Elsevier

Physiology & Behavior

Volume 97, Issue 1, 20 April 2009, Pages 1-13
Physiology & Behavior

Endogenous nociceptin modulates diet preference independent of motivation and reward

https://doi.org/10.1016/j.physbeh.2008.12.008Get rights and content

Abstract

Previous studies show that the opioid peptide nociceptin stimulates food intake. Here, we studied nociceptin receptor knockout (NOP KO) mice in various behavioral paradigms designed to differentiate psychological and physiological loci at which endogenous nociceptin might control feeding. When presented a choice under food restriction, NOP KO mice displayed reduced preference for high sucrose diet, but lower intake of high fat diet under no-choice conditions. These responses were absent under ad libitum feeding conditions. Conditioned place preference to high fat diet under food-deprived conditions was unaltered in NOP KO mice, suggesting no difference in reward responses. Furthermore, operant food self-administration under a variety of conditions showed no genotype-dependent differences, suggesting no differences in the motivational properties of food. Taste reactivity to sucrose was unchanged in NOP KO mice, though NOP KO mice had altered aversive reactions to quinine solutions under ad libitum feeding, suggesting minor differences in the affective impact of palatable and unpalatable tastants. Although NOP KO mice re-fed following food-deprivation showed normal increases in plasma glucose and insulin, multidimensional scaling analysis showed that the relationship between these measures, body weight and plasma leptin was substantially disrupted in NOP KO, particularly in fasted mice. Additionally, the typical positive relationship between body weight and plasma leptin was considerably weaker in NOP KO mice. Together, these findings suggest that endogenous nociceptin differentially modulates diet preference depending on macronutrient content and homeostatic state, independently of the motivating, rewarding or orosensory properties of food, but may involve metabolic or postingestive processes.

Introduction

Changes in dietary patterns, particularly due to increases in readily available foods that are both cheap and have high sugar and fat contents, are believed to be a major factor underlying the increasing prevalence of obesity in Western nations [1]. Amongst the multitude of neurochemical systems involved in regulating feeding behavior, endogenous opioid peptides have been well established [2], [3]. The actions of endogenous opioids may be due to effects on fundamental post-ingestive mechanisms regulating food intake, or effects on higher psychological processes such as motivation and reward (see [2], [4], [5]). For instance, endogenous opioid peptides such as endorphin and enkephalin have well-established roles in mediating the rewarding properties of stimuli such as addictive drugs. Likewise, numerous studies suggest that endogenous opioids mediate the rewarding properties of palatable foods, such as those high in sugar or fat content [6].

Nociceptin (also known as orphanin FQ, abbreviated here to N/OFQ) is a member of the endogenous opioid family (see [7]). Similar to other endogenous opioids, N/OFQ is implicated in rewarded and reinforced behaviors (see [8]). Previous work has led to the hypothesis that N/OFQ generally inhibits reward processes and drug-seeking behavior (see [9] for references), possibly by suppressing activity in neurochemical systems mediating incentive motivation [10] or the hedonic impact of stimuli [11]. Like many neuropeptides, N/OFQ is particularly concentrated in brain areas controlling food intake such as the hypothalamus [12], [13]. When administered intracerebroventricularly (i.c.v.), N/OFQ stimulates food intake [14], [15]. Specifically, it appears that activation of the N/OFQ receptor (termed the “NOP” receptor) initiates and maintains feeding behavior, though a role for N/OFQ in inhibiting processes terminating feeding behavior has also been suggested [16].

Virtually all studies to date have investigated the effects of exogenous N/OFQ on feeding-related behavior. Thus, the purpose of the current study was to seek evidence of a physiological role of endogenous N/OFQ in feeding behavior, particularly in modulating the motivating and rewarding properties of food, by studying NOP receptor KO mice (NOP KO). This is particularly topical as obesity rates are increasing in human populations, and targeting the N/OFQ-NOP receptor system may be beneficial in managing pathological feeding behavior [17]. Thus, we studied NOP KO mice in a battery of behavioral responses to high sucrose or high fat diets (which presumably have different palatabilities) designed to assess these psychological processes. Furthermore, as food deprivation increases the motivation to consume, and the palatability of food [18], many of the responses we studied were compared under free-feeding and food-deprived conditions. We predicted that NOP KO mice would generally consume more of, and prefer palatable diets (i.e. those with high sugar or fat contents) and work harder to obtain them, based on the prediction that such diets would be more rewarding in the absence of endogenous N/OFQ effects [9]. However, we found that NOP KO mice generally consumed less, not more, of high sucrose and high fat diets, though only when food deprived. Furthermore, NOP KO mice did not differ in any behavioral tests aimed at identifying differences in motivation or reward, suggesting that the observed effects were due predominantly to an effect of endogenous N/OFQ on post-ingestive processes.

Section snippets

Animals

Experimental protocols used throughout the study were approved by the institutional review committee and were in accord with NIH ethics guidelines. Adult male wild-type or NOP KO mice (aged 9 to 30 weeks, see specific experiments for details), maintained on a C57BL6 background, were generated by mating heterozygous male and female pairs from a colony maintained in the RIKEN Brain Science Institute animal facility from a previously described NOP KO line [19] kindly provided by Prof. Hiroshi

Experiment 1: Voluntary feeding under food-deprived conditions and drinking behavior under free-feeding conditions

As shown in Fig. 1a, both NOP KO and wild-type mice showed a progressive increase in intake of normal and high sucrose diets when presented on alternating days under non-choice conditions (genotype: F1, 22 = 0.12, p = 0.73; time: F5, 110 = 96.33; p < 0.0001). Notably, abrupt increases in intake were recorded each time normal diet was re-presented, such that intake almost doubled by the third presentation. Both genotypes showed a steady loss of body weight, particularly during the first four days of

Discussion

The purpose of this study was to test the hypothesis that endogenous N/OFQ suppresses the motivating and rewarding properties of foods. We found that mice lacking the influence of endogenous N/OFQ due to genetic deletion of the NOP receptor showed generally lower voluntary intake of solid diets high in sucrose or fat. This is in contrast to drinking of liquid diets such as sucrose solutions or oil (though drinking behavior was only studied here under water-deprived conditions). This effect

Acknowledgements

We thank Ms. Reiko Takahashi for scoring of taste reactivity, Dr. Shuichi Kimura for helpful comments on the study, Dr. Michel Vidal-Naquet for assistance with multidimensional scaling analysis, Dr. Nobuhiko Kojima for providing experimental space and Dr. Hiroshi Takeshima for progenitor mice. This work was supported by the RIKEN Brain Science Institute and a Grant-in-Aid for Scientific Research # 18500256.

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    1

    Current address: Shimojo Implicit Brain Function Project, ERATO, Japan Science and Technology Agency, NTT Atsugi Research and Development Center, Kanagawa 243-0198, Japan.

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