title: Yohimbine depresses excitatory transmission in BNST and impairs extinction of cocaine place preference through orexin-dependent, norepinephrine-independent processes.
abstract: The alpha2 adrenergic receptor (α(2)-AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and reward pathways, and produces an impairment of extinction of cocaine-conditioned place preference (cocaine-CPP) independent of α(2)-AR signaling. Recent studies show yohimbine-induced drug-seeking behavior is attenuated by orexin receptor 1 (OX(1)R) antagonists. Moreover, yohimbine-induced cocaine-seeking behavior is BNST-dependent. Here, we investigated yohimbine-orexin interactions. Our results demonstrate yohimbine-induced depression of excitatory transmission in the BNST is unaffected by alpha1-AR and corticotropin-releasing factor receptor-1 (CRFR(1)) antagonists, but is (1) blocked by OxR antagonists and (2) absent in brain slices from orexin knockout mice. Although the actions of yohimbine were not mimicked by the norepinephrine transporter blocker reboxetine, they were by exogenously applied orexin A. We find that, as with yohimbine, orexin A depression of excitatory transmission in BNST is OX(1)R-dependent. Finally, we find these ex vivo effects are paralleled in vivo, as yohimbine-induced impairment of cocaine-CPP extinction is blocked by a systemically administered OX(1)R antagonist. These data highlight a new mechanism for orexin on excitatory anxiety circuits and demonstrate that some of the actions of yohimbine may be directly dependent upon orexin signaling and independent of norepinephrine and CRF in the BNST.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Conrad
authors.forename: Adeola R
authors.initials: AR
authors.lastname: Davis
authors.forename: Yuval
authors.initials: Y
authors.lastname: Silberman
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Sheffler
authors.forename: Angela D
authors.initials: AD
authors.lastname: Shields
authors.forename: Sam A
authors.initials: SA
authors.lastname: Saleh
authors.forename: Namita
authors.initials: N
authors.lastname: Sen
authors.forename: Heinrich J G
authors.initials: HJ
authors.lastname: Matthies
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009638:Norepinephrine / Q000502:physiology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D064446:Orexin Receptors; D000068797:Orexins; D018408:Patch-Clamp Techniques; D000077593:Reboxetine; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors; D012201:Reward; D012686:Septal Nuclei / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
chemical_list: C547769:Adra2a protein, mouse; D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; C497459:Hcrtr1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D050484:Norepinephrine Plasma Membrane Transport Proteins; D064446:Orexin Receptors; D000068797:Orexins; D018341:Receptors, Adrenergic, alpha-2; D018019:Receptors, Corticotropin-Releasing Hormone; D018013:Receptors, Neuropeptide; C493228:Slc6a2 protein, mouse; D015016:Yohimbine; D000099052:CRF Receptor, Type 1; D000077593:Reboxetine; D003042:Cocaine; D009638:Norepinephrine