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.