Calcitonin Gene-Related Peptide (CGRP) is a vasodilatory peptide that has been detected at high levels in the skin, blood, and cerebral spinal fluid under a variety of inflammatory and chronic pain conditions, presumably derived from peptidergic C and Aδ innervation. Herein, CGRP immunolabeling (IL) was detected in epidermal keratinocytes at levels that were especially high and widespread in the skin of humans from locations afflicted with postherpetic neuralgia (PHN) and complex region pain syndrome type 1 (CRPS), of monkeys infected with simian immunodeficiency virus, and of rats subjected to L5/L6 spinal nerve ligation, sciatic nerve chronic constriction, and subcutaneous injection of Complete Freund’s Adjuvant. Increased CGRP-IL was also detected in epidermal keratinocytes of transgenic mice with keratin-14 promoter driven overexpression of noggin, an antagonist to BMP-4 signaling. Transcriptome microarray, qPCR, and Western blot analyses using laser captured mouse epidermis from transgenics, monolayer cultures of human and mouse keratinocytes, and multilayer human keratinocyte organotypic cultures, revealed that keratinocytes express predominantly the beta isoform of CGRP. Cutaneous peptidergic innervation has been shown to express predominantly the alpha isoform of CGRP. Keratinocytes also express the cognate CGRP receptor components, CRLR, RAMP1, and RCP, consistent with known observations that CGRP promotes several functional changes in keratinocytes, including proliferation and cytokine production. Our results indicate that keratinocyte derived CGRPβ may modulate epidermal homeostasis through autocrine/paracrine signaling and may contribute to chronic pain under pathological conditions.

The Coolidge effect describes the reinitiation of sexual behavior in a "sexually satiated" animal in response to a novel receptive mate. Given the role of the mesolimbic dopamine (DA) system in the initiation and maintenance of motivated behavior, microdialysis was used to monitor nucleus accumbens (NAC) DA transmission during copulation, sexual satiety, and the reinitiation of sexual behavior. In agreement with earlier reports, the presentation of an estrous female behind a screen and copulation were associated with significant increases in NAC DA efflux. Return of NAC DA concentrations to baseline values coincided with a period of sexual satiety, although concentrations of the DA metabolites, dihydroxyphenylacetic acid and homovanillic acid, remained elevated. The presentation of a novel receptive female behind a screen resulted in a slight increase in NAC DA, which was augmented significantly during renewed copulation with the novel female. The present data suggest that the stimulus properties of a novel receptive female may serve to increase NAC DA transmission in a sexually satiated male rat, and this, in turn, may be related to the reinitiation of sexual behavior.

Cystic fibrosis (CF) is a multi-organ disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In patients with CF, abnormalities initiate in several organs prior to birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)-responsive CFTRG551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in pancreas, intestine, and male reproductive tract. Homozygous CFTRG551D/G551D animals showed the greatest VX-770-mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival and reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first two weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment.

Behavioral sensitization caused by repeated and intermittent administration of psychostimulants, such as cocaine and D-amphetamine, is accompanied by enhanced function in limbic-motor circuitry that is involved in the generation of motivated behavior. The present microdialysis study investigated the effect of D-amphetamine-induced sensitization on dopamine (DA) efflux in the nucleus accumbens (NAC) of male rats during sexual behavior. Male rats were given one injection of D-amphetamine (1.5 mg/kg, i.p.) or saline every other day for a total of 10 injections. Three weeks after discontinuation of drug treatment, rats were tested for sexual behavior during a test in which microdialysis was performed. There was an augmented efflux of DA in the NAC of D-amphetamine-sensitized rats compared with nonsensitized control rats when a receptive female was present behind a screen (35 vs 17%). Sensitized rats exhibited facilitated sexual behavior when the screen was removed, as indicated by a significantly shorter latency to mount and an overall increase in the amount of copulatory behavior. Although there was a significant increase in NAC DA concentrations from baseline in both sensitized and nonsensitized rats during copulation, there was a greater increase in DA efflux in the NAC of sensitized rats during the first 10 min copulatory sample (60 vs 37%). These results demonstrate that behavioral sensitization caused by repeated psychostimulant administration can "cross-sensitize" to a natural behavior, such as sex, and that increased NAC DA release may contribute to the facilitation of appetitive and consummatory aspects of this behavior.

The present study investigated the effect of sensitization, induced by repeated injections of d-amphetamine, on sexual behavior in the naive male rat tested in a drug-free state. Injections of either d-amphetamine (1.5 mg/kg, i.p.) or saline were given every other day for a total of ten injections, and this regimen induced behavioral sensitization of locomotor activity in drug-treated rats. After a 3-week post-drug period, d-amphetamine-treated rats exhibited facilitated sexual behavior, as indicated by shorter latencies to mount and intromit, and a greater percentage of rats copulating. These rats also exhibited a general increase in the amount of copulation. Furthermore, sensitized rats displayed a facilitated acquisition of sexual behavior (i.e. mount and intromission latency <300 s for 3 consecutive days). After repeated sexual experience, rats pre-treated with d-amphetamine also showed an augmented increase in level changes made in anticipation of the presentation of a receptive female. Finally, enhanced sexual behavior was independent of the environment in which repeated administration of d-amphetamine occurred, indicating that facilitation was not a consequence of conditioned associations between drug and test environment. These results demonstrate that behavioral sensitization due to repeated psychostimulant administration can "cross-sensitize" to a natural motivated behavior, such as sex. Furthermore, the subsequent facilitation of anticipatory sexual behavior (i.e. level changes) after repeated experience in rats previously treated with d-amphetamine suggests that behavioral sensitization can influence incentive learning.