Yohimbine Depresses Excitatory Transmission in BNST and Impairs Extinction of Cocaine Place Preference Through Orexin-Dependent, Norepinephrine-Independent Processes

Abstract

The alpha2 adrenergic receptor (a 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 a 2 -AR signaling. Recent studies show yohimbineinduced 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.

Hypocretin (orexin) neuromodulation of stress and reward pathways

“…However, while PVN-CRF neurons are mostly glutamatergic, BNST-CRF neurons are primarily GABAergic [30], thereby offering diverse mechanisms for Hcrt modulation of stress circuits. In one recent study, slice application of Hcrt to neurons in the CRF-enriched dorsolateral BNST (dlBNST) of adult mice depressed excitatory post-synaptic currents (EPSCs) in a HcrtR1-specific manner [31]. Interestingly, these effects on excitatory dlBNST transmission mimicked those of yohimbine, the alpha-2 NE receptor antagonist known to reinstate operant alcohol-seeking through a HcrtR1-mediated mechanism [32].…”

“…In a separate study, slice application of Hcrt depolarized a subset of neurons in the posterior BNST of adult rats [33]. These effects contrast with those observed in mice [31], but are consistent with the ability of intra-BNST Hcrt to increase anxiety-like behavior via NMDA receptor activation [33]. Even a single subregion of the BNST can display tremendous cellular heterogeneity [30], and Hcrt's modulatory actions undoubtedly vary across cell types, highlighting the need for detailed studies of Hcrt's effects in genetically- or physiologically-defined BNST neurons.…”

The Role of the Glucocorticoids in Developing Resilience to Stress and Addiction

“…OX-A infusions into the BNST produce anxiety like responses as measured by social interaction test and elevated plus maze test and the effect is mediated by NMDA receptors (107). A recent study also demonstrated that yohimbine activates orexinergic responses, but not adrenergic receptor activity, and depressed excitatory neurotransmission in the BNST that contributed to reinstatement of extinguished cocaine CPP (108). Thus the orexinergic system is involved in mediating stress-induced drug-seeking behavior as it recruits multiple brain regions involved in processing stressful stimuli and addictive behaviors.…”

Adrenaline Rush: The Role of Adrenergic Receptors in Stimulant-Induced Behaviors

“…Yohimbine and atipamezole show equal affinities at all three receptor subtypes, but atipamezole has a 200-fold greater selectivity than yohimbine for the a2AR over the a1AR (Schwartz and Clark, 1998). Because yohimbine interacts with a number of non-noradrenergic systems in addition to acting at the a2AR, its effects should be interpreted with caution (Feuerstein et al, 1985;Millan et al, 2000;Conrad et al, 2012).…”

“…However, when the data were reanalyzed to control for initial preference, a high dose of prazosin accelerated extinction in animals with a high initial preference score (Bernardi and Lattal, 2012b). Yohimbine impaired the extinction of cocaine CPP, although this effect was not replicated with a selective a2AR antagonist and may be mediated by orexin rather than NE (Davis et al, 2008;Conrad et al, 2012).…”