutant mouse lines with an ubiquitous or a forebrain-specific inactivation of PAC1 in several testing paradigms modelling general locomotor activity and anxiety-related behavior. We clearly demonstrate that mice with a ubiquitous but not with a forebrain-specific deletion of PAC1 exhibit 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 demonstrated that PAC1 plays a crucial role in contextual fear conditioning. Therefore the finding that PAC1-deficient mice exhibit reduced anxiety is quite exciting, since the receptor and hence its ligand PACAP seem to be important for both, innate and learned fear.