Appetitive Responding Research Articles

Orphan receptor-GPR52 inverse agonist efficacy in ameliorating chronic stress-related deficits in reward motivation and phasic accumbal dopamine activity in mice

Reward processing dysfunctions e.g., anhedonia, apathy, are common in stress-related neuropsychiatric disorders including depression and schizophrenia, and there are currently no established therapies. One potential therapeutic approach is restoration of reward anticipation during appetitive behavior, deficits in which co-occur with attenuated nucleus accumbens (NAc) activity, possibly due to NAc inhibition of mesolimbic dopamine (DA) signaling. Targeting NAc regulation of ventral tegmental area (VTA) DA neuron responsiveness to reward cues could involve either the direct or indirect—via ventral pallidium (VP)—pathways. One candidate is the orphan G protein-coupled receptor GPR52, expressed by DA receptor 2 NAc neurons that project to VP. In mouse brain-slice preparations, GPR52 inverse agonist (GPR52-IA) attenuated evoked inhibitory postsynaptic currents at NAc-VP neurons, which could disinhibit VTA DA neurons. A mouse model in which chronic social stress leads to reduced reward learning and effortful motivation was applied to investigate GPR52-IA behavioral effects. Control and chronically stressed mice underwent a discriminative learning test of tone-appetitive behavior-sucrose reinforcement: stress reduced appetitive responding and discriminative learning, and these anticipatory behaviors were dose-dependently reinstated by GPR52-IA. The same mice then underwent an effortful motivation test of operant behavior-tone-sucrose reinforcement: stress reduced effortful motivation and GPR52-IA dose-dependently restored it. In a new cohort, GRABDA-sensor fibre photometry was used to measure NAc DA activity during the motivation test: in stressed mice, reduced motivation co-occurred with attenuated NAc DA activity specifically to the tone that signaled reinforcement of effortful behavior, and GPR52-IA ameliorated both deficits. These findings: (1) Demonstrate preclinical efficacy of GPR52 inverse agonism for stress-related deficits in reward anticipation during appetitive behavior. (2) Suggest that GPR52-dependent disinhibition of the NAc-VP-VTA-NAc circuit, leading to increased phasic NAc DA signaling of earned incentive stimuli, could account for these clinically relevant effects.

Activation patterns in male and female forebrain circuitries during food consumption under novelty.

The influence of novelty on feeding behavior is significant and can override both homeostatic and hedonic drives due to the uncertainty of potential danger. Previous work found that novel food hypophagia is enhanced in a novel environment and that males habituate faster than females. The current study's aim was to identify the neural substrates of separate effects of food and context novelty. Adult male and female rats were tested for consumption of a novel or familiar food in either a familiar or in a novel context. Test-induced Fos expression was measured in the amygdalar, thalamic, striatal, and prefrontal cortex regions that are important for appetitive responding, contextual processing, and reward motivation. Food and context novelty induced strikingly different activation patterns. Novel context induced Fos robustly in almost every region analyzed, including the central (CEA) and basolateral complex nuclei of the amygdala, the thalamic paraventricular (PVT) and reuniens nuclei, the nucleus accumbens (ACB), the medial prefrontal cortex prelimbic and infralimbic areas, and the dorsal agranular insular cortex (AI). Novel food induced Fos in a few select regions: the CEA, anterior basomedial nucleus of the amygdala, anterior PVT, and posterior AI. There were also sex differences in activation patterns. The capsular and lateral CEA had greater activation for male groups and the anterior PVT, ACB ventral core and shell had greater activation for female groups. These activation patterns and correlations between regions, suggest that distinct functional circuitries control feeding behavior when food is novel and when eating occurs in a novel environment.

A new circuit underlying the renewal of appetitive Pavlovian responses: Commentary on Brown and Chaudhri (2022).

A new circuit underlying the renewal of appetitive Pavlovian responses: Commentary on Brown and Chaudhri (2022).

