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Publication

Dorsal BNST α2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors.

The Journal of neuroscience : the official journal of the Society for Neuroscience | 2018

Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α2A-adrenergic receptors (α2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α2A-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α2A-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α2A-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine-N-oxide activation of the Gi-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction.SIGNIFICANCE STATEMENT Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-AR) agonist with actions in the bed nucleus of the stria terminalis (BNST) that produces antidepressant actions and uncouples stress from reward-related behaviors. Here, we show that guanfacine increases dorsal BNST neuronal activity through actions at postsynaptic α2A-ARs via a mechanism that involves hyperpolarization-activated cyclic nucleotide gated cation channels. This action is mimicked by activation of the designer receptor hM4Di expressed in the BNST, which also induces anxiety-like behaviors. Together, these data suggest that postsynaptic α2A-ARs in BNST have excitatory actions on BNST neurons and that these actions can be phenocopied by the so-called "inhibitory" DREADDs, suggesting that care must be taken regarding interpretation of data obtained with these tools.

Pubmed ID: 30150361 RIS Download

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Associated grants

Agency: NIDA NIH HHS, United States
Id: F30 DA042501
Agency: NIDDK NIH HHS, United States
Id: P30 DK058404
Agency: NINDS NIH HHS, United States
Id: T32 NS007491
Agency: NIDDK NIH HHS, United States
Id: U2C DK059637
Agency: NICHD NIH HHS, United States
Id: U54 HD083211
Agency: NIGMS NIH HHS, United States
Id: R25 GM062459
Agency: NIDA NIH HHS, United States
Id: R01 DA042475
Agency: NEI NIH HHS, United States
Id: P30 EY008126
Agency: NCI NIH HHS, United States
Id: P30 CA068485
Agency: NIH HHS, United States
Id: S10 OD018075
Agency: NIMH NIH HHS, United States
Id: K01 MH107765
Agency: NIDDK NIH HHS, United States
Id: U24 DK059637
Agency: NIGMS NIH HHS, United States
Id: T32 GM007347
Agency: NIDDK NIH HHS, United States
Id: P30 DK020593

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