Addiction is a tremendous health and financial burden on our society. A growing literature indicates that norepinephrine in the brain plays a key role in stress-reward interactions that may mediate key behavioral responses to drugs of abuse. A previously unappreciated group of noradrenergic neurons in the field of addiction, cells that project through the ventral noradrenergic bundle (VNAB), are thought to supply the key norepinephrine. The primary target of the VNAB in the brain is a group of nuclei referred to as the extended amygdala. In the previous funding periods, we identified actions of each of the major classes of noradrenergic receptors on excitatory synaptic transmission in the bed nucleus of the stria terminalis, a major component of the extended amygdala. Moreover, we identified a novel mechanism whereby the noradrenergic system interacts with the corticotropin releasing factor receptor signaling system to drive recruitment of specific populations of VTA projecting neurons. We also identified novel actions of alpha2-adrenergic receptors in regulation of excitatory drive into the BNST. Adrenergic ligands have been identified as potential prophylactic therapeutic candidates in treating addiction. While results in human studies have been encouraging, their overall success in improving outcomes has been modest. We propose that this is in part due to the many disparate actions that the receptors regulated by these ligands regulate, and that if we could develop a more specific understanding of the regulated actions that were key to drug-seeking, we could fine tune treatment strategies to increase effectiveness. Here, we propose experiments to delineate specific pathways through which catecholamine- CRF signaling interactions regulate stress-induced cocaine seeking, and alpha2-adrenergic receptor-induced suppression of stress-induced reinstatement.
Addiction poses an enormous health and financial burden on our society. Currently, our understanding of the brain circuitries involved in addiction is far from complete. The successful completion of these proposed studies would result in important new information about neurons that may be involved in addiction, potentially creating new targets for therapeutics development.
|Harris, Nicholas A; Isaac, Austin T; Günther, Anne et al. (2018) Dorsal BNST ?2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors. J Neurosci 38:8922-8942|
|Harris, Nicholas A; Winder, Danny G (2018) Synaptic Plasticity in the Bed Nucleus of the Stria Terminalis: Underlying Mechanisms and Potential Ramifications for Reinstatement of Drug- and Alcohol-Seeking Behaviors. ACS Chem Neurosci 9:2173-2187|
|Bergstrom, Hadley C; Lipkin, Anna M; Lieberman, Abby G et al. (2018) Dorsolateral Striatum Engagement Interferes with Early Discrimination Learning. Cell Rep 23:2264-2272|
|Vranjkovic, Oliver; Pina, Melanie; Kash, Thomas L et al. (2017) The bed nucleus of the stria terminalis in drug-associated behavior and affect: A circuit-based perspective. Neuropharmacology 122:100-106|