Effort and Appetitive Responding in Depression: Examining Deficits in Motivational and Consummatory Stages of Reward Processing Using the Effort-Doors Task

BackgroundReward sensitivity is a dimensional construct central to understanding the nature of depression. Psychophysiological research on this construct has primarily focused on the reward positivity, an event-related potential (ERP) that indexes consummatory reward sensitivity. This study extended prior research by focusing on ERPs that index the motivational component of reward. MethodsA novel effort-for-reward task was used to elicit motivational and consummatory ERPs. Groups consisting of 34 participants with depression and 32 participants without depression were compared across a range of reward-related ERPs. ResultsParticipants with depression exhibited reduced responsivity to effort completion cues following high effort expenditure, reduced anticipation of rewards after low effort expenditure (i.e., the stimulus preceding negativity), and reduced reward positivity following high effort expenditure. ERPs occurring prior to reward receipt accounted for unique variance in depression status and differentiated between subgroups of depressed individuals. ConclusionsFindings support the utility of leveraging multiple ERPs that index separate reward processing deficits to better characterize depression and depressive subtypes.

An operant ethanol self-administration paradigm that discriminates between appetitive and consummatory behaviors reveals distinct behavioral phenotypes in commonly used rat strains

Alcohol use disorder (AUD) constitutes a major burden to global health. Recently, the translational success of animal models of AUD has come under increased scrutiny. Efforts to refine models to gain a more precise understanding of the neurobiology of addiction are warranted. Appetitive responding for ethanol (seeking) and its consumption (taking) are governed by distinct neurobiological mechanisms. However, consumption is often inferred from appetitive responding in operant ethanol self-administration paradigms, preventing identification of distinct experimental effects on seeking and taking. In the present study, male Long-Evans, Wistar, and Sprague-Dawley rats were trained to lever press for ethanol using a lickometer-equipped system that precisely measures both appetitive and consummatory behavior. Three distinct operant phenotypes emerged during training: 1) Drinkers, who lever press and consume ethanol; 2) Responders, who lever press but consume little to no ethanol; and 3) Non-responders, who do not lever press. While the prevalence of each phenotype differed across strains, appetitive and consummatory behavior was similar across strains within each phenotype. Appetitive and consummatory behaviors were significantly correlated in Drinkers, but not Responders. Analysis of drinking microstructure showed that greater consumption in Drinkers relative to Responders is due to increased incentive for ethanol rather than increased palatability. Importantly, withdrawal from chronic ethanol exposure resulted in a significant increase in appetitive responding in both Drinkers and Responders, but only Drinkers exhibited a concomitant increase in ethanol consumption. Together, these data reveal important strain differences in appetitive and consummatory responding for ethanol and uncover the presence of distinct operant phenotypes.

Irritability as a Transdiagnostic Vulnerability Trait:Current Issues and Future Directions

In recent years, irritability has received increasing attention among mental health professionals given its transdiagnostic associations with diverse forms of psychopathology. In contrast to other emotional states and traits, however, literature addressing associations between irritability and related temperament and personality constructs is limited. In addition, those who study irritability have diverse perspectives on its neurobiological substrates. In this comment, we situate irritability in the literatures on child temperament and adult personality, and describe a model in which irritability derives from low tonic dopamine (DA) levels and low phasic DA reactivity in subcortical neural structures implicated in appetitive responding. We note that different findings often emerge in neuroimaging studies when irritability is assessed in circumscribed diagnostic groups versus representative samples. We conclude with directions for future research, and propose that more authors use hierarchical Bayesian modeling, which captures functional dependencies between irritability and other dispositional traits (e.g., trait anxiety) that standard regression models are insensitive too. Treatment implications are also considered.

Acquisition and generalization of appetitive responding in obese and healthy weight females

Findings of a few recent studies suggest that obesity is characterized by deficits in appetitive learning about food cues. This could point towards an increased tendency in obese individuals to overgeneralize appetitive responding to stimuli that resemble the conditioned food cue – possibly explaining frequent eating desires and overeating in obesity. The current study aimed to investigate whether obese individuals 1) indeed exhibit appetitive learning deficits and 2) show overgeneralization of conditioned appetitive responses. Obese and matched healthy-weight females (N = 85) completed a differential appetitive conditioning task using food as rewards. First, appetitive responding to a novel stimulus was learned (acquisition phase), after which stimuli with varying resemblance to the food-associated stimulus were presented (generalization phase). Cue-elicited eating expectancies, eating desires, stimulus evaluations, and actual food intake were examined. Results indicated successful acquisition of appetitive responding across all outcome measures. The acquired responses also generalized, indicating that generalization can function as an additional mechanism by which learned food cues can promote food consumption. The data further suggested that overweight and obesity are not characterized by appetitive learning deficits nor by overgeneralization, but that a subgroup of obese individuals (those high in trait anxiety) may be more prone to overgeneralization of appetitive responding.

