PFTα Previous work established interactions between CRF and

Previous work established interactions between CRF and KOR systems in regulating attention (39). The CRF antagonist ANT attenuated, but did not completely reverse, the effects of PACAP (.5 µg) and did not have any effects on its own (Table 2). There were no significant differences in performance among rats treated with carboxymethylcellulose plus VEH, ANT plus VEH, or ANT plus PACAP. Rats that received ANT pretreatment plus PACAP still displayed nominal deficits, but ANT pretreatment reduced the magnitude of impairment. Pretreatment with JDTic had no effect on PACAP-induced performance deficits in the 5CSRTT (Table 2), although it attenuated the effects of PACAP on postcorrect and posterror processing.
Discussion The present study shows that PACAP disrupts motivation, social behavior, and attention, affecting multiple domains disrupted in mood and anxiety disorders. Specifically, we found that PACAP produces anhedonia (as reflected by increased reward thresholds) in the ICSS test, decreases social behaviors and increases anxiety-like behaviors in the SI test, and disrupts performance in the 5CSRTT. Although PACAP-induced increases in startle are reportedly persistent (9), we demonstrate that PACAP effects on motivation and attention recover by the following day. In contrast, PACAP dysregulation of SI behaviors was long-lasting, suggesting that the neural substrates that regulate this behavior are at least partially independent of the neural substrates regulating motivation and attention. These findings are broadly consistent with previous work demonstrating the role of PACAP in stress-related behaviors and extend our understanding of how this peptide influences aspects of complex cognitive behaviors. We used ICSS to assess whether PACAP produces anhedonia, a core feature of mood and anxiety disorders including MDD and PTSD (4). Treatment with PACAP increased ICSS thresholds 45–60 minutes after infusion, indicating a dose-dependently PFTα in reward sensitivity. Threshold elevations are produced by other manipulations that cause depressive-like behaviors, including chronic social defeat stress (40, 41), drug withdrawal (42), and exogenous CRF (43) or KOR agonists (32); these elevations are thought to reflect decreased motivation or anhedonia (33). Our findings corroborate a more recent report (19) that PACAP produces similar effects in the ICSS test, although at a dose (5.0 µg) that we found produced nonspecific disruptions in behavior (e.g., gross motor impairments that produce paradoxical decreases in the acoustic startle test and nonspecific freezing in the home cage) (unpublished observations). In the present study, we demonstrate that PACAP induces anhedonia at much lower doses (.5–1.0 µg), without affecting motor performance (maximum response rates). We also show that ICSS thresholds had normalized within 24 hours of treatment, which is important considering the persistence and intractability of psychiatric illnesses such as MDD and PTSD. We also demonstrate that prior treatment with PACAP does not alter sensitivity to the reward-related effects of cocaine when rats were tested 1 week after treatment, although PACAP may alter cocaine sensitivity or reinstatement of drug seeking under other conditions (44). Social withdrawal (diminished interest or participation in social activities) is another core feature of mood and anxiety disorders (4). We show that rats treated with .5 µg or 1.0 µg PACAP exhibit decreases in active SI (approach, reciprocal behaviors), which is consistent with other studies showing that exposure to an aversive stimulus (predatory order, CRF infusion, fear conditioning) disrupts SI behaviors in rats (45, 46). Our results are broadly consistent with a report showing PAC1 receptor–deficient mice exhibit increases in affiliative behaviors, implicating endogenous PACAP systems in regulating social behavior (47). Importantly, the SI behaviors of the untreated partner rats were not correlated with the PACAP dose administered to the treatment rats. Treatment with PACAP had no effect on avoidance (fleeing) behavior, suggesting that the decreases in SI are driven by increases in impassive behaviors. Rats treated with the high dose of PACAP (1.0 µg) also exhibited increases in anxiety-like behaviors in the SI test, as reflected by increased time spent in corners. This finding is broadly consistent with the anxiogenic effects of PACAP reported in other tests (6, 7, 19). The SI deficits were evident at a dose (.5 µg) that did not increase overt anxiety-like behavior, suggesting that these behaviors represent distinct domains regulated by separate, yet overlapping, neural circuits (40). Rats that received PACAP continued to exhibit dysregulated social behavior when tested 1 week later with a new partner. The dose-response pattern observed at the acute test was reversed at the 1-week test; rats that had received the highest dose of PACAP (1.0 µg) showed increases in direct SI, whereas rats that received the lowest dose of PACAP (.25 µg) showed nominal decreases in SI behaviors and increases in anxiogenic behaviors. The mechanism of this effect is unclear, although biphasic effects of PACAP on fear expression have been described in a preliminary report (48). In that study, PACAP treatment before fear conditioning produced initial reductions in fear expression followed by progressive increases in freezing across test days. Although the pattern of effects on fear is opposite to the effects observed in the SI test (i.e., long-term increased anxiety vs. decreased anxiety), these data demonstrate that biphasic responses may be a consequence of PACAP-induced neuroadaptations. The observation that PACAP-treated rats tested only at the 1-week time point did not exhibit significant differences in active SI or anxiety-related behavior suggesting that an initial SI exposure is necessary for the development of the long-term pattern observed. However, it is unclear why the pattern of these effects is not uniform across behaviors and why PACAP produces persistent effects in some tests (acoustic startle, SI, fear conditioning), but not others (ICSS, 5CSRTT).