An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement

Guilian Tian; May Hui; Desiree Macchia; Pieter Derdeyn; Alexandra Rogers; Elizabeth Hubbard; Chengfeng Liu; Jose J Vasquez; Lara Taniguchi; Katrina Bartas; Sean Carroll; Kevin T Beier

doi:10.1016/j.celrep.2022.110775

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement

Cell Rep. 2022 May 3;39(5):110775. doi: 10.1016/j.celrep.2022.110775.

Authors

Affiliations

¹ Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92617, USA.
² Program in Mathematical, Computational, and Systems Biology, University of California, Irvine, Irvine, CA 92617, USA.
³ Interdepartmental Neuroscience Program, University of California, Irvine, Irvine, CA 92617, USA.
⁴ Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92617, USA; Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92617, USA; Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA; Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92617, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92617, USA; UCI Mind, University of California, Irvine, Irvine, CA 92617, USA. Electronic address: kbeier@uci.edu.

Abstract

Although midbrain dopamine (DA) circuits are central to motivated behaviors, our knowledge of how experience modifies these circuits to facilitate subsequent behavioral adaptations is limited. Here we demonstrate the selective role of a ventral tegmental area DA projection to the amygdala (VTA^DA→amygdala) for cocaine-induced anxiety but not cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach reveals a persistent elevation in spontaneous and task-related activity of inhibitory GABAergic cells from the bed nucleus of the stria terminalis (BNST) and downstream VTA^DA→amygdala cells that can be detected even after a single cocaine exposure. Activity in BNST^GABA→midbrain cells is related to cocaine-induced anxiety but not reward or sensitization, and silencing this projection prevents development of anxiety during protracted withdrawal after cocaine administration. Finally, we observe that VTA^DA→amygdala cells are strongly activated after a challenge exposure to cocaine and that activity in these cells is necessary and sufficient for reinstatement of cocaine place preference.

Keywords: CP: Neuroscience; addiction; anxiety; calcium imaging; chemogenetics; cocaine withdrawal; dopamine; extended amygdala; rabies circuit mapping; reinstatement.

MeSH terms

Amygdala
Anxiety
Cocaine* / adverse effects
Cocaine-Related Disorders*
Dopamine
Humans
Ventral Tegmental Area

Substances

Cocaine
Dopamine

Abstract

MeSH terms

Substances

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