Early-life forebrain glucocorticoid receptor overexpression increases anxiety behavior and cocaine sensitization.

Background: Genetic factors and early-life adversity are critical in the etiology of mood disorders and substance abuse. Because of their role in the transduction of stress responses, glucocorticoid hormones and their receptors could serve as both genetic factors and mediators of environmental influences. We have shown that constitutive overexpression of the glucocorticoid receptor (GR) in forebrain results in increased emotional reactivity and lability in mice.

Overexpressing the glucocorticoid receptor in forebrain causes an aging-like neuroendocrine phenotype and mild cognitive dysfunction.

Repeated stress enhances vulnerability to neural dysfunction that is cumulative over the course of the lifespan. This dysfunction contributes to cognitive deficits observed during aging. In addition, aging is associated with dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis, leading to a delayed termination of the stress response.

Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors.

Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate [35S]-GTPgammaS binding in adult rat brain. Orphanin FQ (OFQ) stimulated [35S]-GTPgammaS binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.