Alcohol use disorder (AUD) is a chronic relapsing disease that has a great impact on individual health as well as the socio-economic well-being of the US as an estimated $184 billion dollars are spent annually on AUD related problems. Therefore, finding pharmacotherapeutic targets to alleviate AUDs is of great importance. Recent research shows that the initial motivation to excessively consume alcohol may be reliant upon activation of the brain's positive reinforcement system which is predominantly mediated by dopamine (DA) release from the ventral tegmental area. At some point in the development of AUDs a transition is thought to occur such that motivation to excessively consume alcohol switches from reliance on positive reinforcement to negative reinforcement systems. The extended amygdala, a brain region important in mediating anxiety and stress responses, and corticotrophin releasing factor (CRF), a neurotransmitter thought to be involved in stress reactivity, are thought to be heavily involved in the negative reinforcement pathways required for AUD development. However, the exact nature and neurocircuitry involved in the switch between utilizing positive and negative reinforcement systems during the development of AUDs is not yet known. Recent work from our lab has shown a potentially direct connection between positive and negative reinforcement systems whereby DA can elevate CRF levels in the bed nucleus of the stria terminalis (BNST), a component of the extended amygdala that is often described as a middle manager of information in both the positive and negative reinforcement pathways. Alcohol exposure has long been shown to increase DA levels in many brain regions, including the BNST, which suggests that alcohol exposure would also increase BNST CRF levels. CRF has been shown to increase the excitability of BNST neurons, which has further been shown to increase anxiety-like behaviors in many rodent models. In addition, withdrawal from alcohol exposure has also been shown to increase CRF levels in the BNST and increase anxiety. Furthermore, repeated CRF receptor stimulation has been shown to cause a sensitization of anxiety-like behaviors regulated by the BNST. Therefore, repeated alcohol exposures and withdrawals would be expected to cause increased levels of CRF in the BNST, both via indirect modulation via DA during alcohol exposure and by directly increasing CRF release during withdrawal. This interaction between alcohol DA and CRF is hypothesized to cause a sensitization of BNST CRF receptors and therefore be the initial transition point between positive and negative reinforcement in AUD development. This proposal will integrate electrophysiological, pharmacological, behavioral, and fluorescent imaging techniques to determine if BNST CRF sensitize following chronic intermittent alcohol exposure and which BNST output neurons are affected by this sensitization. Successful completion of these studies may reveal new insights into AUD development and possibly uncover novel targets for future pharmacological interventions in the treatment of this debilitating disease.
Alcoholism is a devastating and costly disease hypothesized to develop due a transition in the neurocircuitry responsible for initial excessive alcohol drinking and latter dependency. One potential transitional component may be a unique pathway in the bed nucleus of the stria terminalis, a brain region involved in the regulation of the separate reward and stress systems, which may be especially sensitive to insults by chronic alcohol exposures and withdrawals. This proposal aims to examine this unique pathway and determine how it may change following repeated alcohol exposures and withdrawals with the goal of revealing novel targets for the development of new and better treatments for alcoholism.
|Silberman, Yuval; Matthews, Robert T; Winder, Danny G (2013) A corticotropin releasing factor pathway for ethanol regulation of the ventral tegmental area in the bed nucleus of the stria terminalis. J Neurosci 33:950-60|
|Wills, Tiffany A; Klug, Jason R; Silberman, Yuval et al. (2012) GluN2B subunit deletion reveals key role in acute and chronic ethanol sensitivity of glutamate synapses in bed nucleus of the stria terminalis. Proc Natl Acad Sci U S A 109:E278-87|