We also demonstrate that PACAP treatment dose dependently

We also demonstrate that PACAP treatment dose-dependently disrupts performance in the 5CSRTT, suggestive of attentional deficits, another core feature of mood and anxiety disorders. Treatment with PACAP (.5–1.0 µg) decreased the percentage of correct responses, increased the percentage of trials in which the rats failed to respond (omission errors), and decreased accuracy (commission errors). This pattern of effects is broadly consistent with gross impairments in attention (49). It has been shown that PACAP affects feeding and weight (19, 50, 51, 52, 53) and locomotor activity (13), raising the possibility that effects on 5CSRTT performance reflect a reduced motivation for the sugar pellets or a motor impairment. However, it Pentamidine dihydrochloride was reported recently that icv administration of 1.0 µg PACAP does not reduce food intake or weight (53), suggesting that the peptide does not alter motivation for food within the dose range used for the current studies. Moreover, PACAP did not increase the latency to collect food reward, a metric that reflects motor performance and motivation to obtain food reinforcement (34, 49, 54); if anything, latency was reduced at the highest dose. Further, PACAP did not affect maximum rates of responding in the ICSS test, suggesting minimal effects on motor capabilities at the doses tested here. Although .5 µg PACAP produced deficits in correct responding following correct and incorrect responses, we found that .25 µg PACAP reduced accuracy only after incorrect responses. There were no statistically significant impairments in any of the traditional metrics at this dose, suggesting that the error-processing analysis is exceptionally sensitive to depressive-like effects. The deficit in posterror behavior adjustments mimics deficits observed in depressed humans and in rats treated with CRF (36) and may be broadly useful for translational studies. Neurons that express CRF are innervated by PACAP-immunoreactive fibers in the paraventricular nucleus and bed nucleus of the stria terminalis (55, 56), and CRF-R antagonism blocks the anxiogenic and anhedonic effects of PACAP (19). Additionally, PACAP-deficient mice have reduced hypothalamic CRF mRNA activation in response to emotional stressors (11). We investigated whether the CRF-R1 antagonist ANT could mitigate the attention deficits induced by PACAP, using a PACAP dose (.5 µg) that produced intermediate performance deficits in the 5CSRTT. Pretreatment with ANT attenuated the effects of PACAP, reaching an intermediate level of performance that was lower than—but not statistically different from—performance after VEH. Although this finding is consistent with the hypothesized interactions between PACAP and CRF systems, other investigators reported that CRF antagonism completely reverses the anhedonic effects of a much higher dose of PACAP (5.0 µg) in the ICSS test (19). This discrepancy may reflect that PACAP affects motivational and cognitive behaviors through separate neural mechanisms. It is also possible that PACAP effects depend on CRF-R1 and CRF-R2 activation. We used a CRF-1R specific antagonist because CRF-1 receptors have been found to mediate the anxiety-like effects of CRF (57). Accumulating evidence suggests that stress-related effects of CRF are also mediated by KORs (58) and that JDTic attenuates CRF effects in the 5CSRTT (39). We show in the present study that JDTic does not block the effects of PACAP on attention but may partially block the effects of PACAP on posterror adjustments in the 5CSRTT, a potentially more sensitive measure of depressive-like behavior. These data suggest that stress-related PACAP and CRF circuitries may overlap more completely in the regulation of specific domains (e.g., anhedonia). A more detailed understanding of this interaction awaits the development of small molecule PACAP antagonists that can be given systemically. In conclusion, our results show that icv PACAP administration has profound effects on cognitive behaviors that represent domains often dysregulated in mood and anxiety disorders. It is unknown at the present time which brain regions mediate the specific drug effects observed; characterization of PACAP effects on these individual behaviors provides an important first step in the process of identifying the brain circuits involved. In addition to the well-characterized actions of PACAP in the bed nucleus of the stria terminalis, the behavioral effects observed in the present studies provide a rationale for studying effects of PACAP in regions broadly implicated in motivation, emotion, and cognition (e.g., ventral tegmental area, nucleus accumbens, prefrontal cortex, amygdala). Although more work is needed to determine whether the effects of PACAP described here are attributable to different sites or mechanisms, our studies enable a more comprehensive understanding of the degree to which PACAP contributes to core signs of mood disorders. A better understanding of the impact and persistence of the effects of PACAP and its ability to regulate CRF systems (59) may facilitate the development of improved treatments for stress-related illness.