Assessment of the motivation to use artificial sweetener among individuals with an eating disorder

Eating disorders are associated with a range of abnormalities in eating behavior. Some individuals consume large amounts of non-caloric artificial sweeteners, suggesting abnormalities in appetitive responding. The current study aimed to quantify hedonic and motivating effects of artificial sweetener in individuals with and without an eating disorder. Two laboratory studies were conducted. Hedonic preference was estimated using the number of artificial sweetener packets (0–10) added to unsweetened cherry flavored Kool-Aid (study 1). Motivation to obtain sweetener was assessed by a progressive ratio (PR) work task (study 2). Ninety-three participants (25 anorexia nervosa restricting type (AN-R), 23 AN binge/purge type (AN-B/P), 20 bulimia nervosa (BN), and 25 normal controls (NC)) completed the study. No significant difference in hedonic preference was found among participant groups. Work completed at the PR task ranged from 0 to 9500 key-board presses. The AN-B/P group had a significantly higher breakpoint and performed significantly more work for sweetener compared to the BN and NC groups. Among AN-B/P and AN-R participants, the preferred number of Equal packets was significantly correlated with the breakpoint and total work. The increased amount of work for sweetener among individuals with AN-B/P supports an enhanced reward value of sweet taste in this population, and suggests that the characteristic food avoidance in AN cannot be accounted for by decreased reward value of all taste-related stimuli. This study also supports the novel application of a PR ratio task to quantify the motivating effect of sweet taste among individuals with an eating disorder.

Treatment for Anhedonia: A Neuroscience Driven Approach.

Anhedonia, or loss of interest or pleasure in usual activities, is characteristic of depression, some types of anxiety, as well as substance abuse and schizophrenia. Anhedonia is a predictor of poor long-term outcomes, including suicide, and poor treatment response. Because extant psychological and pharmacological treatments are relatively ineffective for anhedonia, there is an unmet therapeutic need for this high-risk symptom. Current psychological and drug treatments for anxiety and depression focus largely on reducing excesses in negative affect rather than improving deficits in positive affect. Recent advances in affective neuroscience posit that anhedonia is associated with deficits in the appetitive reward system, specifically the anticipation, consumption, and learning of reward. In this paper, we review the evidence for positive affect as a symptom cluster, and its neural underpinnings, and introduce a novel psychological treatment for anxiety and depression that targets appetitive responding. First, we review anhedonia in relation to positive and negative valence systems and current treatment approaches. Second, we discuss the evidence linking anhedonia to biological, experiential, and behavioral deficits in the reward subsystems. Third, we describe the therapeutic approach for Positive Affect Treatment (PAT), an intervention designed to specifically target deficits in reward sensitivity.

Editorial: Reward- and aversion-related processing in the brain: translational evidence for separate and shared circuits.

The dynamic evaluation of experience is existentially essential. Assigning value to events and objects drives neural development and plasticity and impacts our changing perceptual interpretations of the world and future behaviors (Nelson et al., 2014). The affective foundation of behavior provides more than a mere phenomenological “coloring” of experience. In fact, affect may be an inseparable component of sensation and cognition instead of an oft-considered byproduct (Inzlicht et al., 2015), and translational neuroanatomical evidence suggests that the major brain areas and tracts involved appear largely conserved across species (Panksepp, 2011).

Tryptophan Depletion Promotes Habitual over Goal-Directed Control of Appetitive Responding in Humans.

