The projection from the entopeduncular nucleus to the lateral habenula encodes aspects of cocaine withdrawal

MEYE FJ; SOIZA REILLY M; SMIT T; SCHWARZ M; MAMELI M

Milano

Congreso; 6th European Synapse Meeting. Milano, Italy.; 2017

The lateral habenula (LHb) plays a pivotal role in the processing of negative emotional states, including those that occur after the intake of addictive drugs. The negative withdrawal state is an important contributor to relapse behavior and the maintenance of drug addiction. Therefore it is critical to understand the neural underpinnings of aversive drug withdrawal. Previously, we found that cocaine induces synaptic and intrinsic plasticity inthe LHb, which results in hyperexcitability of this region, and which promotes the development of a negative emotional state. However, it is currently unknown how specific afferent regions that project to the LHb play a role in this. In the current study we investigate the role of the projection from the entopeduncular (EP) nucleus, the output structure of the basal ganglia, to the LHb in cocaine withdrawal. To this end we make use of a combination of in vitro electrophysiology and optogenetics. After stereotactic injection of viral vectors encoding for channelrhodopsin-2 into the EP, we treated mice with chronic saline or cocaine.After 1.5 days or 2 weeks of withdrawal, whole-cell voltage clamp recordings in LHb were made and EPLHb connectivity was assessed. We show that abstinence after cocaine exposure induces persistent GABAergic synaptic plasticity in the EPLHb projection. We also demonstrate the functional relevance of these modifications in controlling LHb neuronal output, as GABAergic masking of the excitatory transmission from EP to LHb neurons wasreduced after cocaine exposure. To determine the neural circuits affected by these cocaine-evoked modifications, we use rabies viral strategies to determine which downstream neuronal subpopulation in the midbrain is mostly affected by EP-LHb signaling. Overall, our findings show that the connection between the basal ganglia and lateral habenula can be relevant in encoding aspects of drug withdrawal.