Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Abstract

Hypocretin (orexin) and dynorphin are neuropeptides with opposing actions on motivated behavior. Orexin is implicated in states of arousal and reward, whereas dynorphin is implicated in depressive-like states. We show that, despite their opposing actions, these peptides are packaged in the same synaptic vesicles within the hypothalamus. Disruption of orexin function blunts the rewarding effects of lateral hypothalamic (LH) stimulation, eliminates cocaine-induced impulsivity, and reduces cocaine selfadministration. Concomitant disruption of dynorphin function reverses these behavioral changes. We also show that orexin and dynorphin have opposing actions on excitability of ventral tegmental area (VTA) dopamine neurons, a prominent target of orexin-containing neurons, and that intra-VTA orexin antagonism causes decreases in cocaine self-administration and LH self-stimulation that are reversed by dynorphin antagonism. Our findings identify a unique cellular process by which orexin can occlude the reward threshold-elevating effects of coreleased dynorphin and thereby act in a permissive fashion to facilitate reward.O rexin promotes arousal (1) and has been implicated in the rewarding effects of food (2, 3), sexual behavior (4), and drugs of abuse (5, 6). It is produced primarily within the hypothalamus (7), and acts at orexin 1 receptor (OX 1 R) and OX 2 R (also known as Hcrt-R1 and Hcrt-R2), which are expressed in many brain areas, including the ventral tegmental area (VTA) of the midbrain (8). Dynorphin, in contrast, is expressed widely, promotes depressive-like behaviors, and plays a key role in mediating the aversive effects of stress (9, 10). Activation of kappaopioid receptor (KORs), the receptors at which dynorphin acts (11), can attenuate the rewarding effects of drugs of abuse (12, 13) via actions that are mediated, at least in part, within midbrain dopamine (DA) systems (14, 15). Despite their seemingly opposing effects on motivation, there is evidence that these peptides may act in tandem; for example, both orexin and dynorphin are released during electrical stimulation of the hypothalamus (16). Like DA neurons, orexin and dynorphin neurons increase their activity in response to arousing stimuli like rewards and stressors (17). The functional effects of this pattern of neuropeptide coexpression on brain reward systems, and, in turn, on motivated behavior, are poorly understood because orexin and dynorphin are not traditionally studied together. Given their opposing effects on behavior and neuronal physiology when studied alone, it can be hypothesized that dominance in the effects of one peptide over the other could cause widely divergent behavioral phenotypes in reward sensitivity. For example, dominant orexin signaling may enhance reward sensitivity and reward seeking, whereas dominant dynorphin signaling may result in decreased reward sensitivity and anergia. Because these states have major relevance to psychiatric illnesses like addiction and depression, where reward processing is disordered, we sought ...

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