Many strong rewards, including abused drugs, also produce aversive effects that are poorly understood. For example, cocaine can produce aversive conditioning after its rewarding effects have dissipated, consistent with opponent process theory, but the neural mechanisms involved are not well known. Using electrophysiological recordings in awake rats, we found that some neurons in the lateral habenula (LHb), where activation produces aversive conditioning, exhibited biphasic responses to single doses of intravenous cocaine, with an initial inhibition followed by delayed excitation paralleling cocaine's shift from rewarding to aversive. Recordings in LHb slice preparations revealed similar cocaine-induced biphasic responses and further demonstrated that biphasic responses were mimicked by dopamine, that the inhibitory phase depended on dopamine D2-like receptors, and that the delayed excitation persisted after drug washout for prolonged durations consistent with findings in vivo. c-Fos experiments further showed that cocaine-activated LHb neurons preferentially projected to and activated neurons in the rostromedial tegmental nucleus (RMTg), a recently identified target of LHb axons that is activated by negative motivational stimuli and inhibits dopamine neurons. Finally, pharmacological excitation of the RMTg produced conditioned place aversion, whereas cocaine-induced avoidance behaviors in a runway operant paradigm were abolished by lesions of LHb efferents, lesions of the RMTg, or by optogenetic inactivation of the RMTg selectively during the period when LHb neurons are activated by cocaine. Together, these results indicate that LHb/RMTg pathways contribute critically to cocaine-induced avoidance behaviors, while also participating in reciprocally inhibitory interactions with dopamine neurons.

Background Psychiatric disorders such as addiction and mania are marked by persistent reward-seeking despite highly negative or aversive outcomes, but the neural mechanisms underlying this aberrant decision-making are unknown. The recently identified rostromedial tegmental nucleus (RMTg) encodes a wide variety of aversive stimuli and sends robust inhibitory projections to midbrain dopamine neurons, leading to the hypothesis that the RMTg provides a brake to reward signaling in response to aversive costs (1, 2). Methods To test the role of the RMTg in punished reward seeking, adult male Sprague Dawley rats were tested in several cost-benefit decision tasks after excitotoxic lesions of the RMTg, or temporally specific optogenetic inhibition of RMTg efferents in the ventral tegmental area (VTA). Results RMTg lesions drastically impaired the ability of footshock to suppress operant responding for food. Optogenetic inhibition showed that this resistance to punishment was due in part to RMTg activity at the precise moment of shock delivery and mediated by projections to the VTA, consistent with an aversive “teaching signal” role for the RMTg during encoding of the aversive event. We observed a similar resistance to punishment when the RMTg was selectively inhibited immediately prior to the operant lever press, consistent with a second distinct role for the RMTg during action selection. These effects were not attributable to RMTg effects on learning rate, locomotion, shock sensitivity, or perseveration. Conclusions The RMTg has two strong and dissociable roles during both encoding and recall of aversive consequences of behavior.