A major problem in the treatment of cocaine addiction is high rates of relapse. Relapse is often provoked by acute reexposure to cocaine-associated cues or to cocaine itself. The lateral habenula (LHb), an epithalamic nucleus, regulates midbrain dopaminergic systems that are known to be involved in cocaine taking and seeking behaviors. However, the role of this nucleus in cocaine self-administration and reinstatement of cocaine seeking has not been entirely parsed out. We used an operant self-administration and reinstatement procedure to explore the effect of Designer Receptors Exclusively Activated by Designer Drug (DREADD)-induced transient inhibition of LHb neurons on cocaine taking and seeking. Firstly, rats were injected with adeno-associated viral vectors expressing hM 4 D i (a G i/o-coupled DREADD) into the LHb, trained to self-administer cocaine (0.75 mg/kg/infusion), and the effect of clozapine-N-oxide (an inert ligand that activates DREADDs) was assessed on cocaine self-administration. Secondly, rats were injected with hM 4 D i into the LHb, trained to self-administer cocaine; the operant response was extinguished, and cue-and cocaine priming-induced reinstatement was assessed. Thirdly, we tested the generality of the effect of inhibiting LHb neurons by assessing the effect of this manipulation on food-taking and seeking. hM 4 D i-induced inhibition of LHb neurons increased cocaine but not food self-administration. In contrast, this manipulation decreased reinstatement of cocaine, but not food-seeking. Taken together, our data suggest that hM 4 D i-induced LHb inhibition specifically mediates taking and seeking behaviors reinforced by cocaine but not by natural reinforcers. Further, our data indicate a dissociation in the role of LHb neurons on cocaine self-administration versus reinstatement of cocaine seeking.

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