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Nat Neurosci. 2016 Aug;19(8):1019-24. doi: 10.1038/nn.4334. Epub 2016 Jun 27.

Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse.

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Institut du Fer à Moulin, Paris, France.
Inserm, UMR-S 839, Paris, France.
Université Pierre et Marie Curie (UPMC), Paris, France.
Graduate School of Life Sciences, University of Utrecht, Utrecht, the Netherlands.
UPMC University Paris 06, UM 119 Neuroscience Paris Seine (NPS), CNRS UMR 8246, Inserm U1130, Paris, France.
Clinic for Epilepsy Life &Brain Center, University Clinic of Bonn, Bonn, Germany.


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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