Day-to-day decision-making and long-term goal pursuit require circuits that mediate reward and motivation. It is essential that reward-seeking behavior occurs at appropriate times and in the most suitable locations to achieve optimal fitness. Information regarding these diverse factors is integrated with that from other sources in dopaminergic neurons located in the ventral tegmental area (VTA).

One set of inputs that regulates VTA dopaminergic neurons originates from orexin/hypocretin neurons, which are situated exclusively in the lateral hypothalamus (LH; Korotkova et al., 2003). Orexin stimulates arousal and appetite by binding to Gq-coupled orexin 1 receptors (OxR1), which produce excitatory effects in downstream neurons (de Lecea et al., 1998; Sakurai et al., 1998). Intriguingly, lateral hypothalamic neurons that contain and release orexin also contain and release dynorphin. This is surprising because orexin and dynorphin have opposing effects. Dynorphin binds to Gi/o-coupled kappa opioid receptors (KOR), resulting in the inhibition of spiking and neurotransmitter release in target neurons, including dopaminergic neurons in the VTA (Margolis et al., 2003). In general, dynorphin exerts aversive and anxiogenic effects and reduces food consumption, and dysregulation of the dynorphin–KOR has been linked to alcohol and drug addiction (Anderson et al., 2018). Notably, previous work has suggested that orexin and dynorphin neuropeptides are packaged in the same dense core vesicles and are thus coreleased (Chou et al., 2001; Muschamp et al., 2014). Furthermore, both KORs and OxR1 are expressed in several regions associated with motivation and reward, including the VTA, nucleus accumbens (NAc), bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and PFC (Anderson et al., 2018). This raises a puzzling question: How does the corelease of neuropeptides with opposing effects influence the activity …

Correspondence should be addressed to Nathalie Krauth at nathalie.krauthsund.ku.dk.