The anxiogenic drug yohimbine activates central viscerosensory circuits in rats

Abstract

Systemic administration of the alpha(2)-adrenoceptor antagonist yohimbine (YO) activates the HPA stress axis and promotes anxiety in humans and experimental animals. We propose that visceral malaise contributes to the stressful and anxiogenic effects of systemic YO and that YO recruits brainstem noradrenergic (NA) and peptidergic neurons that relay viscerosensory signals to the hypothalamus and limbic forebrain. To begin testing these hypotheses, the present study explored dose-related effects of YO on food intake, conditioned flavor avoidance (CFA), and Fos immunolabeling in rats. Systemic YO (5.0 mg/kg BW, i.p.) inhibited food intake, supported CFA, and increased Fos immunolabeling in identified NA neurons in the ventrolateral medulla, nucleus of the solitary tract, and locus coeruleus. YO also increased Fos in the majority of corticotropin releasing hormone-positive neurons in the paraventricular nucleus of the hypothalamus. YO administered at 1.0 mg/kg BW did not inhibit food intake, did not support CFA, and did not increase Fos immunolabeling. Retrograde neural tracing demonstrated that neurons activated by YO at 5.0 mg/kg BW included medullary and pontine neurons that project to the central nucleus of the amygdala and to the lateral bed nucleus of the stria terminalis, the latter region receiving comparatively greater input by Fos-positive neurons. We conclude that YO produces anorexigenic and aversive effects that correlate with activation of brainstem viscerosensory inputs to the limbic forebrain. These findings invite continued investigation of how central viscerosensory signaling pathways interact with hypothalamic and limbic regions to influence interrelated physiological and behavioral components of anxiety, stress, and visceral malaise.

Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions

“…Given the diversity of sensory inputs received by A2 neurons, it is not surprising that they respond to a broad array of interoceptive signals, including hormonal, osmotic, gastrointestinal, cardiovascular, respiratory, and inflammatory signals (20,23,43,45,66,77,97,112,120,167,168,201,202,207,212,213,230). In these and many other studies, stimulusinduced A2 neuronal activation is characterized by immunocytochemical localization of the immediate-early gene product, Fos, together with immunolabeling for TH or DbH.…”

Chronic Corticosterone Exposure during Adolescence Reduces Impulsive Action but Increases Impulsive Choice and Sensitivity to Yohimbine in Male Sprague-Dawley Rats

“…Yohimbine is also anxiogenic and activates the HPA axis (Charney et al, 1984;Myers et al, 2005). Therefore, because the adolescent CORT-treated rats may have differential reactions to a pharmacological stressor, we tested the propensity of yohimbine to increase impulsive responses on the 5CSRTT in these animals.…”

Orexin-1 Receptor Mediation of Cocaine Seeking in Male and Female Rats

“…Systemic yohimbine treatment activates hypothalamic pathways via its noradrenergic actions (Myers et al, 2005). In the hypothalamus, female rats express higher levels of orexin-A and OX1R than males (Taheri et al, 1999;Jöhren et al, 2001), a difference that may affect response to yohimbine.…”