The hypocretins and the reward function: what have we learned so far?

Abstract

A general consensus acknowledges that drug consumption (including alcohol, tobacco, and illicit drugs) constitutes the leading cause of preventable death worldwide. But the global burden of drug abuse extends the mortality statistics. Indeed, the comorbid long-term debilitating effects of the disease also significantly deteriorate the quality of life of individuals suffering from addiction disorders. Despite the large body of evidence delineating the cellular and molecular adaptations induced by chronic drug consumption, the brain mechanisms responsible for drug craving and relapse remain insufficiently understood, and even the most recent developments in the field have not brought significant improvement in the management of drug dependence. Though, recent preclinical evidence suggests that disrupting the hypocretin (orexin) system may serve as an anticraving medication therapy. Here, we discuss how the hypocretins, which orchestrate normal wakefulness, metabolic health and the execution of goal-oriented behaviors, may be compromised and contribute to elicit compulsive drug seeking. We propose an overview on the most recent studies demonstrating an important role for the hypocretin neuropeptide system in the regulation of drug reward and the prevention of drug relapse, and we question the relevance of disrupting the hypocretin system to alleviate symptoms of drug addiction.

Motivational activation: a unifying hypothesis of orexin/hypocretin function

“…Reminiscent of their role in food seeking, orexins are preferentially involved in highly motivated drug seeking (for example, under progressive ratio reinforcement schedules or seeking that is triggered by salient external stimuli such as drug-paired cues or stressors) 30,36,39,41–43 . Acute drug withdrawal also involves orexins, leading some to speculate that orexin neuron activity during withdrawal facilitates drug seeking to alleviate this specific ‘drug need state’ 42 . In sum, orexins have a crucial, but conditional, role in facilitating reward seeking, primarily when the external world and/or the internal milieu signals a need for highly motivated action.…”

Hypocretin (orexin) neuromodulation of stress and reward pathways

“…Intra-VTA infusion of Hcrt increases DA efflux in the prefrontal cortex and NAcc, suggesting that Hcrt modulation of the VTA promotes appetitive responding and motivation for salient environmental cues via enhanced DA receptor signaling [16,17]. An expansive literature describes the contributions of Hcrt neurons and HcrtR signaling to reward-related behavior [18,19]. Here, we simply highlight a few recent examples that add to the growing understanding of how Hcrt modulation of the VTA fits within the context of brain reward function and drug-seeking behavior.…”

“…Hcrt robustly innervates the VTA [13], induces excitatory synaptic plasticity in VTA-DA neurons [14,15], and causes DA release in VTA target regions [16,17]. Reward-seeking behavior (i.e., expression of conditioned place preference, operant self-administration, or reinstatement of either) is associated with activation of Hcrt neurons, and largely attenuated by systemic HcrtR blockade [18,19]. …”

Do Orexins contribute to impulsivity-driven binge consumption of rewarding stimulus and transition to drug/food dependence?

“…Pharmacological evidence has consistently shown a role for OX signaling in drug sensitization, drug seeking behavior and withdrawal syndrome in rodents exposed to ethanol, nicotine, morphine or cocaine (Mahler et al, 2012;Boutrel et al, 2013). Intra-VTA microinjection of OX-A produced a renewal of morphine-induced conditioned place preference, while administration of the OXr1 antagonist SB-334867 decreased the expression of conditioned place preference to morphine (Harris et al, 2005).…”