Food-associated Cues Research Articles

You eye what you eat: BMI, consumption patterns, and dieting status predict temporal attentional bias to food-associated images

People know that overconsumption of high-fat high-sugar (HFHS) foods have negative consequences for physical and cognitive wellbeing but continue to consume these foods in excess, leading to recent proposals to model obesity as an addiction disorder. The current experiment tested, in a large undergraduate sample (N = 306), the hypothesis that obesity and overconsumption is linked with an oversensitivity to rewards that drives attentional biases towards foods and food-associated cues. Using a modified emotion-induced blindness task with food-related distractors, we examined the extent to which attentional biases to images of HFHS foods were accounted for by BMI, HFHS food intake, self-reported hunger, time since last meal, diet status, food preferences, and attentional control. We also examined whether the same individual differences predicted attentional priority to cues that have a learned association with HFHS foods (i.e., images of food logos). Contrary to our predictions, higher BMI predicted less attentional priority for images of food and food logos. At the same time, increased consumption of HFHS foods predicted increased attentional priority for food images, whereas dieting predicted increased attentional priority for food logo images. Our results suggest that different people may preferentially attend to food versus food logo imagery based on their relationships with food. More broadly, our results support the theoretical perspective that attentional biases to food-associated stimuli can be affected by various competing, state-related factors.

Habituation or sensitization of brain response to food cues: Temporal dynamic analysis in an functional magnetic resonance imaging study.

In the modern obesogenic environment, heightened reactivity to food-associated cues plays a major role in overconsumption by evoking appetitive responses. Accordingly, functional magnetic resonance imaging (fMRI) studies have implicated regions of the salience and rewards processing in this dysfunctional food cue-reactivity, but the temporal dynamics of brain activation (sensitization or habituation over time) remain poorly understood. Forty-nine obese or overweight adults were scanned in a single fMRI session to examine brain activation during the performance of a food cue-reactivity task. A general linear model (GLM) was used to validate the activation pattern of food cue reactivity in food > neutral contrast. The linear mixed effect models were used to examine the effect of time on the neuronal response during the paradigm of food cue reactivity. Neuro-behavioral relationships were investigated with Pearson's correlation tests and group factor analysis (GFA). A linear mixed-effect model revealed a trend for the time-by-condition interactions in the left medial amygdala [t(289) = 2.21, β = 0.1, P = 0.028], right lateral amygdala [t(289) = 2.01, β = 0.26, P = 0.045], right nucleus accumbens (NAc) [t(289) = 2.81, β = 0.13, P = 0.005] and left dorsolateral prefrontal cortex (DLPFC) [t(289) = 2.58, β = 0.14, P = 0.01], as well as in the left superior temporal cortex [42 Area: t(289) = 2.53, β = 0.15, P = 0.012; TE1.0_TE1.2 Area: t(289) = 3.13, β = 0.27, P = 0.002]. Habituation of blood-oxygenation-level-dependent (BOLD) signal during exposure to food vs. neutral stimuli was evident in these regions. We have not found any area in the brain with significant increased response to food-related cues over time (sensitization). Our results elucidate the temporal dynamics of cue-reactivity in overweight and obese individuals with food-induced craving. Both subcortical areas involved in reward processing and cortical areas involved in inhibitory processing are getting habituated over time in response to food vs. neutral cues. There were significant bivariate correlations between self-report behavioral/psychological measures with individual habituation slopes for the regions with dynamic activity, but no robust cross-unit latent factors were identified between the behavioral, demographic, and self-report psychological groups. This work provides novel insights into dynamic neural circuit mechanisms supporting food cue reactivity, thereby suggesting pathways in biomarker development and cue-desensitization interventions.

Acute high-intensity interval exercise attenuates incubation of craving for foods high in fat.

