Abstract
BackgroundThe current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. Loss-of-control over eating and addiction to drugs of abuse share overlapping brain mechanisms including changes in motivational drive, such that stimuli that are often no longer ‘liked’ are still intensely ‘wanted’ [7], . The neurokinin 1 (NK1) receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; however, its role in natural reward seeking remains unknown.Methodology/Principal FindingsWe sought to determine whether the NK1-receptor system plays a role in the reinforcing properties of sucrose using a novel selective and clinically safe NK1-receptor antagonist, ezlopitant (CJ-11,974), in three animal models of sucrose consumption and seeking. Furthermore, we compared the effect of ezlopitant on ethanol consumption and seeking in rodents. The NK1-receptor antagonist, ezlopitant decreased appetitive responding for sucrose more potently than for ethanol using an operant self-administration protocol without affecting general locomotor activity. To further evaluate the selectivity of the NK1-receptor antagonist in decreasing consumption of sweetened solutions, we compared the effects of ezlopitant on water, saccharin-, and sodium chloride (NaCl) solution consumption. Ezlopitant decreased intake of saccharin but had no effect on water or salty solution consumption.Conclusions/SignificanceThe present study indicates that the NK1-receptor may be a part of a common pathway regulating the self-administration, motivational and reinforcing aspects of sweetened solutions, regardless of caloric value, and those of substances of abuse. Additionally, these results indicate that the NK1-receptor system may serve as a therapeutic target for obesity induced by over-consumption of natural reinforcers.
Highlights
Obesity-related pathology is an alarming public health problem worldwide
The effect of the neurokinin 1 (NK1)-receptor antagonist, ezlopitant on sucrose and ethanol operant self-administration was evaluated in Long-Evans rats that had a stable level of ethanol or sucrose responding on a fixed ratio 3 schedule of reinforcement (FR3) schedule
Ezlopitant treatment had an overall main effect on the number of presses on the active lever during operant self-administration of 5% sucrose [F(3,15) = 21.9, P,0.001] and post hoc analysis revealed that all doses of ezlopitant attenuated the number of active lever presses for 5% sucrose (Figure 1A)
Summary
Obesity-related pathology is an alarming public health problem worldwide. Homeostatic control systems precisely regulate body weight and adiposity in a restrictive food environment [1]. The current obesity epidemic is suggested to be partly driven by over-consumption of natural reinforcers such as sugar [2,3,4,5,6]. Natural reinforcers, including sucrose, activate neurons in the ventral tegmental area (VTA). Sucrose consumption increases dopamine release in the nucleus accumbens [17], a brain area exhibiting opiate-like activation following excessive sugar intake [18]. The current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. Loss-of-control over eating and addiction to drugs of abuse share overlapping brain mechanisms including changes in motivational drive, such that stimuli that are often no longer ‘liked’ are still intensely ‘wanted’ [7,8]. The neurokinin 1 (NK1) receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; its role in natural reward seeking remains unknown
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