Correlates of motivation and reward

Ikemoto, Satoshi

Abstract

Psychostimulant drugs can elicit seemingly paradoxical mixtures of appetitive and aversive behaviors. To investigate the neural bases of these behaviors, we gave awake behaving rats systemic injections of amphetamine while making single-unit recordings from the lateral habenula (LHb), a region previously shown to encode negative reward prediction errors. At a population level, LHb units were inhibited in a dose-dependent manner by amphetamine injections (1mg/kg and 3mg/kg, i.p.). Closer examination showed that X/Y (??%) of LHb units were inhibited (XX%), while the other half showed no response or, in a few cases, weak excitation. These results closely parallel those from intracellularly recorded LHb cells in brain slices. Dopamine (DA, 50uM) application inhibited 29/49 (59.2%) neurons, an effect that was completely blocked by the D2 antagonist eticlopride (200nM), while quinpirole inhibited 7/13 (53.8%) cells. The remaining neurons either did not respond to DA or were slightly excited, similar to the in vivo results. Further, bath applied amphetamine (n = 5, 10uM) resulted in a 66% reduction in action potential firing frequency, which correlated with a 50pA change in holding current. In awake behaving rats, inhibition of LHb units peaked at 15 minutes post-injection, and persisted for nearly an hour. Interestingly, a subset of LHb neurons show compensatory rebound excitations persisting for much longer, in some cases up to 3 hours after injection. These rebound excitations occur at a time when the rewarding effects of amphetamine (as measured by conditioned place preference) are greatly attenuated, possibly reflecting early stages of drug withdrawal. We hypothesize that this delayed excitation reflects a compensatory reaction that contributes to the subjective properties of drug withdrawal. Furthermore, because LHb stimulation inhibits a large percentage of dopamine neurons, presumably via GABAergic neurons in the rostromedial tegmentum (RMTg), our findings suggest the possibility that dopamine neurons and LHb neurons are reciprocally inhibitory, although further study is needed to test this hypothesis.