Food-seeking behaviors can be driven by food-associated cues, and palatable food seeking in response to food cues is a risk factor for obesity development. Cue-induced food seeking increases following a period of abstinence, a behavioral phenomenon known as "incubation of craving," which may contribute to an individual's difficulty abstaining from palatable foods. Pharmacological and environmental manipulations have been employed to try and reduce incubation of craving, albeit primarily in drug abuse paradigms. The goal of this study was to determine whether forced exercise can attenuate incubation of high-fat food craving. Male Sprague Dawley rats learned to self-administer high-fat pellets (60%) in combination with a compound cue (light + tone). The influence of high-intensity interval exercise on the time-dependent increase in cue-induced lever responding was investigated 30 days after the first cue test. Rats exposed to exercise during abstinence did not express incubation of craving. The results suggest that high-intensity exercise can prevent the establishment of incubation of craving for foods high in fat and may reduce cue-induced maladaptive food-seeking behaviors that contribute to overeating and obesity.

Dopamine D1-like receptors in prelimbic, but not infralimbic, medial prefrontal cortex contribute to chronic stress-induced increases in cue-induced relapse to palatable food seeking during forced abstinence

Chronic stress exposure causes increased vulnerability to future relapse-like behavior in male, but not female, rats with a history of palatable food self-administration. These effects are mediated by dopamine D1-like receptors, but the anatomical location of chronic stress’ dopaminergic mechanism is not known. Thus, male rats were trained to respond for palatable food pellets in daily sessions. During subsequent forced abstinence from food self-administration, stress was manipulated (0 or 3 h restraint/day for 7 days). Rats also received bilateral microinjections of the D1-like receptor antagonist SCH-23390 (0.25 μg/0.5 μl/side) or vehicle (0.5 μl/side) delivered to either prelimbic or infralimbic medial prefrontal cortex prior to daily treatments. Relapse tests in the presence of food-associated cues were conducted 7 days after the last treatment. Stress caused an increase and a decrease in responding during relapse tests in rats that received prelimbic vehicle and SCH-23390 infusions, respectively, relative to unstressed rats. In rats receiving IL infusions, however, stress caused an increase in responding regardless of whether the infusion was vehicle or SCH-23390. These results establish a specific role for prelimbic D1-like receptors in chronic stress-potentiated relapse.

Food addiction symptoms are related to neuroaffective responses to preferred binge food and erotic cues

It has been proposed that some individuals succumb to maladaptive eating behaviors because, like those with addiction, they attribute high incentive salience to food-associated cues. Here, we tested whether women that attribute high incentive salience to food-associated cues report high food addiction symptomatology. In 76 college women, we assessed self-reported food addiction symptoms using the Yale Food Addiction Scale and we recorded event-related potentials (ERPs, a direct measure of brain activity) to preferred food, erotic, unpleasant, and neutral images. We used the amplitude of the late positive potential (LPP, a component of the ERPs) as an index of the incentive salience attributed to the images. Using a multivariate classification algorithm (k-means cluster analysis), we identified two neuroaffective reactivity profiles that have been previously associated with individual differences in the tendency to attribute incentive salience to cues and with differences in vulnerability to addictive behaviors. Results showed that women with elevated LPP responses to preferred food cues relative to erotic images report higher food addiction symptoms than women with low LPP responses to preferred food cues relative to other motivationally relevant stimuli. These results support the hypothesis that individual differences in the tendency to attribute incentive salience to food cues play an important role in modulating food addiction symptomatology.

