Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY Alcohol use disorder is a major public health problem. To date, available treatment options are limited to psychosocial intervention, three FDA approved medications (disulfuram, acamprosate, and naltrexone) and a few drugs approved for other indications, all with relatively small effect sizes. There is a clear need for additional treatments based on a deeper understanding of neurobiological mechanisms. Corticotrophin releasing factor (CRF) is a 41-amino acid neuropeptide produced mainly by neurons of the paraventricular hypothalamus, central amygdala (CeA), and bed nucleus of the stria terminalis (BNST) where it plays an important role in behavioral and physiological responses to stress. CRF has been long implicated in driving excessive ethanol consumption through prior studies that used CRF receptor antagonists in rodents. However, recent attempts to test CRF receptor antagonists as treatments for alcohol craving in humans have been disappointing. Part of this lack of success may be due to inadequate drug-like properties of some compounds and by a need for different human laboratory models that test drug effects on withdrawal and negative reinforcement in dependent subjects. Another reason may be due to the fact that CRF is released from neurons with other peptides and neurotransmitters that may act in synergy to drive excessive drinking. Understanding which of these co-released factors is important necessitates a different strategy that focuses on the CRF neurons themselves rather than on CRF receptors. The lack of genetic access to subpopulations of CRF neurons has made it difficult to study the biology of CRF neurons, the sources of CRF in different brain regions, and the circuitry underlying CRF-regulated behaviors. To fill this gap, we generated a BAC transgenic Wistar rat line in which Cre recombinase is expressed from the Crh gene promoter to enable genetic access to CRF neurons. In this project, we will use these rats to pursue the hypothesis that as animals develop ethanol dependence, CRF neurons in the CeA and BNST promote ethanol consumption through the coordinated release of GABA, CRF, and other neuropeptides. We will examine this hypothesis by selectively activating or inhibiting these neuronal populations and their projections using chemogenetic tools, and we will address the relative importance of the different transmitters and modulators released from these neurons using Cre-dependent RNA interference. Finally, we will investigate the role of repeated ethanol consumption on the transcriptome of these CRF neuronal populations to understand how ethanol changes their phenotype, which should provide us with important new clues as to how they drive excessive drinking. !
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
