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  • In conclusion the results of this investigation suggest that

    2023-01-21

    In conclusion, the results of this investigation suggest that the involvement of PGE2 in the pathogenesis of pulpal inflammation and repair may be related to its induction of cAMP production. PGE2-induced cAMP production in dental pulp cells is mediated by binding to the EP2 receptor, activation of PLC, intracellular calcium release, and calcium-calmodulin signaling to stimulate adenylate cyclase. These results are important for understanding the role of PGE2 in pulpal inflammation and repair and possible future drug intervention by blocking the signal transduction molecules.
    Acknowledgments
    Severe or prolonged stress is linked to the etiology of mood and anxiety disorders such as major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) (, , ). These disorders are often associated with persistent dysregulation of domains including motivation, social behavior, and attention (, ). Despite the broad impact of these illnesses, the mechanisms by which stress induces maladaptive behavioral responses are not fully understood. Pituitary adenylate cyclase–activating polypeptide (PACAP) is a neuropeptide that plays an important role in regulating stress effects and is modified by stressful experiences (, ). PACAP and its cognate receptor (PAC1) are widely expressed in stress- and anxiety-associated THZ531 regions, including the amygdala and bed nucleus of the stria terminalis (, ). In rodents, chronic stress increases expression of PACAP messenger RNA within these regions (, ), raising the possibility that neuroadaptive changes in PACAP systems alter sensitivity to subsequent stressors. Mice that are deficient in PACAP exhibit reduced corticosterone responses (), anxiety-like behavior (, , ), and sensitivity to chronic social defeat stress (). Exogenous PACAP administration produces many of the same physiologic and behavioral effects of severe or chronic stress, including hypothalamic-pituitary adrenal axis activation (), elevations in plasma corticosterone levels (), increases in corticotropin-releasing factor (CRF) expression (), and increases in anxiety-like behavior (, , ). Importantly, a single administration of PACAP produces a persistent (lasting at least 1 week) elevation in the acoustic startle response, a putative indicator of hypervigilance (). PACAP also has been associated with fear responses in humans () and the development of affective disorders, including PTSD (, , ) and MDD (). Thus, PACAP is implicated in both the acute and long-lasting effects of stress. Mood and anxiety disorders involve many domains, including domains affecting motivational, cognitive, and social function. It was reported recently that PACAP produces acute anhedonia (reduced sensitivity to reward), and this effect is dependent on CRF systems (). Considering that psychiatric illnesses are persistent, the present studies were designed to investigate the dose-dependent and time-dependent effects of exogenous PACAP on motivation, social behavior, and attention as assessed by the intracranial self-stimulation (ICSS) test, social interaction (SI) test, and 5-choice serial reaction time task (5CSRTT). Because addiction is often comorbid with stress and anxiety disorders (, ), we also evaluated whether PACAP exposure would affect sensitivity to the reward-related effects of cocaine. Finally, we evaluated whether CRF receptor (CRF-R) or κ opioid receptor (KOR) antagonists attenuate PACAP effects on attention; we focused on this domain because our previous work suggested that it depends critically on interactions between CRF-Rs and KORs (, ). METHODS AND MATERIALS
    Results Thresholds in the ICSS test were dose-dependently increased by PACAP, indicating reduced sensitivity to the rewarding stimulation (anhedonia) (Figure 1A). Effects of PACAP on ICSS thresholds depended on main effects of dose (F3,20 = 5.23, p < .01) and time (F5,100 = 8.09, p < .01). Administration of .5 µg PACAP elevated thresholds 45 (p < .05), 60 (p < .01), and 90 (p < .05) minutes after treatment compared with VEH, whereas 1.0 µg PACAP elevated ICSS thresholds 75 (p < .01) and 90 (p < .05) minutes after treatment. Collapsed across time (F3,20 = 4.68, p < .05) (Figure 1B), PACAP elevated ICSS thresholds in rats treated with .5 µg (p < .05) and 1.0 µg (p < .01). Although PACAP did not affect maximum response rates (Figure 1C), there was a main effect of time (F5,100 = 3.86, p < .01). Collapsed across time, there were no significant differences among treatment groups (Figure 1D). Rats were tested for an additional 7 days without any additional treatment; for clarity, only select days are shown (Figure 1E). The PACAP effects across this time period depended on main effects of dose (F3,20 = 3.53, p < .05) and time (F3,60 = 4.02, p < .05). Administration of .5 µg and 1.0 µg PACAP increased thresholds on PACAP treatment day compared with VEH (all p < .05), but thresholds returned to pretreatment baseline levels the following day. These data indicate that PACAP produces acute but transient anhedonia. Regardless of PACAP dose administered on the treatment day, all rats displayed equivalent sensitivity to the threshold-lowering effects of cocaine (Figure 1F). There was a main effect of time (F3,60 = 12.25, p < .01), but not of PACAP dose (F3,20 = .37, p = .78).