Inactivation of the lateral habenula reduces anxiogenic behavior and cocaine seeking under conditions of heightened stress

Recent anatomical and functional studies have renewed interest in the lateral habenula (LHb), a critical brain region that works in an opponent manner to modulate aversive and appetitive processes. In particular, increased LHb activation is believed to drive anxiogenic states during stressful conditions. Here, we reversibly inactivated the LHb with GABA receptor agonists (baclofen/muscimol) in rats prior to testing in an open field, elevated plus maze, and defensive burying task in the presence or absence of yohimbine, a noradrenergic α2-receptor antagonist that acts as an anxiogenic stressor. In a second set of experiments using a cocaine self-administration and reinstatement model, we inactivated the LHb during extinction responding and cue-induced reinstatement of cocaine seeking in the presence or absence of yohimbine pretreatment. Inactivation of the LHb after yohimbine treatment attenuated anxiogenic behavior by increasing time spent in the open arms and reducing the time spent burying. Inactivation of the LHb also reduced cocaine seeking when cue-induced reinstatement occurred in the presence of yohimbine, but did not affect extinction responding or cue-induced reinstatement by itself. These data demonstrate that the LHb critically regulates states of heightened anxiety during both unconditioned behavior and conditioned appetitive processes.