Background:Optimal behavioral performance results from a balance between goal-directed and habitual systems of behavioral control, which are modulated by ascending monoaminergic projections. While the role of the dopaminergic system in behavioral control has been recently addressed, the extent to which changes in global serotonin neurotransmission could influence these 2 systems is still poorly understood.Methods:We employed the dietary acute tryptophan depletion procedure to reduce serotonin neurotransmission in 18 healthy volunteers and 18 matched controls. We used a 3-stage instrumental learning paradigm that includes an initial instrumental learning stage, a subsequent outcome-devaluation test, and a slip-of-action stage, which directly tests the balance between hypothetical goal-directed and habitual systems. We also employed a separate response inhibition control test to assess the behavioral specificity of the results.Results:Acute tryptophan depletion produced a shift of behavioral performance towards habitual responding as indexed by performance on the slip-of-action test. Moreover, greater habitual responding in the acute tryptophan depletion group was predicted by a steeper decline in plasma tryptophan levels. In contrast, acute tryptophan depletion left intact the ability to use discriminative stimuli to guide instrumental choice as indexed by the instrumental learning stage and did not impair inhibitory response control.Conclusions:The major implication of this study is that serotonin modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. Our findings thus imply that diminished serotonin neurotransmission shifts behavioral control towards habitual responding.

Brief prenatal ethanol exposure alters behavioral sensitivity to the kappa opioid receptor agonist (U62,066E) and antagonist (Nor-BNI) and reduces kappa opioid receptor expression.

Approximately 10 to 15% of women consume alcohol (ethanol [EtOH]) during pregnancy in the United States. Even low amounts of EtOH consumption during pregnancy can elicit long-term consequences. Prenatal experience with as few as 3 drinks has been associated with increase problem drinking in adulthood. Such effects are corroborated in rodents; however, the underlying neural adaptations contributing to this effect are not clear. In the current set of experiments, we investigated whether changes in EtOH responding following prenatal EtOH exposure involved kappa opioid receptor activation and expression. Sprague-Dawley rats were prenatally exposed to low levels of alcohol (1.0g/kg) during late gestation (gestational days 17 to 20 [GD17-20]) via intragastric intubation of pregnant dams. Following birth, EtOH intake, kappa- and mu-opioid-induced place conditioning, and kappa opioid receptor expression in mesolimbic brain regions were assessed in infant rats (postnatal days 14 to 15 [PD14-15]) that were offspring of dams given EtOH, vehicle, or untreated, during pregnancy. Animals exposed to prenatal alcohol drank more alcohol later in life and exhibited significant changes in the kappa opioid system. While control subjects found kappa opioid activation aversive, animals exposed to EtOH prenatally exhibited either no aversion or appetitive responding. Further analysis revealed that synaptosomal kappa opioid receptor expression was significantly decreased in brain areas implicated in responding to EtOH. Overall, these data suggest that prenatal EtOH affects kappa opioid function and expression and that these changes may be involved in increased drinking later in life.

Amyloid and Tau Neuropathology Differentially Affect Prefrontal Synaptic Plasticity and Cognitive Performance in Mouse Models of Alzheimer's Disease

Alzheimer's disease (AD) is a consequence of degenerative brain pathology with amyloid plaque deposition and neurofibrillary tangle formation. These distinct aspects of AD neuropathology have been suggested to induce a cascade of pathological events ultimately leading to neurodegeneration as well as cognitive and behavioral decline. Amyloid and tau neuropathology is known to develop along distinct stages and affect parts of the brain differentially. In this study, we examined two mouse AD lines (AβPPPS1-21 and Tau22 mice), which mimic different partial aspects of AD pathology, at comparable stages of their pathology. Since prefrontal cortex (PFC) is one of the first regions to be affected in clinical AD, we compared long-term potentiation (LTP) of synaptic responses in medial PFC of AβPPPS1-21 and Tau22 mice. Frontal LTP was impaired in AβPPPS1-21 mice, but not in Tau22 mice. Consequently, we observed different behavioral defects between AβPPPS1-21 and Tau22 animals. Apart from spatial learning deficits, AβPPPS1-21 transgenic mice were impaired in fear learning, aversion learning, and extinction learning, whereas THY-Tau22 were impaired in appetitive responding. Discriminant function analysis identified critical behavioral variables that differentiated AβPPPS1-21 and THY-Tau22 mice from wild type littermates, and further confirmed that amyloid- versus tau-pathology differentially affects brain function.

