A Corticotropin Releasing Factor Pathway for Ethanol Regulation of the Ventral Tegmental Area in the Bed Nucleus of the Stria Terminalis

Abstract

A growing literature suggests that catecholamines and corticotropin releasing factor (CRF) interact in a serial manner to activate the bed nucleus of the stria terminalis (BNST) in order to drive stress- or cue-induced drug- and alcohol-seeking behaviors. Data suggests that these behaviors are driven in part by BNST projections to the ventral tegmental area (VTA). Together these findings suggest the existence of a CRF-signaling pathway within the BNST that is engaged by catecholamines and regulates the activity of BNST neurons projecting to the VTA. Here we test three aspects of this model: 1) whether catecholamines modify CRF neuron activity in the BNST, 2) whether CRF regulates excitatory drive onto VTA-projecting BNST neurons, and 3) whether this system is altered by ethanol exposure and withdrawal. A CRF neuron fluorescent reporter strategy was utilized to identify BNST CRF neurons for whole cell patch clamp analysis in acutely prepared slices. Using this approach, we found that both dopamine and isoproterenol significantly depolarized BNST CRF neurons. Furthermore, using a fluorescent microsphere based identification strategy; we found that CRF enhances the frequency of spontaneous EPSCs onto VTA-projecting BNST neurons in naïve mice. This action of CRF was occluded during acute withdrawal from chronic intermittent ethanol exposure. These findings suggest that dopamine and isoproterenol may enhance CRF release from local BNST sources, leading to enhancement of excitatory neurotransmission on VTA-projecting neurons, and that this pathway is engaged by patterns of alcohol exposure and withdrawal known to drive excessive alcohol intake.

The Human BNST: Functional Role in Anxiety and Addiction

“…Koob and Volkow (2010) provide a comprehensive model of addiction neurobiology that proposes distinct neural circuits for three stages of addiction: binge/intoxication; withdrawal/negative affect; and preoccupation/craving addiction (also see Koob and Moal, 1997). In the Koob and Volkow model, the BNST has a prominent role in the withdrawal/negative affect stage of addiction, consistent with evidence that highlights the role of BNST in withdrawal across drugs of abuse, including alcohol (Silberman et al, 2013;Wills et al, 2012) and opiates (Wang et al, 2006;Delfs et al, 2000). The withdrawal/negative affect stage has been described as the 'dark side of addiction' and includes core components of anxiety disorders.…”

“…Emerging evidence suggests that a tiny region in the ventral forebrain-the bed nucleus of the stria terminalis (BNST)-is a critical node in the stress response neurocircuitry and may play a significant role in both anxiety and addiction, two highly prevalent and debilitating stress-related disorders. Rodent studies of the BNST over the past two decades have led to exciting discoveries about its potential role in human psychopathology-seminal studies have shown a unique role for the BNST in contextual fear and sustained, anxiety-like responses in rodents (see, eg, Davis et al, 2010;Walker et al, 2003), and parallel work in drug addiction demonstrates the role of BNST in withdrawal related-anxiety and relapse (Buffalari and See, 2011;Silberman et al, 2013;Wenzel et al, 2014). Although anxiety and addiction are often considered to have distinct neurobiological bases-anxiety related to fear neurocircuitry and addiction related to reward circuitry-we now understand the two disorders also have many commonalities; for example, anxiety and addiction are both triggered by stress (Koob, 2009;McEwen, 2012), risk for both disorders is heightened in individuals with altered stress reactivity (Lovallo, 2006;Villada et al, 2014), and the two disorders are highly comorbid (Grant et al, 2004;Kessler et al, 2005b).…”

Relaxin-3/RXFP3 system regulates alcohol-seeking

“…The BNST, which contains a high density of RXFP3 (19,21), has an established role in stress-induced reinstatement via a CRF-signaling pathway (41,43) and therefore was an obvious candidate region for targeted injections of R3(B1-22)R. Accordingly, intra-BNST injections of R3(B1-22)R produced a significant decrease in both alcohol selfadministration and stress (yohimbine)-induced reinstatement of alcohol-seeking. The attenuation of alcohol-seeking, rather than complete prevention, suggests other brain regions may also be involved.…”

Contrasting distribution of physiological cell types in different regions of the bed nucleus of the stria terminalis

“…Indeed, most electrophysiological studies have focused on other aspects of BNST physiology such as the influence of various peptides/transmitters (Grueter et al 2005;Krawczyk et al 2011a;Li et al 2012;Lungwitz et al 2012;McElligott and Winder 2008;Nobis et al 2011;Puente et al 2010;Shields et al 2009), particularly corticotropin releasing factor (Gafford et al 2012;Ide et al 2013;Kash and Winder 2006;Oberlander and Henderson 2012;Silberman et al 2013), mechanisms of addiction and relapse to drug seeking (Conrad et al 2012;Davis et al 2008;Dumont and Williams 2004;Dumont et al 2005Dumont et al , 2008Grueter et al 2008;Kash et al 2008aKash et al ,b, 2009Krawczyk et al 2011b), synaptic plasticity (Weitlauf et al 2005), and the impact of stress (Conrad et al 2011).…”