Bumble bees show an induced preference for flowers when primed with caffeinated nectar and a target floral odor

Caffeine is a widely occurring plant defense chemical1,2 that occurs in the nectar of some plants, e.g., Coffea or Citrus spp., where it may influence pollinator behavior to enhance pollination.3,4 Honey bees fed caffeine form longer lasting olfactory memory associations,5 which could give plants with caffeinated nectar an adaptive advantage by inducing more visits to flowers. Caffeinated free-flying bees show enhanced learning performance6 and are more likely to revisit a caffeinated target feeder or artificial flower,7-9 although it is not clear whether improved memory of the target cues or the perception of caffeine as a reward is the cause. Here, we show that inexperienced bumble bees (Bombus terrestris) locate new food sources emitting a learned floral odor more consistently if they have been fed caffeine. In laboratory arena tests, we fed bees a caffeinated food alongside a floral odor blend (priming) and then used robotic experimental flowers10 to disentangle the effects of caffeine improving memory for learned food-associated cues versus caffeine as a reward. Inexperienced bees primed with caffeine made more initial visits to target robotic flowers emitting the target odor compared to control bees or those primed with odor alone. Caffeine-primed bees tended to improve their floral handling time faster. Although the effects of caffeine were short lived, we show that food-locating behaviors in free-flying bumble bees can be enhanced by caffeine provided in the nest. Consequently, there is potential to redesign commercial colonies to enhance bees' forage focus or even bias bees to forage on a specific crop.

Reward-related dynamical coupling between basolateral amygdala and nucleus accumbens.

Recognizing reward-related stimuli is crucial for survival. Neuronal projections from the basolateral amygdala (BLA) to the nucleus accumbens (NAc) play an important role in processing reward-related cues. Previous studies revealed synchronization between distant brain regions in reward-sensitive neurocircuits; however, whether the NAc synchronizes with the BLA is unknown. Here, we recorded local field potentials simultaneously from the BLA and NAc of rats during social preference tests and an appetitive conditioning test in which explicit stimuli were associated with food. BLA-NAc coherence in the theta band (5-8Hz) increased in response to food-associated cues. Meanwhile, the modulatory strength of theta-high gamma (50-110Hz) phase-amplitude cross-frequency coupling (PAC) in the NAc decreased. Importantly, both of these neuromodulations disappeared upon extinction. In contrast, both theta and gamma power oscillations in each region increased in the presence of social conspecifics or contexts associated with conspecifics, but coherence did not change. To potentially disrupt behavior and associated neural activity, a subgroup of rats was exposed prenatally to valproic acid (VPA), which has been shown to disrupt transcriptome and excitatory/inhibitory balance in the amygdala. VPA-exposed rats demonstrated impulsive-like behavior, but VPA did not affect BLA-NAc coherence. These findings reveal changes in BLA-NAc coherence in response to select reward-related stimuli (i.e., food-predictive cues); the differences between the tasks used here could shed light onto the functional nature of BLA-NAc coherence and are discussed.

Changes in neural network connectivity in mice brain following exposures to palatable food

Previously, satiated animals or human subjects can still be motivated to eat by palatable food-associated cues. However, neural circuitries of hedonic hunger have not been well investigated. This study identified neural network connectivities between major brain areas in response to chocolate-associated cues following repeated exposures to chocolate. Adult male Swiss albino ICR mice were anesthetized and implanted with intracranial electrodes in the lateral hypothalamus (LHa), nucleus accumbens (NAc), olfactory bulb (OB) and hippocampus (HP) for local field potential (LFP) recording. LFP oscillations were recorded before and after repeated exposures to chocolate for chocolate experienced group whereas control group was not exposed to chocolate. On testing days, satiated animals were individually put into a place preference-like apparatus with two opposite chambers of chocolate and normal chow scent cues, separately. The results showed that chocolate experienced group significantly increased time spent in chocolate chamber whereas control group did not. One-way ANOVA revealed significant influence of chocolate sessions on LFP spectral powers of multiple frequencies in the LHa (delta, low gamma and high gamma) and NAc (high gamma). Moreover, coherence function analyses also highlighted significant increases in LHa-NAc and LHa-OB, and decrease in LHa-HP coherent activities in response to olfactory cues of chocolate. This study demonstrated modifications of neural network connectivity and associative learning following multiple exposures to palatable food. These findings might explain why energy homeostatic hunger is overridden by hedonic hunger.

