Noradrenergic Inputs to the Bed Nucleus of the Stria Terminalis and Paraventricular Nucleus of the Hypothalamus Underlie Hypothalamic–Pituitary–Adrenal Axis But Not Hypophagic or Conditioned Avoidance Responses to Systemic Yohimbine

Abstract

The ␣2 adrenoceptor antagonist yohimbine (YO) increases transmitter release from adrenergic/noradrenergic (NA) neurons. Systemic YO activates the hypothalamic-pituitary-adrenal (HPA) axis, inhibits feeding, and supports conditioned flavor avoidance (CFA) in rats. To determine whether these effects require NA inputs to the bed nucleus of the stria terminalis (BNST), vehicle or saporin toxin conjugated to an antibody against dopamine ␤ hydroxylase (DSAP) was microinjected bilaterally into the BNST to remove its NA inputs. Subsequent tests failed to reveal any lesion effect on the ability of YO (5.0 mg/kg, i.p.) to inhibit food intake or to support CFA. Conversely, HPA axis responses to YO were significantly blunted in DSAP rats. In a terminal experiment, DSAP and control rats were perfused 90 -120 min after intraperitoneal injection of YO or vehicle. Brains were processed to reveal Fos immunolabeling and lesion extent. NA fibers were markedly depleted in the BNST and medial parvocellular paraventricular hypothalamus (PVNmp) in DSAP rats, evidence for collateralized NA inputs to these regions. DSAP rats displayed significant loss of caudal medullary NA neurons, and markedly blunted Fos activation in the BNST and in corticotropin-releasing hormone-positive PVNmp neurons after YO. We conclude that a population of medullary NA neurons provides collateral inputs to the BNST and PVNmp, and that these inputs contribute importantly to Fos expression and HPA axis activation after YO treatment. Conversely, NA-mediated activation of BNST and PVNmp neurons is unnecessary for YO to inhibit food intake or support CFA, evidence for the sufficiency of other intact neural pathways in mediating those effects.

Visceral sensory inputs to the endocrine hypothalamus

“…Similar preliminary results have been obtained in toxin-lesioned rats subsequently treated with systemic lithium chloride (LiCl) (Figure 2). Conversely, inputs to magnocellular regions of the PVN and SON appear to arise from medullary NA neurons that do not also project to either the BNST or the PVNmp [102]. This finding complements previous evidence that magnocellular and parvocellular PVN subdivisions are differentially innervated by NA inputs arising from the VLM and NST, respectively [91].…”

“…Immunotoxic lesioning methods have demonstrated that these NA inputs are necessary for systemic yohimbine (a sympathomimetic adrenergic signal-enhancing drug) to activate neural expression of the immediate-early gene product, Fos, in CRF neurons within the PVNmp, and to increase plasma corticosterone levels [102]. Similar preliminary results have been obtained in toxin-lesioned rats subsequently treated with systemic lithium chloride (LiCl) (Figure 2).…”

“…Recent findings indicate that NA inputs to the PVNmp are provided by NST and/or VLM neurons with collateralized inputs to the BNST [102]. Immunotoxic lesioning methods have demonstrated that these NA inputs are necessary for systemic yohimbine (a sympathomimetic adrenergic signal-enhancing drug) to activate neural expression of the immediate-early gene product, Fos, in CRF neurons within the PVNmp, and to increase plasma corticosterone levels [102].…”

α1-Adrenergic Receptor-Induced Heterosynaptic Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted in Mouse Models of Affective Disorders

“…Microdialysis studies have demonstrated that NE levels remain elevated above the baseline in the BNST over an hour after restraint stress and blocking a 1 -ARs attenuates stress-induced rises in adrenocorticotropic hormone (ACTH) (Pacak et al, 1995;Cecchi et al, 2002). Moreover, Banihashemi and Rinaman (2006) showed that ablating BNST NE inputs prevents increases in corticosterone to i.p. yohimbine 90 min post injection.…”

“…a 1 -ARs in the BNST modulate ACTH levels in animals who have been exposed to a stressor (Cecchi et al, 2002). Moreover it has recently been shown that the same axon collaterals from the nucleus tractus solitarius that project to the BNST also may project to the PVN (Banihashemi and Rinaman, 2006). NE may therefore modulate this circuitry regardless of input from cortical structures.…”