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Cocaine withdrawal reduces GABA B R transmission at entopeduncular nucleus – lateral habenula synapses
Author(s) -
Tan Dorine,
NunoPerez Alvaro,
Mameli Manuel,
Meye Frank J.
Publication year - 2019
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.14120
Subject(s) - gabaa receptor , neurotransmission , baclofen , neuroscience , gabab receptor , gabaergic , metabotropic receptor , postsynaptic potential , chemistry , muscimol , glutamate receptor , agonist , inhibitory postsynaptic potential , biology , receptor , biochemistry
Lateral habenula ( LH b) hyperactivity plays a pivotal role in the emergence of negative emotional states, including those occurring during withdrawal from addictive drugs. We have previously implicated cocaine‐driven adaptations at synapses from the entopeduncular nucleus ( EPN ) to the LH b in this process. Specifically, ionotropic GABA A receptor (R)‐mediated neurotransmission at EPN ‐to‐ LH b synapses is reduced during cocaine withdrawal, due to impaired vesicle filling. Recent studies have shown that metabotropic GABA B R signaling also controls LH b activity, although its role at EPN ‐to‐ LH b synapses during drug withdrawal is unknown. Here, we predicted that cocaine treatment would reduce GABA B R ‐mediated neurotransmission at EPN ‐to‐ LH b synapses. We chronically treated mice with saline or cocaine, prepared brain slices after two days of withdrawal and performed voltage‐clamp recordings from LH b neurons whilst optogenetically stimulating EPN terminals. Compared with controls, mice in cocaine withdrawal exhibited reduced GABA A R ‐mediated input to LH b neurons, and a reduced occurrence of GABA B R ‐signaling at EPN ‐to‐ LH b synapses. We then assessed the underlying mechanism of this decrease. Application of GABA B R agonist baclofen evoked similar postsynaptic responses in EPN ‐innervated LH b neurons in saline‐ and cocaine‐treated mice. Release probability at EPN ‐to‐ LH b GABA ergic synapses was also comparable between groups. However, incubating brain slices in glutamine to facilitate GABA vesicle filling, normalized GABA B R ‐currents at EPN ‐to‐ LH b synapses in cocaine‐treated mice. Overall, we show that during cocaine withdrawal, together with reduced GABA A R transmission, also GABA B R ‐mediated inhibitory signaling is diminished at EPN ‐to‐ LH b synapses, likely via the same presynaptic deficit. In concert, these alterations are predicted to contribute to the emergence of drug withdrawal symptoms, facilitating drug relapse.