Diverse Food-Sensing Neurons Trigger Idiothetic Local Search in Drosophila

Foraging animals may benefit from remembering the location of a newly discovered food patch while continuing to explore nearby [1, 2]. For example, after encountering a drop of yeast or sugar, hungry flies often perform a local search [3, 4]. That is, rather than remaining on the food or simply walking away, flies execute a series of exploratory excursions during which they repeatedly depart and return to the resource. Fruit flies, Drosophila melanogaster, can perform this food-centered search behavior in the absence of external landmarks, instead relying on internal (idiothetic) cues [5]. This path-integration behavior may represent a deeply conserved navigational capacity in insects [6, 7], but its underlying neural basis remains unknown. Here, we used optogenetic activation to screen candidate cell classes and found that local searches can be initiated by diverse sensory neurons. Optogenetically induced searches resemble those triggered by actual food, are modulated by starvation state, and exhibit key features of path integration. Flies perform tightly centered searches around the fictive food site, even within a constrained maze, and they can return to the fictive food site after long excursions. Together, these results suggest that flies enact local searches in response to a wide variety of food-associated cues and that these sensory pathways may converge upon a common neural system for navigation. Using a virtual reality system, we demonstrate that local searches can be optogenetically induced in tethered flies walking on a spherical treadmill, laying the groundwork for future studies to image the brain during path integration. VIDEO ABSTRACT.

Anterior insula activity regulates the associated behaviors of high fat food binge intake and cue reactivity in male rats

Binge eating episodes are characterized by uncontrollable, excessive intake of food and are associated with binge eating disorder and some subtypes of obesity. One factor thought to contribute to binge episodes is a high level of reactivity to food-associated cues (i.e., cue reactivity). The insula is a neural node poised to regulate both binge eating and cue reactivity because of its prominent role in interpretation of internal and external cues. This work established a positive association between high fat food (HFF) binge intake and cue reactivity in male rats. Furthermore, we demonstrated that activation of the anterior insula suppressed both HFF binge intake and cue reactivity, without altering homeostatic intake of food. We further show that attenuation of HFF binge intake and cue reactivity is not due to decreased food-reward efficacy or deficits in motivation. Together, these data establish a key role for the anterior insula in the control of binge eating related-behaviors and support novel avenues for the treatment of binge eating.

Mood and restrained eating moderate food-associated response inhibition in obese individuals with binge eating disorder

Recent research suggests that obese individuals with binge eating disorder (BED) show deficits in response inhibition, but findings are not consistent, especially when food-associated stimuli are presented. The aim of the present study was to assess the role of moderating factors by taking into account restrained eating and mood. Seventeen obese women with BED, 20 obese women without BED and 20 normal-weight controls (NW) were recruited. A go/no-go task with food-associated and control stimuli and questionnaires were administered. Obese BED showed less impairment of response inhibition to food-associated than to control stimuli, while this pattern was reversed in NW; no differences were observed for obese participants. Interestingly, group differences were moderated by the interaction of restrained eating and mood, and obese BED made the most commission errors to food-associated stimuli when they were restrained eaters and in a very positive mood at the time of testing. Our results might explain why some studies did not observe deficits in response inhibition to food-associated cues in BED.

Food-Related Odors Activate Dopaminergic Brain Areas.

Food-associated cues of different sensory categories have often been shown to be a potent elicitor of cerebral activity in brain reward circuits. Smells influence and modify the hedonic qualities of eating experience, and in contrast to smells not associated with food, perception of food-associated odors may activate dopaminergic brain areas. In this study, we aimed to verify previous findings related to the rewarding value of food-associated odors by means of an fMRI design involving carefully preselected odors of edible and non-edible substances. We compared activations generated by three food and three non-food odorants matching in terms of intensity, pleasantness and trigeminal qualities. We observed that for our mixed sample of 30 hungry and satiated participants, food odors generated significantly higher activation in the anterior cingulate cortex (right and left), insula (right), and putamen (right) than non-food odors. Among hungry subjects, regardless of the odor type, we found significant activation in the ventral tegmental area in response to olfactory stimulation. As our stimuli were matched in terms of various perceptual qualities, this result suggests that edibility of an odor source indeed generates specific activation in dopaminergic brain areas.

