Corticotropin releasing factor and norepinephrine related circuitry changes in the bed nucleus of the stria terminalis in stress and alcohol and substance use disorders

Abstract

Alcohol Use Disorder (AUD) affects around 14.5 million individuals in the United States, with Substance Use Disorder (SUD) affecting an additional 8.3 million individuals. Relapse is a major barrier to effective long-term treatment of this illness with stress often described as a key trigger for a person with AUD or SUD to relapse during a period of abstinence. Two signaling molecules, norepinephrine (NE) and corticotropin releasing factor (CRF), are released during the stress response, and also play important roles in reward behaviors and the addiction process. Within the addiction literature, one brain region in which there has been increasing research focus in recent years is the bed nucleus of the stria terminalis (BNST). The BNST is a limbic structure with numerous cytoarchitecturally and functionally different subregions that has been implicated in drug-seeking behaviors and stress responses. This review focuses on drug and stress-related neurocircuitry changes in the BNST, particularly within the CRF and NE systems, with an emphasis on differences and similarities between the major dorsal and ventral BNST subregions.

Keywords: AUD; Adrenergic receptor; Alcohol; Alcohol use disorder; BNST; CRF; Corticotropin releasing factor; Drug use; Norepinephrine; Stress; Substance use disorder.

Figure 1.. Anterior BNST subregions: dorsal and ventral BNST.

The dorsal BNST includes the anterolateral dorsal area, anteromedial dorsal area, juxtacapsular nucleus, and oval nucleus. The ventral BNST consists of the anteromedial ventral area, the anterolateral ventral area, and the fusiform nucleus. This figure was adapted from the Adult Mouse Allen Brain Reference Atlas.

Figure 2.. Summary model of potential targets for stress and drug interactions within dorsal and ventral BNST noradrenergic and corticotropin releasing factor circuits.

In general, stress and drug or alcohol exposure are thought to increase norepinephrine (NE) release in the BNST. Evoked NE release is greater in the ventral (vBNST) than dorsal (dBNST) subregions, which may be due to a greater density of noradrenergic inputs into the vBNST. Stress increases dBNST corticotropin releasing factor (CRF) neuron activation via NE signaling, and NE activates CRF neurons via β-ARs and α1-ARs after stress exposure or during acute drug withdrawal. Activation of CRF neurons in the dBNST reliably produces aversive and anxiety-like behaviors, and may inhibit anxiolytic output. In both the dBNST and vBNST α2_A-AR autoreceptors are likely located on noradrenergic terminals and modulate incoming NE signaling. In the dBNST, α2_A-AR heteroreceptors are located on glutamatergic terminals, such as those from the parabrachial nucleus, to decrease glutamatergic transmission. α2_A-ARs are also present on local GABAergic neurons, which may directly inhibit CRF neuron function and lead to a disinhibition of potential anti-anxiety circuits. In the vBNST, β2-ARs are critical for stress-induced reinstatement behaviors and exert their effects via downstream CRFR1 signaling, suggesting that β2-ARs are located on CRF neurons themselves. Electrophysiology studies reveal a role for vBNST α1 and α2-ARs in modulating noradrenergic, GABAergic, and glutamatergic signaling although their exact cellular location is currently unknown.