The response of neurons in the bed nucleus of the stria terminalis to serotonin: Implications for anxiety

Department of Psychology, University of Vermont, 2 Colchester Avenue, John Dewey Hall, Burlington, VT 05405, USA.
Progress in Neuro-Psychopharmacology and Biological Psychiatry (Impact Factor: 4.03). 06/2009; 33(8):1309-20. DOI: 10.1016/j.pnpbp.2009.05.013
Source: PubMed

ABSTRACT Substantial evidence has suggested that the activity of the bed nucleus of the stria terminalis (BNST) mediates many forms of anxiety-like behavior in human and non-human animals. These data have led many investigators to suggest that abnormal processing within this nucleus may underlie anxiety disorders in humans, and effective anxiety treatments may restore normal BNST functioning. Currently some of the most effective treatments for anxiety disorders are drugs that modulate serotonin (5-HT) systems, and several decades of research have suggested that the activation of 5-HT can modulate anxiety-like behavior. Despite these facts, relatively few studies have examined how activity within the BNST is modulated by 5-HT. Here we review our own investigations using in vitro whole-cell patch-clamp electrophysiological methods on brain sections containing the BNST to determine the response of BNST neurons to exogenous 5-HT application. Our data suggest that the response of BNST neurons to 5-HT is complex, displaying both inhibitory and excitatory components, which are mediated by 5-HT(1A), 5-HT(2A), 5-HT(2C) and 5-HT(7) receptors. Moreover, we have shown that the selective activation of the inhibitory response to 5-HT reduces anxiety-like behavior, and we describe data suggesting that the activation of the excitatory response to 5-HT may be anxiogenic. We propose that in the normal state, the function of 5-HT is to dampen activity within the BNST (and consequent anxiety-like behavior) during exposure to threatening stimuli; however, we suggest that changes in the balance of the function of BNST 5-HT receptor subtypes could alter the response of BNST neurons to favor excitation and produce a pathological state of increased anxiety.

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Available from: Joanna Dabrowska, Jul 29, 2015
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    • "In an extensively tested framework on how fear-potentiated startle is regulated by fear versus anxiety responses, the BNST is strongly implicated in contextual responses specifically (Davis et al., 2010), which are modeled in our context condition. As proposed by Hammack et al. (2009), exposure to stressful circumstances may downregulate 5-HT 1A receptor functioning and with that, reduce the negative feedback that limits activation of the BNST. Via that route, variability in this gene may cause variability in individuals' adaptivity in response to stressful circumstances. "
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    • "A subsequent study identified 5HT1A-induced recruitment of a G-protein coupled potassium channel as responsible for the 5HT-induced hyperpolarization (Levita et al., 2004). A recent study demonstrated that this depolarization was due in part to 5HT2C-Rs (Guo et al., 2009; Hammack et al., 2009). It bears noting, however, that there are also 5HT2A receptors in the BNST which may also play a role in this depolarization. "
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    • "As discussed above, it is likely that the brain regions implicated in LH and conditioned defeat are important targets for current pharmacological approaches in the treatment of MDD and PTSD, and we have previously suggested that changes in the 5-HT response of brain regions like the BNST and DRN mediate the efficacy of some of these treatments ((Hammack et al., 2009b), also see (Berendsen, 1995; Stahl, 1994; Strome et al., 2005; Yatham et al., 1999)). However, the data described above suggest that other mechanisms for modulating these neural circuits may represent novel treatments for trauma-related disorders; some of these are discussed below. "
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