Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse
Abstract
Cocaine withdrawal produces aversive states and vulnerability to relapse, hallmarks of addiction. The lateral habenula (LHb) encodes negative stimuli and contributes to aversive withdrawal symptoms. However, it remains unclear which inputs to LHb promote this and what the consequences are for relapse susceptibility. We report, using rabies-based retrolabeling and optogenetic mapping, that the entopeduncular nucleus (EPN, the mouse equivalent of the globus pallidus interna) projects to an LHb neuronal subset innervating aversion-encoding midbrain GABA neurons. EPN-to-LHb excitatory signaling is limited by GABAergic cotransmission. This inhibitory component decreases during cocaine withdrawal as a result of reduced presynaptic vesicular GABA transporter (VGAT). This shifts the EPN-to-LHb GABA/glutamate balance, disinhibiting EPN-driven LHb activity. Selective virally mediated VGAT overexpression at EPN-to-LHb terminals during withdrawal normalizes GABAergic neurotransmission. This intervention rescues cocaine-evoked aversive states and prevents stress-induced reinstatement, used to model relapse. This identifies diminished inhibitory transmission at EPN-to-LHb GABA/glutamate synapses as a mechanism contributing to the relapsing feature of addictive behavior.
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The excitatory/inhibitory ratio at each synapse can be adjusted independently by regulating vesicular transporter activity or postsynaptic receptor composition.
“The excitatory/ inhibitory ratio at each synapse can be adjusted independently by regulating the activity of the vesicular transporters 26,41 or adjusting the composition of postsynaptic receptors.”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [41]
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- Authors
- Meye, F. J., Soiza-Reilly, M., Smit, T., Diana, M. A., Schwarz, M. K., & Mameli, M.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- University Hospital Bonn (DE)
- Corresponding author
- Mameli, Manuel
- Venue
- Nature Neuroscience
- Published
- 2016-08
- Volume
- 19
- Issue
- 8
- Pages
- 1019-1024
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2475195708
- Cited by
- 173
- References
- 35
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 27 · 2023: 16 · 2022: 22 · 2021: 15 · 2020: 12 · 2019: 11 · 2018: 15 · 2017: 20 · 2016: 7
- FWCI
- 9.91
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-03-05)
- Open access
- closed
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- cocaine withdrawal, cocaine relapse, lateral habenula, entopeduncular nucleus, globus pallidus internus, glutamate, vesicular GABA transporter, synaptic inhibition, aversive states, stress-induced reinstatement, addiction
- MeSH terms
- Animals, Cocaine, gamma-Aminobutyric Acid, Male, Mesencephalon, Mice, Transgenic, Neural Pathways, Synaptic Transmission, Neurons, Recurrence, Synapses, Glutamic Acid, Habenula, Vesicular Glutamate Transport Protein 2, Mice
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