Pituitary adenylate cyclase‐activating polypeptide (PACAP) is a neuropeptide with pleiotropic functions. We report here that PACAP‐deficient (PACAP−/−) mice showed increased immobility in a forced swimming test, which was reduced by the antidepressant desipramine, to a similar extent as in wild‐type mice. The atypical antipsychotic risperidone and the selective serotonin (5‐HT)2 antagonist ritanserin normalized the depression‐like behavior in PACAP−/− mice. The 5‐HT2 agonist (±)‐2,5‐dimethoxy‐4‐iodoamphetamine‐induced 5‐HT syndrome was exaggerated in PACAP−/− mice, which suggests a 5‐HT2‐receptor‐dependent mechanism in the depression‐like behavior. The circadian rhythm of plasma corticosterone and body core temperature was significantly flattened in the mutants. mRNA expression of glucocorticoid receptor was reduced in the mutant hippocampus. The present results suggest that alterations in PACAP signaling might contribute to the pathogenesis of certain depressive conditions amenable to atypical antipsychotic drugs.

BackgroundThe photopigment melanopsin has been suggested to act as a dominant photoreceptor in nonvisual photoreception including resetting of the circadian clock (entrainment), direct tuning or masking of vital status (activity, sleep/wake cycles, etc.), and the pupillary light reflex (PLR). Pituitary adenylate cyclase-activating polypeptide (PACAP) is exclusively coexpressed with melanopsin in a small subset of retinal ganglion cells and is predicted to be involved extensively in these responses; however, there were inconsistencies in the previous reports, and its functional role has not been well understood.Methodology/Principal FindingsHere we show that PACAP-deficient mice exhibited severe dysfunctions of entrainment in a time-dependent manner. The abnormalities in the mutant mice were intensity-dependent in phase delay and duration-dependent in phase advance. The knockout mice also displayed blunted masking, which was dependent on lighting conditions, but not completely lost. The dysfunctions of masking in the mutant mice were recovered by infusion of PACAP-38. By contrast, these mutant mice show a normal PLR. We examined the retinal morphology and innervations in the mutant mice, and no apparent changes were observed in melanopsin-immunoreactive cells. These data suggest that the dysfunctions of entrainment and masking were caused by the loss of PACAP, not by the loss of light input itself. Moreover, PACAP-deficient mice express an unusually early onset of activities, from approximately four hours before the dark period, without influencing the phase of the endogenous circadian clock.Conclusions/SignificanceAlthough some groups including us reported the abnormalities in photic entrainments in PACAP- and PAC1-knockout mice, there were inconsistencies in their results [1], [2], [3], [4]. The time-dependent dysfunctions of photic entrainment in the PACAP-knockout mice described in this paper can integrate the incompatible data in previous reports. The recovery of impaired masking by infusion of PACAP-38 in the mutant mice is the first direct evidence of the relationship between PACAP and masking. These results indicate that PACAP regulates particular nonvisual light responses by conveying parametric light information—that is, intensity and duration. The “early-bird” phenotype in the mutant mice originally reported in this paper supposed that PACAP also has a critical role in daily behavioral patterns, especially during the light-to-dark transition period.

Background Vascular targeted photodynamic therapy (PDT) is a novel and promising therapy for the treatment of portwine stains (PWS). There has been little prior exploration to our knowledge of how the dermatological vascular pattern may predict the response to PDT. Objectives To analyse whether the vascular pattern classifications of PWS by dermoscopy can predict the efficacy of PDT. Methods This prospective cohort study included 163 patients with a clinical diagnosis of PWS who were treated twice with hemoporfin-mediated photodynamic therapy (HMME-PDT) at two-month intervals and followed up for 6 months. The vascular manifestations of dermoscopy with PWS were independently classified into 8 categories by 3 dermatologists. Images of the lesions were taken using VISIA, and the vascular patterns were imaged by dermoscopy by the same investigator. Images were captured before and after each treatment. The efficacy was evaluated with pre-and post-treatment VISIA images, and correlations between efficacy and vascular patterns were analysed by four dermatologists in a blinded and independent manner, between 10 January 2019 and 11 December 2019. Results In the dermoscopy images for the whole cohort, dotted and globular vessels (15.3%), short clubbed vessels (18.4%) and curved vessels (12.9%) were highly associated with cure and beneficial treatment effects. Pale halos surrounding brown dots (8.0%) and arborizing vessels (9.8%) were mainly correlated with skin lesion alleviation. Mixed vessels (12.9%), a grey-whitish veil (11.7%) and reticular patterns (11.0%) were mainly associated with no effect. The differences between each subgroup were statistically significant (P = 0.000). Conclusions There is a clear correlation between the efficacy of PDT and the dermoscopy pattern in patients with PWS. Dermoscopy may therefore provide very useful clinical information prior to treatment in these cases. In addition, the vascular manifestations of PWS determined by dermoscopy help to predict response to PDT and manage patient expectations.

Opioid analgesics are the standard therapeutic agents for the treatment of pain, but their prolonged use is limited because of the development of tolerance and dependence. Recently, we reported the development of a -opioid receptor knock-in (KI) mouse in which the -opioid receptor was replaced by a mutant receptor (S196A) using a homologous recombination gene-targeting strategy. In these animals, the opioid antagonist naltrexone elicited antinociceptive effects similar to those of partial agonists acting in wild-type (WT) mice; however, development of tolerance and physical dependence were greatly reduced. In this study, we test the hypothesis that the failure of naltrexone to produce tolerance in these KI mice is attributable to its simultaneous inhibition of ␦-opioid receptors and activation of -opioid receptors. Simultaneous implantation of a morphine pellet and continuous infusion of the ␦-opioid receptor antagonist naltrindole prevented tolerance development to morphine in both WT and KI animals. Moreover, administration of SNC-80 [(ϩ)-4-[(␣R)-␣-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide], a ␦ agonist, in the naltrexonepelleted KI animals resulted in a dose-dependent induction in tolerance development to both morphine-and naltrexone-induced analgesia. We conclude that although simultaneous activation of both -and ␦-opioid receptors results in tolerance development, -opioid receptor activation in conjunction with ␦-opioid receptor blockade significantly attenuates the development of tolerance.