Emerging role for corticotropin releasing factor signaling in the bed nucleus of the stria terminalis at the intersection of stress and reward

Abstract

Stress and anxiety play an important role in the development and maintenance of drug and alcohol addiction. The bed nucleus of the stria terminalis (BNST), a brain region involved in the production of long-term stress-related behaviors, plays an important role in animal models of relapse, such as reinstatement to previously extinguished drug-seeking behaviors. While a number of neurotransmitter systems have been suggested to play a role in these behaviors, recent evidence points to the neuropeptide corticotropin releasing factor (CRF) as being critically important in BNST-mediated reinstatement behaviors. Although numerous studies indicate that the BNST is a complex brain region with multiple afferent and efferent systems and a variety of cell types, there has only been limited work to determine how CRF modulates this complex neuronal system at the circuit level. Recent work from our lab and others have begun to unravel these BNST neurocircuits and explore their roles in CRF-related reinstatement behaviors. This review will examine the role of CRF signaling in drug addiction and reinstatement with an emphasis on critical neurocircuitry within the BNST that may offer new insights into treatments for addiction.

Keywords: addiction; excitatory transmission; extended amygdala; reinstatement; relapse.

Figure 1

Model of Chronic Intermittent Ethanol-Withdrawal Modulation of BNST CRF Circuitry. (A) Dopamine and norepinephrine afferents synapse onto CRF-producing neurons in the BNST which in turn influence neurotransmitter release from glutamatergic afferents onto BNST neurons projecting to the VTA. (B) Close up view of proposed neurocircuitry described in (A). (C,D) Model of CRF modulation of glutamatergic transmission onto a VTA-projecting BNST neuron in a drug-naïve state (C) or during acute ethanol withdrawal following CIE (D). Note that there are higher levels of CRF and glutamate release during withdrawal compared to the drug-naïve state. Figure reprinted from (Silberman et al., 2013).

Figure 2

Summary Model of Reinstatement Related BNST and VTA Connectivity. CRF+ neurons modulate the activity of VTA-projecting BNST neurons. Evidence (Kudo et al., 2012) shows that at least three types of VTA-projecting neurons are located in the BNST: (1) a GABAergic projection (∼90% of all BNST projection neurons) that selectively innervates VTA GABA neurons to provide disinhibition of VTA DA neurons; (2) a glutamatergic (Glut) projection that selectively targets VTA DA neurons; and (3) a mixed GABA/Glut projection that also targets VTA DA neurons. These projection neuron populations may exist in both the dorsal and ventral BNST subregions (d and vBNST, respectively) and each projection pathway may have distinct and coordinated responses to chronic drug exposure, withdrawal, and reinstatement. Coordinated activity of dBNST and vBNST projection neurons is likely regulated by dBNST interneurons, of which CRF+ neurons may be a critical component. This local CRF neuron coordination of BNST activity might also be altered by chronic exposure and withdrawal and may be an important target for the prevention of relapse-like behaviors.