The stress system is well known to play an important role in relapse to drug abuse and excessive eating and is largely controlled by corticotropin hormone receptors (CRHR) and their endogenous ligands. Our studies suggest that CRHR1 antagonists such as antalarmin may be useful in the treatment of human alcohol dependence and relapse to other drugs of abuse. Nonpeptide antagonists of corticotropin hormone receptor system have also been shown to blunt excessive eating in animal models of binge eating with high sucrose low fat diets. We studied 10-minute access to a sweet high fat system and found that CRHR antagonist R121919 did not affect binge eating in this model but that the cannabinoid receptor (CB1) antagonist SR147778 reduced binge-like food intake. Our results indicate that CB1 mediated positive reinforcement rather than stress mechanisms mediate binge eating behavior in this model. In another area, we examined the effect of restraint stress on tau-phosphorylation (tau-p) and solubility, putative indicators of the pathogenesis of Alzheimers disease. Repeated stress produced robust tau-p responses in WT and CRHR2 null mice in contrast to CRFR1 and CRFR double-KO mice where no response was observed. Treatment with the nonpeptide CRFR1 antagonist R121919 attenuated stress induced tau-p and aggregation of tau-p as well as conformational changes in tau. Collectively, these data may suggest a link between stress and an Alzheimers-like pathogenesis in mice.
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