The Role of the Bed Nucleus of the Stria Terminalis-Norepinephrine System in Amphetamine-type Stimulant Use Disorders - PROJECT SUMMARY/ABSTRACT Amphetamine-type stimulants (ATS), such as methamphetamine (METH) are highly addictive and are the second most used illicit drugs in the world. Even though ATS production in the US has dramatically increased and stimulant use remain an important public health, financial, and legal issue, there are no proven pharmacotherapies to treat ATS use disorders (AUD) due to a limited understanding of the brain circuits underlying AUD and their complex mechanisms of action. Although many ATS increase both brain norepinephrine (NE) and dopamine (DA), and have higher affinities for the NE transporter (NET) than the DA transporter, far less attention has been paid to the role of central NE circuits as a potential target for treatment of AUD. Recent preclinical and clinical studies have highlighted NE in the bed nucleus of the stria terminalis (BNST) as an important contributor to substance abuse, withdrawal, and stress-induced reinstatement of drug seeking. NE transmission in the ventral (v)BNST, which primarily originates from the nucleus of the solitary tract (NST), integrates information from reward and stress related stimuli and mediates subsequent behavioral responses. However, little is known about how the NST-NE vBNST pathway is implicated in AUD and how it contributes to behavioral changes due to methodological limitations in selectively studying NE in the anatomically small/complex and neurochemically heterogeneous BNST. Furthermore, the BNST is sexually dimorphic and much smaller in volume (2.5X less for humans) in females than males, yet little is known about sex differences in the NST-NE vBNST system and its effect on AUD. Aim 1 of this proposal will (i) identify anatomical and neurochemical differences in the NST-NEvBNST system between male and female rats and (ii) characterize the effects of METH on NE regulation in the NST and vBNST and the correlation of the NE system with stress-induced behavioral changes. Aim 2 will determine the functional role of the NST-NEvBNST pathway in animal models of stress-induced METH seeking (relapse/craving) by chemogenetically modulating this pathway in METH self-administration paradigms. To achieve these Aims, we propose an innovative and integrative approach utilizing fast-scan cyclic voltammetry and chemogenetic modulation of NST-NE projection neurons to the vBNST in wild-type rats. This study will fill an important gap in our understanding of the NST-NEvBNST pathway and its contributions to the chronic effects of METH-induced neurochemical and behavioral changes and its distinct sex differences. These results will provide insight into the underlying neurobiological mechanisms of ATS use and may lead to novel therapeutics for of AUD using sex specific treatment strategies.
