The role of biogenic amine signaling in the bed nucleus of the stria terminals in alcohol abuse
Section snippets
Micro-circuitry of the BNST
The BNST acts as a critical node in the brain, receiving glutamatergic inputs from cortical, thalamic and amygdalar regions, GABAergic inputs from amygdalar region, and modulatory inputs from brainstem and hypothalamic regions, and then projecting out to many of these same regions (Fig. 1). The circuitry in the BNST is complex, perhaps due to the critical role it plays in so many diverse behaviors and processes. Neurons in the BNST are thought to be primarily GABAergic (Sun & Cassell, 1993).
The BNST as a critical regulator of the stress response/anxiety
Manipulations of stress and anxiety can shape ethanol related behaviors. The BNST acts as a critical regulator of both stress response and anxiety via a series of projections to the brainstem and hypothalamus (Fig. 1). Given that several of these target regions also project to the BNST, it has been proposed that these circuits can form feed-forward loops that when engaged, can lead to aberrant behavior. The ability of the BNST to alter the stress response is well characterized. Functionally,
The BNST plays a key role in modulating rewarding properties of drugs of abuse
The BNST is heavily inter-connected with ‘reward’ regions in particular the ventral tegmental area (VTA) (Fig. 1) (Dong & Swanson, 2004). In keeping with this, it has been shown that acute exposure to multiple drugs of abuse, including ethanol, leads to increased dopamine levels in the BNST (Carboni, Silvagni, Rolando, & Di Chiara, 2000). Moreover, several studies have demonstrated that disruption of GABAergic (Hyytia & Koob, 1995) or dopaminergic signaling (Eiler, Seyoum, Foster, Mailey, &
The BNST receives dopamine from the VTA and the A10dc (vlPAG/DR)
The traditional view of dopamine signaling in the brain has been that dopamine released from cells in the ventral tegmental area (VTA) and substantia nigra (SN) constitutes the virtual entirety of CNS dopaminergic signaling. In addition to this classical dopaminergic afferent, however, the BNST also receives nearly 50% of its dopaminergic input from the A10dc located in the vlPAG region (Hasue & Shammah-Lagnado, 2002; Meloni, Gerety, Knoll, Cohen, & Carlezon, 2006). This population of neurons
BNST regulation of DA neuron function
One of the hallmarks of the interactions between the BNST and brainstem structures is a bi-directional interaction, as discussed above in the overview of the anatomy and shown in Fig. 1. As such, the BNST receives DA inputs, and can also regulate DA neuron function. Early studies from George and Aston-Jones demonstrated that this was a complicated projection, with both inhibitory and excitatory components (Georges & Aston-Jones, 2001). In expanding this work, they have found that the BNST plays
Dopamine signaling in the BNST
Drugs of abuse, including ethanol, potently elevate extracellular dopamine in the BNST (Carboni et al., 2000) and that antagonizing D1 receptors within the BNST can reduce alcohol seeking behavior (Eiler et al., 2003). Moreover, in vivo administration of multiple drugs of abuse, including alcohol, engage the MAP kinase (ERK1/2) signaling cascade in BNST neurons in a D1-dopamine receptor antagonist sensitive manner (Valjent, Pages, Herve, Girault, & Caboche, 2004). Beyond reward, dopamine
Serotonin involvement in alcoholism
Studies in alcoholics have demonstrated alterations in markers of 5HT function. Specifically, alcohol-dependent individuals exhibited increases in the 5HT biosynthetic enzyme tryptophan hydroxylase (TPH) in dorsal raphe, the brainstem nucleus that acts as the principle source of serotonin to the brain, including the BNST (Bonkale, Turecki, & Austin, 2006). Additionally, recent reports have demonstrated alterations in serotonin transporter (SERT) density in the amygdala of Type 2, or aggressive,
Serotonin signaling in the BNST
Similar to the amygdala, the BNST receives a 5HT input from the DR (Phelix, Liposits, & Paull, 1992). Systemic administration of the 5HT2 receptor agonist, mCPP, can activate the BNST, as denoted by an increase in c-fos (Singewald, Salchner, & Sharp, 2003). Recent studies have demonstrated that activation of 5HT receptors in the BNST can modulate anxiety-like behavior. Specifically, a study from the Rainnie group demonstrated that 5HT1A receptor activation in the BNSTal leads to a reduction in
Norepinephrine signaling in the BNST: potential role in alcohol abuse
In addition to dopamine and serotonin, the BNST receives a large noradrenergic input (Egli & Winder, 2003). While early anatomical analysis of these noradrenergic projections suggested that this was predominantly from the nucleus of the solitary tract (NTS) (Forray, Gysling, Andres, Bustos, & Araneda, 2000), recent functional evidence suggested that the locus coeruleus and the NTS can release norepinephrine (NE) in the BNST (Park, Kile, & Wightman, 2009). Norepinephrine signaling in the BNST
Summary
The BNST is a structure that appears to play a critical role in several aspects of alcohol abuse and addiction. The complicated circuitry of this structure provides a fertile ground for discovery, but this same complexity can make it difficult to understand how modulatory systems such as serotonin and dopamine are working on a network level. For example, the GABAergic projection from the CeA has been thought to play a critical role in alcohol abuse and anxiety. To date, technical limitations
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2020, Brain ResearchCitation Excerpt :An overall reduction in GABA transmission via presynaptic mechanisms was observed following KOR activation in the BNST; selective circuit manipulation using optogenetics revealed that this KOR-mediated reduction in GABA transmission was specific to the CeA → BNST projection (Li et al., 2012; Normandeau et al., 2018). In addition to GABAergic afferents, BNST receives glutamatergic projections from the BLA and the PFC (Kash, 2012). Surprisingly, KOR activation using an agonist as well as local dynorphin neuron stimulation within the BNST selectively inhibit BLA glutamate transmission but not PFC glutamatergic projection in the BNST (Crowley et al., 2016).
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