Cocaine withdrawal reduces GABA(B)R transmission at entopeduncular nucleus – lateral habenula synapses

Lateral habenula (LHb) 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 LHb in this process. Specifically, ionotropic GABA(A) receptor (R)‐mediated neurotransmission at EPN‐to‐LHb synapses is reduced during cocaine withdrawal, due to impaired vesicle filling. Recent studies have shown that metabotropic GABA(B)R signaling also controls LHb activity, although its role at EPN‐to‐LHb synapses during drug withdrawal is unknown. Here, we predicted that cocaine treatment would reduce GABA(B)R‐mediated neurotransmission at EPN‐to‐LHb synapses. We chronically treated mice with saline or cocaine, prepared brain slices after two days of withdrawal and performed voltage‐clamp recordings from LHb neurons whilst optogenetically stimulating EPN terminals. Compared with controls, mice in cocaine withdrawal exhibited reduced GABA(A)R‐mediated input to LHb neurons, and a reduced occurrence of GABA(B)R‐signaling at EPN‐to‐LHb synapses. We then assessed the underlying mechanism of this decrease. Application of GABA(B)R agonist baclofen evoked similar postsynaptic responses in EPN‐innervated LHb neurons in saline‐ and cocaine‐treated mice. Release probability at EPN‐to‐LHb GABAergic 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‐LHb 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‐LHb 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.