The mechanisms underlying food restriction-induced enhancement of central rewarding potency of both lateral hypothalamic self-stimulation and drugs of abuse remain unclear.3133 However, two hormones have been mainly involved in the modulation of the LHSS induced by food restriction, insulin30 and leptin.4276 Notably, intracerebroventricular (ICV) infusion of leptin attenuates the effectiveness of the rewarding electrical stimulation in areas of the LH where previous stimulations were enhanced by chronic food restriction, an effect that persists as long as 4 days after a single injection.42 Interestingly, Hcrt neurons express leptin receptors, and leptin regulates Hcrt neurons.3977 Secondly, neurons containing hypocretin/orexin in the LH are activated by insulin-induced acute hypoglycemia.4078 Therefore, it is possible that the hypocretin system mediates both insulin and leptin effects on LHSS, and thus could be considered as the link between the controls of energy homeostasis and the brain reward function. Interestingly, the hypocretin neurons have been proposed to regulate arousal according to energy balance in mice. Indeed, hypocretin/orexin neurons-ablated mice fail to exhibit fasting-induced arousal whereas fasting induces a significant increase in both wakefulness and locomotor activity in wild type mice.41 Hence, evidence showing elevations in ICSS thresholds after Hcrt-1 administration reflects a transient decrease in brain reward function, which may ultimately reflect incentive motivation for food-seeking. All together, these observations suggest that the hypocretin system could integrate sensory stimuli (including metabolic needs), and relay the information to the brainstem nuclei, notably the LC, the LDT/PPT and the VTA. Activation of the HPA axis could also be involved given that the Hcrt system regulates CRF release,22-24 and that CRF directly regulates brain reward function.79 In this perspective, hypocretin-induced modulation of brain reward function (via the LDT/PPT) could act in concert with the activation of the LC and the HPA axis to increase the animal's arousal and motivation for food-seeking. The feeding-induced leptin release could then contribute to decrease the firing rate of hypocretin neurons,41 leading ultimately to lowering of arousal threshold, and concomitant decreased motivation for food seeking.
Nevertheless, glucose has complex effects on Hcrt neurons;8081 indeed, whereas decreasing glucose concentrations increase the activity of these neurons (suggesting a role of the hypocretin/orexin system in the phenomenon of hypoglycemic awareness),41 increasing glucose concentrations induce a cessation of firing in isolated Hcrt neurons. Hence, the feeding-induced leptin release provides a signal to the brain that energy stores are high, thus leptin-induced inhibition of Hcrt neurons contributes to a lowering of motivation for food-seeking as previously suggested. To consolidate this feed-back regulation, high concentrations of glucose also decrease Hcrt neurons firing.
To summarize, starvation activates the hypocretin/orexin system which relay these signals to the brainstem nuclei involved in the modulation of brain reward function and arousal. The concomitant brain reward function decrease, usually observed under drug withdrawal, can be considered here as a "food withdrawal" which will lead to food seeking and, ultimately, food taking. In this perspective, the hypocretin system could be considered as a key relay that promotes incentive motivation for food-seeking, and as such enhances wakefulness and locomotor activity.82
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