Aims: 

Literature data on the role of pituitary adenylate-cyclase activating polypeptide (PACAP) in behavioral abnormalities and psychiatric disorders are contradictory. The various experimental behavioral anomalies could be explained by a hypothetic modulatory role of PACAP on neuronal activation in stress-related brain centers.

Methods: 

We performed functional studies on PACAP deficient (PACAP^-/-) and wild type (PACAP^+/+) mice in anxiety tests [e.g. light-dark box (LDB), marble burying (MB), open field (OF)] and in forced swim test (FST) for depression-like behavior. Two hours after FST mice were perfused for immunocytochemistry and the immediate-early activation marker c-Fos expression was quantified by cell counting in stress-related brain centers.

Results: 

PACAP^-/- mice in OF showed two times higher locomotor activity, they spent 30% longer time in the lit area of LDB, moreover, they buried 44% less marbles. In FST PACAP^-/- mice showed significantly increased immobility time. However, stress in both groups effectively increased the number of c-Fos immunoreactive neurons in the oval, anterolateral and anteromedial divisions of the bed nucleus of the stria terminalis (BNST), in the dorsal raphe (DR), Edinger-Westphal (EW) nuclei, and in the ventral part of the lateral septum (LSv); in PACAP deficiency the rise in neuronal activation was blunted by about 50% compared to the PACAP^+/+ group. In the periaqueductal gray matter (PAG), in the paraventricular nucleus of the hypothalamus (PVN) and in the basolateral nucleus of the amygdala (BLA) the c-Fos expression was not affected by PACAP deficiency per se, but we found significant interaction between stress and PACAP genotype in these brain centers of stress adaptation.

Conclusion: 

According to our results PACAP modulates the neuronal activation of the BNST, DR, EW and LSv, therefore it might have an important role in anxiety, stress-related behavior and mood disorders.