Stress plays an important role in the development and maintenance of alcohol use disorder. In response to stress, corticotropin releasing factor activates the hypothalamic-pituitary-adrenal axis, leading to the subsequent release of glucocorticoids. The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the CRF binding protein (CRFBP), but compared to the receptors the binding protein has been much less investigated. Therefore, identification of the exact contribution of each protein that mediates CRF effects is necessary to design effective therapeutic strategies for alcohol use disorder.
[Photo: Dr. Carolina Haass-Koffler]
The purpose of this study, led by Dr. Carolina Haass-Koffler, assistant professor of behavioral and social sciences and faculty member in the Center for Alcohol and Addiction Studies, was to conduct a series of in vitro/in vivo experiments across different species to define the biologically discrete role of CRFBP in alcohol use disorder. First, to establish the CRFBP role in receptor signaling, the researchers developed a novel chimeric cell-based assay and showed that CFRBP full length can stably be expressed on the plasma membrane. They discovered that only CRFBP (10 kD) fragment is able to potentiate CRF-intracellular Ca2+ release. They also provided evidence that CRHBP gene loss increased ethanol consumption in mice. Then, the researchers demonstrated that selective reduction of CRHBP expression in the center nucleus of the amygdala (CeA) decreased ethanol consumption in ethanol-dependent rats. CRFBP amygdalar downregulation, however, did not attenuate yohimbine-induced ethanol self-administration. This effect was associated with decreased hemodynamic brain activity in the CRFBP-downregulated CeA and increased hemodynamic activity in the caudate putamen during yohimbine administration. Finally, in alcohol-dependent patients, genetic variants related to the CRFBP(10 kD) fragment were associated with greater risk for alcoholism and anxiety, while other genetic variants were associated with reduced risk for anxiety.
The results of this study suggest that CRFBP may possess a dual role: CRFBP(27kD) is responsible for neutralizing CRF effects, while CRFBP(10 kD) has a potential excitatory function. Evaluating the individual functional interaction of each CRFBP fragment with each receptor may elucidate many aspects of stress and alcohol use disorder, and lead to the development of novel effective treatments.
This study was published in Translational Psychiatry, Volume 6 (ahead of print).
For more information: https://www.ncbi.nlm.nih.gov/pubmed/27845775