Food-Predicting Stimuli Differentially Influence Eye Movements and Goal-Directed Behavior in Normal-Weight, Overweight, and Obese Individuals.

Obese individuals have been shown to exhibit abnormal sensitivity to rewards and reward-predicting cues as for example food-associated cues frequently used in advertisements. It has also been shown that food-associated cues can increase goal-directed behavior but it is currently unknown, whether this effect differs between normal-weight, overweight, and obese individuals. Here, we investigate this question by using a Pavlovian-to-instrumental transfer (PIT) task in normal-weight (N = 20), overweight (N = 17), and obese (N = 17) individuals. Furthermore, we applied eye tracking during Pavlovian conditioning to measure the participants’ conditioned response as a proxy of the incentive salience of the predicted reward. Our results show that the goal-directed behavior of overweight individuals was more strongly influenced by food-predicting cues (i.e., stronger PIT effect) than that of normal-weight and obese individuals (p < 0.001). The weight groups were matched for age, gender, education, and parental education. Eye movements during Pavlovian conditioning also differed between weight categories (p < 0.05) and were used to categorize individuals based on their fixation style into “high eye index” versus “low eye index” as well. Our main finding was that the fixation style exhibited a complex interaction with the weight category. Furthermore, we found that normal-weight individuals of the group “high eye index” had higher body mass index within the healthy range than individuals of the group “low eye index” (p < 0.001), but this relationship was not found within in the overweight or obese groups (p > 0.646). Our findings are largely consistent with the incentive sensitization theory predicting that overweight individuals are more susceptible to food-related cues than normal-weight controls. However, this hypersensitivity might be reduced in obese individuals, possibly due to habitual/compulsive overeating or differences in reward valuation.

Cue-induced food seeking after punishment is associated with increased Fos expression in the lateral hypothalamus and basolateral and medial amygdala.

In humans, relapse to unhealthy eating habits following dieting is a significant impediment to obesity treatment. Food-associated cues are one of the main triggers of relapse to unhealthy eating during self-imposed abstinence. Here we report a behavioral method examining cue-induced relapse to food seeking following punishment-induced suppression of food taking. We trained male rats to lever press for food pellets that were delivered after a 10-s conditional stimulus (CS) (appetitive). Following training, 25% of reinforced lever presses resulted in the presentation of a compound stimulus consisting of a novel CS (aversive) and the appetitive CS followed by a pellet and footshock. After punishment-imposed abstinence, we tested the rats in an extinction test where lever pressing resulted in the presentation of either the appetitive or aversive CS. We then compared activity of lateral hypothalamus (LH) and associated extrahypothalamic regions following this test. We also assessed Fos expression in LH orexin and GABA neurons. We found that cue-induced relapse of food seeking on test was higher in rats tested with the appetitive CS compared to the aversive CS. Relapse induced by the appetitive CS was associated with increased Fos expression in LH, caudal basolateral amygdala (BLA), and medial amygdala (MeA). This relapse was also associated with increased Fos expression in LH orexin and VGAT-expressing neurons. These data show that relapse to food seeking can be induced by food-associated cues after punishment-imposed abstinence, and this relapse is associated with increased activity in LH, caudal BLA, and MeA. (PsycINFO Database Record

Hunger-Dependent Enhancement of Food Cue Responses in Mouse Postrhinal Cortex and Lateral Amygdala

The needs of the body can direct behavioral and neural processing toward motivationally relevant sensory cues. For example, human imaging studies have consistently found specific cortical areas with biased responses to food-associated visual cues inhungry subjects, but not in sated subjects. To obtain a cellular-level understanding of these hunger-dependent cortical response biases, we performed chronic two-photon calcium imaging in postrhinal association cortex (POR) and primary visual cortex (V1) of behaving mice. As in humans, neurons in mouse POR, but not V1, exhibited biases toward food-associated cues that were abolished by satiety. This emergent bias was mirrored by the innervation pattern of amygdalo-cortical feedback axons. Strikingly, these axons exhibited even stronger food cue biases and sensitivity to hunger state and trial history. These findings highlight a direct pathway by which the lateral amygdala may contribute to state-dependent cortical processing of motivationally relevant sensory cues.

