Calcitonin Gene-related Neuropeptide Research Articles

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice.

Alcohol use disorder (AUD) is a complex psychiatric disease characterized by periods of heavy drinking and periods of withdrawal. Chronic exposure to ethanol causes profound neuroadaptations in the extended amygdala, which cause allostatic changes promoting excessive drinking. The bed nucleus of the stria terminalis (BNST), a brain region involved in both excessive drinking and anxiety-like behavior, shows particularly high levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a key mediator of the stress response. Recently, a role for PACAP in withdrawal-induced alcohol drinking and anxiety-like behavior in alcohol-dependent rats has been proposed; whether the PACAP system of the BNST is also recruited in other models of alcohol addiction and whether it is of local or nonlocal origin is currently unknown. Here, we show that PACAP immunoreactivity is increased selectively in the BNST of C57BL/6J mice exposed to a chronic, intermittent access to ethanol. While pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor-expressing cells were unchanged by chronic alcohol, the levels of a peptide closely related to PACAP, the calcitonin gene-related neuropeptide, were found to also be increased in the BNST. Finally, using a retrograde chemogenetic approach in PACAP-ires-Cre mice, we found that the inhibition of PACAP neuronal afferents to the BNST reduced heavy ethanol drinking. Our data suggest that the PACAP system of the BNST is recruited by chronic, voluntary alcohol drinking in mice and that nonlocally originating PACAP projections to the BNST regulate heavy alcohol intake, indicating that this system may represent a promising target for novel AUD therapies.

Serum calcitonin gene-related neuropeptide (CGRP) in patients with benign and malignant breast lesions: Correlation with mammographic breast density.

78 Background: The aim of this study was to assess the variation of the serum neo-angiogenic neuropeptide CGRP in patients with benign and malignant breast lesions and to evaluate its possible correlation with mammographic findings. Methods: Our study included forty eight women with histologically confirmed breast lesions: mild epithelial hyperplasia (MEH): n=12, florid epithelial hyperplasia (FEH): n=5, atypical hyperplasia (AH): n=4, ductal carcinoma in situ (DCIS): n=5, mixed in situ with invasive ductal carcinoma (DCIS+IDC): n=9 and pure IDC: n=13. Serum CGRP levels were measured by RIA methods and compared among the various groups by Mann-Whitney test. Mammographic breasy density (BD%) was calculated using computer-assisted methods and was correlated with serum CGRP concentration by applying linear regression analysis. Results: Serum CGRP concentration (mean±SD: pg/mL) in the various groups, was: MEH: 96.8±22.5, FEH: 135.5±33.5, AH: 139±44.4, DCIS: 131.4±37.5, DCIS+IDC: 1167.5±927.5, pure IDC: 198±82. DCIS+IDC lesions presented statistically significantly higher serum CGRP levels (versus: MEH p<0.001, FEH p<0.001, AH p<0.001, DCIS p<0.001 and IDC p<0.001). Serum CGRP concentration presented statistically significant correlation with BD% (r=0.947, p<0.0001). Conclusions: Statistically increased serum CGRP concentration was determined in women with DCIS+IDC lesions. The significant correlation between serum CGRP levels and BD, enhances the suggestion that DCIS+IDC represents a distinct pathological entity, associated with an interactive mechanism between BD and serum CGRP expression. Therefore, serum CGRP levels could constitute a future useful preoperative index of the nature or type of suspicious mammographic lesions, in order to schedule the appropriate therapeutic treatment, and potentially propounds the perspective of adjunctive therapeutic administration of anti-CGRP peptides.

A mnemonical or negative-co-operativity model for the activation of adenylate cyclase by a common G-protein-coupled calcitonin-gene-related neuropeptide (CGRP)/amylin receptor

Both amylin and calcitonin-gene-related neuropeptide (CGRP) activated adenylate cyclase activity in hepatocyte membranes around 5-fold in a dose-dependent fashion, with EC50 values of 120 +/- 14 and 0.3 +/- 0.14 nM respectively. Whereas amylin exhibited normal activation kinetics (Hill coefficient, h approximately 1), CGRP showed kinetics indicative of either multiple sites/receptor species having different affinities for this ligand or a single receptor species exhibiting apparent negative co-operativity (h approximately 0.21). The CGRP antagonist CGRP-(8-37)-peptide inhibited adenylate cyclase stimulated by EC50 concentrations of either amylin or CGRP. Inhibition by CGRP-(8-37) was selective in that markedly lower concentrations were required to block the action of amylin (IC50 = 3 +/- 1 nM) compared with that of CGRP itself (IC50 = 120 +/- 11 nM). Dose-effect data for inhibition of CGRP action by CGRP-(8-37) showed normal saturation kinetics (h approximately 1), whereas CGRP-(8-37) inhibited amylin-stimulated adenylate cyclase activity in a fashion which was indicative of either multiple sites or apparent negative co-operativity (h approximately 0.24). Observed changes in the kinetics of inhibition by CGRP-(8-37) of CGRP, but not amylin-stimulated adenylate cyclase, at concentrations of agonists below their EC50 values militated against a model of two distinct populations of non-interacting receptors each able to bind both amylin and CGRP. A kinetic model is proposed whereby a single receptor, capable of being activated by both CGRP and amylin, obeys either a mnemonical kinetic mechanism or one of negative co-operativity with respect to CGRP but not to amylin. The relative merits of these two models are discussed together with a proposal suggesting that the activation of adenylate cyclase by various G-protein-linked receptors may be described by a mnemonical model mechanism.