Medullary Norepinephrine Projections Release Norepinephrine into the Contralateral Bed Nucleus of the Stria Terminalis

Abstract

Central norepinephrine signaling influences a wide range of behavioral and physiological processes, and the ventral bed nucleus of the stria terminalis (vBNST) receives some of the densest norepinephrine innervation in the brain. Previous work describes norepinephrine neurons as projecting primarily unilaterally; however, recent evidence for cross-hemispheric catecholamine signaling challenges this idea. Here, we use fast-scan cyclic voltammetry and retrograde tracing to characterize cross-hemispheric norepinephrine signaling in the vBNST. We delivered stimulations to noradrenergic pathways originating in the A1/A2 and locus coeruleus and found hemispherically equivalent norepinephrine release in the vBNST regardless of stimulated hemisphere. Unilateral retrograde tracing revealed that medullary, but not locus coeruleus norepinephrine neurons send cross-hemispheric projections to the vBNST. Further characterization with pharmacological lesions revealed that stimulations of the locus coeruleus and its axon bundles likely elicit vBNST norepinephrine release through indirect activation. These experiments are the first to demonstrate contralateral norepinephrine release and establish that medullary, but not coerulean neurons are responsible for norepinephrine release in the vBNST.

In vivo voltammetric evidence that locus coeruleus activation predominantly releases norepinephrine in the infralimbic cortex: Effect of acute ethanol

“…In fact, pharmacological analysis revealed that LC stimulation selectively induces NE release in these terminals. NE was released in a frequency-dependent manner at the concentration range that was previously found in other NE terminals following LC stimulation (Fox, Bucher, Johnson, & Wightman, 2016;Herr et al, 2012;Park, Kile, & Wightman, 2009;Park et al, 2017).…”

Stress Alters the Effect of Alcohol on Catecholamine Dynamics in the Basolateral Amygdala

“…Fox et al, 2016;Deal et al, 2019), our results for the first time demonstrate the possibility to measure real-time NE efflux in the BLA. Based on pharmacological characterizations, we ruled out the involvement of DA efflux in the signal measured in naïve rats as previously reported for the prefrontal cortex and bed nucleus of the stria terminals (Park et al, 2011;Fox et al, 2016;Deal et al, 2019). As expected, the electrically-evoked NE release was frequency-dependent, while the average maximum concentrations were ∼2-3 fold lower than concentrations in the prefrontal cortex (Deal et al, 2019).…”

“…of saline, raclopride (dopamine D 2 receptor antagonist; 2 mg/kg), idazoxan (α 2 adrenergic receptor antagonist; 5 mg/kg), or alcohol (2 g/kg ethanol) was administered. These idazoxan and raclopride doses effectively increase an electrically-evoked catecholamine efflux clarifying whether DA (raclopride) or NE (idazoxan) is detected in the rat brain with FSCV (Park et al, 2015;Fox et al, 2016;Mikhailova et al, 2019;Deal et al, 2018;. Some rats received more than one drug during the FSCV experiment.…”

“…To explore these questions, we used in vivo FSCV, a methodology that permits the real-time detection of extracellular DA and NE concentrations at terminals following electrical stimulation of cell body regions (Budygin et al, 2000(Budygin et al, , 2007(Budygin et al, , 2017Mateo et al, 2004;Oleson et al, 2009;Park et al, 2011Park et al, , 2012Fox et al, 2015Fox et al, , 2016. This approach allowed us to examine the effects of two different stressors, repeated social defeat stress (RSDS) and forced swim test (FST), on LC-evoked CA release in the BLA and the sensitivity of the CA signal to acute alcohol.…”

Stressing the potential of guanfacine as a treatment for cocaine use disorder

“…The BNST is a common node in the circuitry underlying stress-induced and anxiety-like behavior [ 6 ]. Noradrenergic neurons in the locus coeruleus and A1/A2 nucleus of the medulla innervate the BNST via the dorsal and ventral noradrenergic bundles, respectively, although the ventral bundle is the dominant source of NE within the region [ 3 , 7 ]. Pharmacological disruption of NE signaling in the BNST prevents stress-induced reinstatement of cocaine-seeking behavior, an animal model of relapse [ 2 , 3 , 6 ].…”