Yohimbine anxiogenesis in the elevated plus maze requires hindbrain noradrenergic neurons that target the anterior ventrolateral bed nucleus of the stria terminalis

Abstract

The α2 adrenergic receptor antagonist yohimbine (YO) increases transmitter release from noradrenergic (NA) terminals in cortical and subcortical brain regions, including the bed nucleus of the stria terminalis (BST). YO activates the HPA stress axis and is potently anxiogenic in rats and humans. We previously reported that hindbrain NA neurons within the caudal nucleus of the solitary tract (NST-A2/C2) and ventrolateral medulla (VLM-A1/C1) that innervate the anterior ventrolateral (vl)BST contribute to the ability of YO to activate the HPA stress axis in rats. To determine whether the same NA pathway also contributes to YO-induced anxiogenesis in the elevated plus maze (EPMZ), a selective saporin ribotoxin conjugate (DSAP) was microinjected bilaterally into the anterior vlBST to destroy its NA inputs. Sham-lesioned controls were microinjected with vehicle. Two experiments were conducted to determine DSAP lesion effects on EPMZ behavior. DSAP lesions did not alter maze behavior in rats after i.p. saline, and did not alter the significant effect of prior maze experience to reduce exploratory and open arm maze activities. However, in maze-naïve rats, DSAP lesions abolished YO anxiogenesis in the EPMZ. Postmortem immunocytochemical analyses confirmed that DSAP consistently ablated caudal NST-A2/C2 and VLM-A1/C1 neurons that innervate the anterior vlBST. DSAP lesions did not destroy non-NA inputs to the anterior vlBST, and produced inconsistent cell loss within the pontine locus coeruleus (A6 cell group) that was unrelated to YO anxiogenesis. Thus, the ability of YO to increase anxiety-like behavior in the EPMZ depends on hindbrain NA neurons that target the anterior vlBST.

Inactivation of the lateral habenula reduces anxiogenic behavior and cocaine seeking under conditions of heightened stress

“…The current finding is also consistent with evidence that stress-induced reinstatement relies on CRH activity in the bed nucleus of the stria terminalis, (Erb et al, 1998; Ghitza et al, 2006; Shaham et al, 1997). A previous study also found that depletion of NE in the ventrolateral bed nucleus of the stria terminalis blocked the anxiogenic effects of yohimbine (Zheng and Rinaman, 2012). In contrast, results of footshock-induced reinstatement suggest that CRH is particularly important for reinstatement, as CRH infusion induced reinstatement (Erb and Stewart, 1999), while infusion of a CRH antagonist in the bed nucleus of the stria terminalis blocked footshock-induced reinstatement (Erb and Stewart, 1999).…”

GLP‐1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract

“…Hindbrain GLP-1 neurons and PrRP+ A2 neurons are robustly activated in rats after exposure to visceral or cognitive stressors, and published evidence supports the view that both neural populations contribute to the central control of stress responsiveness and motivated behavior via widespread axonal projections that reach multiple CNS regions implicated in these processes (Banihashemi & Rinaman, 2006;Bechtold & Luckman, 2006;Ellacott et al, 2002;Gu et al, 2013;Holt & Trapp, 2016;Kreisler, Davis, & Rinaman, 2014;Larsen et al, 1997;Lawrence et al, 2000;Lawrence, Liu, Stock, & Luckman, 2004;Llewellyn-Smith et al, 2013;Maniscalco et al, 2013Maniscalco et al, , 2015Maniscalco & Rinaman, 2018;Myers & Rinaman, 2002;Rinaman, 1999bRinaman, , 2003Rinaman, , 2010Zheng & Rinaman, 2013). both neural populations as "stress-sensitive" (Maniscalco et al, 2015).…”

Modulation of imidazoline I2 binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats

“…Conversely, when we tried to block the analgesic effect of CR4056 with substances that do not interact with imidazoline I2 receptors, we failed to show a significant antagonism. A relevant exception was the moderate (about 30%) but significant effect of yohimbine, a classical α2-adrenoceptor antagonist, administered at the maximum possible dose not inducing obvious behavioural changes (Arrant et al, 2013;Zheng and Rinaman, 2013). As yohimbine did not antago- Figure 1 (A) Anti-hyperalgesic effect of CR4056 on postoperative paininduced mechanical hyperalgesia in male rats (Randall-Selitto test).…”