title: Cocaine evokes projection-specific synaptic plasticity of lateral habenula neurons.
abstract: Addictive drugs share the ability to increase dopamine (DA) levels and trigger synaptic adaptations in the mesocorticolimbic system, two cellular processes engaged in the early stages of drug seeking. Neurons located in the lateral habenula (LHb) modulate the activity of DA neurons and DA release, and adaptively tune goal-directed behaviors. Whether synaptic modifications in LHb neurons occur upon drug exposure remains, however, unknown. Here, we assessed the influence of cocaine experience on excitatory transmission onto subsets of LHb neurons using a combination of retrograde tracing and ex vivo patch-clamp recordings in mice. Recent evidence demonstrates that AMPA receptors lacking the GluA2 subunit mediate glutamatergic transmission in LHb neurons. We find that cocaine selectively potentiates AMPA receptor-mediated EPSCs in LHb neurons that send axons to the rostromedial tegmental nucleus, a GABAergic structure that modulates the activity of midbrain DA neurons. Cocaine induces a postsynaptic accumulation of AMPA receptors without modifying their subunit composition or single-channel conductance. As a consequence, a protocol pairing presynaptic glutamate release with somatic hyperpolarization, to increase the efficiency of GluA2-lacking AMPA receptors, elicited a long-term potentiation in neurons only from cocaine-treated mice. This suggests that cocaine resets the rules for the induction of synaptic long-term plasticity in the LHb. Our study unravels an early, projection-specific, cocaine-evoked synaptic potentiation in the LHb that may represent a permissive step for the functional reorganization of the mesolimbic system after drug exposure.
authors.affiliation: Institut du Fer à Moulin, 75005 Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Maroteaux
authors.forename: Manuel
authors.initials: M
authors.lastname: Mameli
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D005260:Female; D019262:Habenula / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology
chemical_list: D003042:Cocaine