Alcoholism is known to be a chronic relapsing disorder. As alcohol use transitions to dependence, there is a shift in the motivational drive from being initially influenced by positive reinforcement (pleasurable effects from ethanol) to later reliance on negative reinforcement (withdrawal/negative affect from ethanol). One behavior that modulates relapse in dependent subjects during withdrawal is anxiety. Therefore, understanding the mechanisms that contribute to anxiety during withdrawal is critically important to the treatment of alcoholism. A region that is particularly involved in the modulation of anxiety and stress is the extended amygdala (bed nucleus of the stria terminalis;BNST and central nucleus of the amygdala;CeA).These nuclei have been shown to modulate responses to anxiogenic stimuli and stress- induced relapse to drug taking and, therefore, critical to the understanding of ethanol dependence. One neurotransmitter system present in the extended amygdala that is particularly susceptible to the effects of ethanol is glutamate. Multiple lines of evidence have illustrated that acute ethanol administration at pharmacologically relevant doses selectively inhibits glutamate transmission through the NMDA receptor (NMDAR). Further, ethanol also seems to be selectivity more sensitive to NMDARs that contain NR2B (also referred to as the GluN2B) subunit. While there is an inhibition of NMDAR function following acute ethanol, more chronic ethanol administrations either enhance or inhibit glutamate transmission depending on the region evaluated. Several studies have demonstrated that these effects of ethanol on NMDARs occur in regions of the extended amygdala (BNST and CeA). In the CeA, acute ethanol inhibited NMDARs, while chronic ethanol treatment enhanced this inhibition. Further, a NR2B antagonist was able to block this ethanol induced inhibition from acute and chronic ethanol treatment. In the BNST, acute ethanol inhibits NMDAR responses and chronic ethanol exposure enhances their function in an NR2B related manner. Since these regions of the extended amygdala are critical for the modulation of anxiety, it is possible the disrupted glutamate transmission in these regions could contribute to the production of ethanol withdrawal-induced anxiety. The major complication in evaluating the specific role of NR2B in ethanol's effects is the complex pharmacology of NMDARs. These problems can be circumvented with the use of both a conditional and viral knock-out (KO) of NR2B. This proposal will evaluate the requirement of NR2B (with conditional and viral KO of NR2B) in the inhibition of NMDAR function following acute ethanol and the enhancement/inhibition of NMDAR function following chronic treatment (Aim 1). Further, this work will assess the role of the NR2B subunit, with conditional and viral KOs, in basal and withdrawal induced anxiety from chronic ethanol exposure (Aim 2).
Understanding of the development of anxiety during alcohol withdrawal is critical to the prevention of relapse during alcohol abstinence and overall treatment of alcoholism. This project investigates the effects of alcohol on a primary neurotransmitter system (glutamate) in key brain areas (the extended amygdala) known to be important for the development of anxiety. This work will provide information necessary for the development of novel treatments for alcoholism.
|Wills, T A; Kash, T L; Winder, D G (2013) Developmental changes in the acute ethanol sensitivity of glutamatergic and GABAergic transmission in the BNST. Alcohol 47:531-7|
|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|
|Wieczorek, L; Majumdar, D; Wills, T A et al. (2012) Absence of Ca2+-stimulated adenylyl cyclases leads to reduced synaptic plasticity and impaired experience-dependent fear memory. Transl Psychiatry 2:e126|