Enhancing inhibitory learning to reduce overeating: Design and rationale of a cue exposure therapy trial in overweight and obese women

The prevalence of overweight and obesity has increased substantially over the last decades. Weight loss attempts in overweight individuals are common, though they seldom result in successful long-term weight loss. One very promising treatment is food cue exposure therapy, during which overweight individuals are repeatedly exposed to food-associated cues (e.g., the sight, smell and taste of high-calorie foods, overeating environments) without eating in order to extinguish cue-elicited appetitive responses to food cues. However, only few studies have tested the effectiveness of cue exposure, especially with regards to weight loss. For exposure treatment of anxiety disorders, it has been proposed that inhibitory learning is critical for exposure to be effective. In this RCT, we translated techniques proposed by Craske et al. (2014) to the appetitive domain and developed a novel cue exposure therapy for overeating aimed at maximizing inhibitory learning. The current RCT tested the effectiveness of this 8-session cue exposure intervention relative to a control intervention in 45 overweight adult (aged 18–60) females at post-treatment and 3-month follow-up, of which 39 participants completed the study. Weight loss, eating psychopathology, food cue reactivity, and snacking behaviour were studied as main treatment outcomes, and mediators and moderators of treatment effects were studied. The presented study design represents an innovative effort to provide valuable clinical recommendations for the treatment of overeating and obesity.

Drosophila Food-Associated Pheromones: Effect of Experience, Genotype and Antibiotics on Larval Behavior.

Animals ubiquitously use chemical signals to communicate many aspects of their social life. These chemical signals often consist of environmental cues mixed with species-specific signals—pheromones—emitted by conspecifics. During their life, insects can use pheromones to aggregate, disperse, choose a mate, or find the most suitable food source on which to lay eggs. Before pupariation, larvae of several Drosophila species migrate to food sources depending on their composition and the presence of pheromones. Some pheromones derive from microbiota gut activity and these food-associated cues can enhance larval attraction or repulsion. To explore the mechanisms underlying the preference (attraction/repulsion) to these cues and clarify their effect, we manipulated factors potentially involved in larval response. In particular, we found that the (i) early exposure to conspecifics, (ii) genotype, and (iii) antibiotic treatment changed D. melanogaster larval behavior. Generally, larvae—tested either individually or in groups—strongly avoided food processed by other larvae. Compared to previous reports on larval attractive pheromones, our data suggest that such attractive effects are largely masked by food-associated compounds eliciting larval aversion. The antagonistic effect of attractive vs. aversive compounds could modulate larval choice of a pupariation site and impact the dispersion of individuals in nature.

Orexin/Hypocretin-1 Receptor Antagonism Selectively Reduces Cue-Induced Feeding in Sated Rats and Recruits Medial Prefrontal Cortex and Thalamus.

The orexin/hypocretin system is important for reward-seeking behaviors, however less is known about its function in non-homeostatic feeding. Environmental influences, particularly cues for food can stimulate feeding in the absence of hunger and lead to maladaptive overeating behavior. The key components of the neural network that mediates this cue-induced overeating in sated rats include lateral hypothalamus, amygdala, and medial prefrontal cortex (mPFC), yet the neuropharmacological mechanisms within this network remain unknown. The current study investigated a causal role for orexin in cue-driven feeding, and examined the neural substrates through which orexin mediates this effect. Systemic administration of the orexin-1 receptor (OX1R) antagonist SB-334867 had no effect on baseline eating, but significantly reduced cue-driven consumption in sated rats. Complementary neural analysis revealed that decreased cue-induced feeding under SB-334867 increased Fos expression in mPFC and paraventricular thalamus. These results demonstrate that OX1R signaling critically regulates cue-induced feeding, and suggest orexin is acting through prefrontal cortical and thalamic sites to drive eating in the absence of hunger. These findings inform our understanding of how food-associated cues override signals from the body to promote overeating, and indicate OX1R antagonism as a potential pharmacologic target for treatment of disordered eating in humans.