Neuropeptide Y (NPY) in the central nucleus of the amygdala (CeA) does not affect ethanol-reinforced responding in binge-drinking, nondependent rats

The central nucleus of the amygdala (CeA) has been implicated as having a significant role in mediating alcohol-drinking behavior. Neuropeptide Y (NPY) has been investigated as a potential pharmacotherapeutic due to its ability to attenuate ethanol intake, particularly when administered into the CeA. Previous research suggests, though the evidence is somewhat conflicting, that the efficacy of NPY is contingent upon genetic background and/or prior history of ethanol dependence in rats. However, studies looking at the effects of NPY in nonselected animals lacking a history of ethanol dependence have two factors that could impact the interpretation of the results: ethanol history/selection AND relatively low baseline ethanol intakes as compared to ethanol-dependent and/or genetically selected controls. The purpose of the present study was to generate higher baseline ethanol intakes upon which to examine the effects of NPY on ethanol and sucrose drinking in nonselected rats using a binge drinking model. Long Evans rats were trained to complete a single response requirement resulting in access to either 2% sucrose (Sucrose Group) or 2% sucrose/10% ethanol (Ethanol Group) for a 20-min drinking session. On treatment days, rats were bilaterally microinjected into the CeA with aCSF or one of three doses of NPY (0.25μg, 0.50μg, or 1.00μg/.5μL). Subjects in the Ethanol Group were consuming an average of 1.2g/kg of ethanol (yielding BELs of ~90mg%) during the 20min access period following aCSF treatments. The results revealed that NPY had no effect on either sucrose or ethanol consumption or on appetitive responding (latency to respond). Overall, the findings indicate that even a history of binge-like ethanol consumption is not sufficient to recruit CeA NPY activity, and are consistent with previous studies showing that the role of NPY in regulating ethanol reinforcement in the CeA may be contingent upon a prior history of ethanol dependence.

Intertrial pellets influence the acquisition and expression of timed appetitive responding in rats

Two experiments examined temporally based changes in the conditioned magazine-entries of rats when a target food pellet arrived at a fixed time before the termination of a conditioned stimulus. Both experiments found that increasing the rate of intertrial pellets systematically interfered with the rate of acquisition. When intertrial pellets were featured in acquisition, their omission on test trials also resulted in a very poorly expressed conditioned response. On test trials preceded by intertrial pellets, however, peak times in groups trained with intertrial pellets were shifted in a rightward direction under a long but not short interstimulus interval. This rightward shift was accompanied by a smaller standard deviation. Our key findings are best accommodated by real-time associative models.

A novel IV cocaine self-administration procedure in rats: differential effects of dopamine, serotonin, and GABA drug pre-treatments on cocaine consumption and maximal price paid

Behavior occurring during cocaine self-administration can be classified as either consummatory or appetitive. These two concepts are usually addressed independently using separate reinforcement schedules. For example, appetitive behavior can be assessed with a progressive ratio schedule, whereas consummatory behavior is typically measured using a fixed ratio schedule. Depending on the schedule used, it is often difficult to determine whether a particular drug pretreatment is affecting self-administration through an effect on appetitive responding, consummatory responding, or perhaps both. In the present study, we tested the effect of pretreating rats with four different drugs on appetitive and consummatory behaviors. We recently developed a technique that provides an independent assessment of both behavioral concepts within the same experimental session. In this threshold procedure, rats are offered a descending series of 11 unit doses (422-1.3 μg/injection) during consecutive timed intervals under a fixed-ratio schedule. Consummatory behavior can be analyzed by assessing intake at high unit doses; an estimate of appetitive responding can be determined from responding occurring at the threshold dose. Applying behavioral economics to these data provides dependent measures of consumption when minimally constrained by price and the maximal price paid (P (max)) for cocaine. Haloperidol increased cocaine consumption when minimally constrained by price but decreased P (max). In contrast, D: -amphetamine increased P (max). Fluoxetine decreased P (max) and consumption when minimally constrained by price. Baclofen selectively decreased P (max). These data suggest that drug pretreatments can alter consummatory and appetitive behavior differently because each concept involves distinct neural mechanisms.

