The Effects of α2A-Adrenergic Receptors on Glutamatergic Signaling in the Bed Nucleus of the Stria Terminalis

Abstract

Drug addiction is a chronically relapsing disorder characterized by cycles of drug use, withdrawal, and relapse. Stress-induced relapse of drug use is a significant barrier to curing addiction. The bed nucleus of the stria terminalis (BNST) is a brain region that has been shown to be involved in stress-induced relapse of drug-seeking behavior in rodent models. More specifically, norepinephrine signaling within the BNST has been shown to play a role in stress-induced relapse of drug-seeking. Additionally, α2-adrenergic receptor (AR) agonists within the BNST have been shown to block stress-induced reinstatement. Recently, a clinical trial was done testing the efficacy of a α2A-AR agonist guanfacine in preventing stress-induced relapse of drug-seeking behavior in humans. However, while α2-AR agonists are effective in blocking stress-induced relapse of drug-seeking in rodent models, the efficacy of guanfacine in humans was much less than expected. This decreased efficacy of guanfacine in humans may be due to multiple, possibly competing, effects of guanfacine on synaptic transmission in the BNST. Previously, it has been shown that α2A-ARs in the BNST can heterosynaptically decrease excitatory transmission and can decrease presynaptic release of norepinephrine homosynaptically. Using a combination of optogenetic approaches and immunoelectron microscopy, this dissertation reveals several novel actions of guanfacine in the BNST including 1) a decrease in glutamatergic transmission from the parabrachial nucleus input to the BNST, 2) a relative insensitivity of the basolateral amygdala input to guanfacine, and 3) an increased postsynaptic response mediated by α2A-ARs. This dissertation begins preliminary work to characterize these novel actions of guanfacine in the BNST, but future work outlined in this dissertation will be needed to understand if these actions work together to block stress-induced relapse of drug seeking in rodents or if these actions work at cross purposes. A better understanding of the specific actions of guanfacine in the BNST may allow for more selective targeting of guanfacine that will increase efficacy in preventing stress-induced relapse in humans.