Integration of reward signalling and appetite regulating peptide systems in the control of food-cue responses.

Understanding the neurobiological substrates that encode learning about food-associated cues and how those signals are modulated is of great clinical importance especially in light of the worldwide obesity problem. Inappropriate or maladaptive responses to food-associated cues can promote over-consumption, leading to excessive energy intake and weight gain. Chronic exposure to foods rich in fat and sugar alters the reinforcing value of foods and weakens inhibitory neural control, triggering learned, but maladaptive, associations between environmental cues and food rewards. Thus, responses to food-associated cues can promote cravings and food-seeking by activating mesocorticolimbic dopamine neurocircuitry, and exert physiological effects including salivation. These responses may be analogous to the cravings experienced by abstaining drug addicts that can trigger relapse into drug self-administration. Preventing cue-triggered eating may therefore reduce the over-consumption seen in obesity and binge-eating disorder. In this review we discuss recent research examining how cues associated with palatable foods can promote reward-based feeding behaviours and the potential involvement of appetite-regulating peptides including leptin, ghrelin, orexin and melanin concentrating hormone. These peptide signals interface with mesolimbic dopaminergic regions including the ventral tegmental area to modulate reactivity to cues associated with palatable foods. Thus, a novel target for anti-obesity therapeutics is to reduce non-homeostatic, reward driven eating behaviour, which can be triggered by environmental cues associated with highly palatable, fat and sugar rich foods.

Relaxin-3 receptor (Rxfp3) gene deletion reduces operant sucrose- but not alcohol-responding in mice.

The pervasive use of refined sugars in highly accessible, palatable foods and persistent exposure to reinforcing food-associated cues has contributed to overconsumption of sugar-rich diets and the current obesity epidemic in Western society. We have shown previously that brain relaxin-3 mRNA levels positively correlate with sucrose and alcohol intake, and that central antagonism of relaxin-3 receptors (RXFP3) attenuates alcohol self-administration and alcohol-seeking in rats, but food-seeking behaviour and palatable food consumption in mice. To further examine the relationship between motivated appetitive behaviours and relaxin-3/RXFP3 signalling, we investigated the effect of Rxfp3 gene deletion in C57BL/6J mice on sucrose and alcohol self-administration and cue-induced reinstatement (RNST) of sucrose- and alcohol-seeking. Acquisition and maintenance of sucrose and alcohol self-administration was assessed in male wild-type (WT) and Rxfp3 knockout (KO) (C57BL/6J(RXFP3TM1) (/) (DGen) ) littermate mice using fixed ratio (FR) schedules of reinforcement. Mice were subsequently challenged with a progressive ratio (PR) test to measure motivation and, following extinction training, re-exposed to reward-associated cues to evaluate RNST of active lever-responding. Wild-type and Rxfp3 KO mice displayed similar acquisition of FR1 sucrose self-administration, but Rxfp3 KO mice responded less when the instrumental requirement was increased to FR3. These mice also showed a lower breakpoint for sucrose and attenuated cue-induced RNST of sucrose-seeking. Notably, no marked genotype differences in alcohol-responding were observed. In mice, endogenous relaxin-3/RXFP3 signalling promotes self-administration of sucrose under high response requirements and cue-induced RNST of sucrose-seeking, but does not apparently regulate motivation to consume alcohol or alcohol-seeking behaviour.