Measuring appetitive responding with the postauricular reflex

Recent research has provided evidence that the postauricular reflex (PAR) is potentiated while people view pleasant images relative to unpleasant and neutral images. The present study sought to extend these findings by investigating whether the PAR is more robustly modulated by the appetitive salience of the stimuli. Eyeblink startle and PAR responses of 51 participants were recorded while they viewed images that varied in valence and thematic content. Participants displayed significantly greater mean PAR magnitude during appetitive-related images (e.g., food, erotica, families) compared with non-appetitive-related pleasant images. These findings support the contention that the PAR is a useful tool for measuring appetitive responding in humans.

Renewal and spontaneous recovery, but not latent inhibition, are mediated by gamma-aminobutyric acid in appetitive conditioning.

Previous research has reported a role for the neurotransmitter gamma-aminobutyric acid (GABA) in the extinction and renewal of conditioned fear. Here, the authors examine whether GABA is involved in the acquisition, extinction, renewal, spontaneous recovery, and latent inhibition of appetitive conditioning. Using Long-Evans rats, systemic injection of the GABA A receptor inverse agonist FG 7142 was shown to eliminate ABA renewal (Experiment 1) and spontaneous recovery (Experiment 4) of appetitive responding by selectively reducing the recovery of extinguished magazine approach. Furthermore, treatment with FG 7142 had no effects on acquisition or single-session extinction (Experiment 3) or on the context-specific expression of latent inhibition (Experiment 2). These data suggest that ABA renewal and spontaneous recovery, but not latent inhibition or responding during acquisition and an initial extinction session, are mediated by GABAergic mechanisms in appetitive Pavlovian conditioning. They provide support for the view that renewal and spontaneous recovery share a common psychological mechanism.

Contributions of the hippocampus and medial prefrontal cortex to energy and body weight regulation

The effects of selective ibotenate lesions of the complete hippocampus (CHip), the hippocampal ventral pole (VP), or the medial prefrontal cortex (mPFC) in male rats were assessed on several measures related to energy regulation (i.e., body weight gain, food intake, body adiposity, metabolic activity, general behavioral activity, conditioned appetitive responding). The testing conditions were designed to minimize the nonspecific debilitating effects of these surgeries on intake and body weight. Rats with CHip and VP lesions exhibited significantly greater weight gain and food intake compared with controls. Furthermore, CHip-lesioned rats, but not rats with VP lesions, showed elevated metabolic activity, general activity in the dark phase of the light-dark cycle, and greater conditioned appetitive behavior, compared with control rats without these brain lesions. In contrast, rats with mPFC lesions were not different from controls on any of these measures. These results indicate that hippocampal damage interferes with energy and body weight regulation, perhaps by disrupting higher-order learning and memory processes that contribute to the control of appetitive and consummatory behavior.

Acute Hippocampal Brain-Derived Neurotrophic Factor Restores Motivational and Forced Swim Performance After Corticosterone

Alterations in cellular survival and plasticity are implicated in the neurobiology of depression, based primarily on the characterization of antidepressant efficacy in naïve rodents rather than on models that capture the debilitating and protracted feelings of anhedonia and loss of motivation that are core features of depression. In adult male mice, we evaluated persistent effects of oral corticosterone (CORT) exposure on anhedonic-like behavior, immobility in the forced swim test (FST), motivational performance in the progressive ratio task, and later endogenous CORT secretion. After verifying long-term decreases in hippocampal brain-derived neurotrophic factor (BDNF) and cAMP Response Element Binding protein phosphorylation (pCREB), the ability of direct hippocampal BDNF microinfusion after CORT exposure to reverse deficits was investigated. Prior CORT exposure decreased sucrose consumption, appetitive responding, and FST mobility without long-term effects on water/quinine discrimination and endogenous CORT secretion. Critically, BDNF replacement mimicked chronic antidepressant treatment (ADT) by reversing CORT-induced reductions in instrumental performance and FST mobility. Together these findings link persistent alterations in hippocampal BDNF expression and CREB transcriptional activity with a persistent depressive-like state-as opposed to ADT efficacy. These results identify hippocampal BDNF as an essential molecular substrate that bidirectionally regulates appetitive instrumental behavior. Additionally, we suggest this CORT model might provide a powerful tool for future investigation into the neurobiology of complex stress-associated depressive symptoms that persist long after stress exposure itself.