Mesolimbic Dopaminergic Reward System Research Articles

Association Study of Serotonin 1A Receptor Gene, Personality, and Anxiety in Women with Alcohol Use Disorder.

Alcohol use disorder is considered a chronic and relapsing disorder affecting the central nervous system. The serotonergic system, mainly through its influence on the mesolimbic dopaminergic reward system, has been postulated to play a pivotal role in the underlying mechanism of alcohol dependence. The study aims to analyse the association of the rs6295 polymorphism of the 5HTR1A gene in women with alcohol use disorder and the association of personality traits with the development of alcohol dependence, as well as the interaction of the rs6295, personality traits, and anxiety with alcohol dependence in women. The study group consisted of 213 female volunteers: 101 with alcohol use disorder and 112 controls. NEO Five-Factor and State-Trait Anxiety Inventories were applied for psychometric testing. Genotyping of rs6295 was performed by real-time PCR. We did not observe significant differences in 5HTR1A rs6295 genotypes (p = 0.2709) or allele distribution (p = 0.4513). The AUD subjects scored higher on the anxiety trait (p < 0.0001) and anxiety state (p < 0.0001) scales, as well as on the neuroticism (p < 0.0001) and openness (p = 0134) scales. Significantly lower scores were obtained by the AUD subjects on the extraversion (p < 0.0001), agreeability (p < 0.0001), and conscientiousness (p < 0.0001) scales. Additionally, we observed a significant effect of 5HTR1A rs6295 genotype interaction and alcohol dependency, or lack thereof, on the openness scale (p = 0.0016). In summary, this study offers a comprehensive overview of alcohol dependence among women. It offers valuable insights into this complex topic, contributing to a more nuanced understanding of substance use among this specific demographic. Additionally, these findings may have implications for developing prevention and intervention strategies tailored to individual genetic and, most importantly, personality and anxiety differences.

The differential processing of verbal jokes by neural substrates in indigenous and Han Chinese populations: An fMRI study

Limited research has been conducted on humor among the Taiwanese indigenous (IND) population. This study attempted to identify the differential neural correlates of humor comprehension and appreciation between IND and Han Chinese (HAN) populations. Each participant was presented with jokes and non-jokes. IND participants when encountered with jokes displayed a greater activation of the mesolimbic dopaminergic reward system, including the amygdala, midbrain, and nucleus accumbens than HAN participants. This suggests a more pleasurable response and appreciation of humor. The IND group also displayed greater activation in the right temporoparietal junction (rTPJ) than HAN, suggesting that the IND group may experience a greater sense of novelty and be more involved in social understanding, thus exhibiting greater humor appreciation. In terms of humor comprehension, both IND and HAN showed greater activation in the superior temporal gyrus (STG) and dorsal anterior cingulate cortex (dACC). IND exhibited greater activation in the anterior STG (aSTG), while HAN showed greater activation in the posterior STG (pSTG). This suggests that the IND tends to integrate emotional messages, whereas the HAN focuses on comprehending semantic cognitive information. Interestingly, HAN did not show any greater activation than IND in terms of appreciation of humor. These group disparities have substantial implications for advancing our knowledge of the neural mechanisms underlying humor comprehension and appreciation.

A Thirst for Knowledge: Grounding Curiosity, Creativity, and Aesthetics in Memory and Reward Neural Systems

ABSTRACT Curiosity, creativity, and aesthetics are typically studied separately. The extent to which they share psychological and neural mechanisms is not well understood, despite all being linked to broader personality characteristics like Openness to Experience and are driven by a desire for information and knowledge. Here, we review evidence and advance the hypothesis that creative and aesthetic experiences depend on curiosity as a driver of information-seeking and exploratory behavior because they are exemplars of situations that highlight gaps in knowledge or require problem finding and solving. At the psychological level, we link curiosity, creativity, and aesthetics to Openness to Experience and to ones’ semantic memory. We demonstrate how Openness is a critical personality trait in enhancing curious behaviors, as well as creative and aesthetic acts. Furthermore, we highlight the role of semantic memory in such information-seeking behavior, leading to knowledge acquisition. At the neural level, we examine the neurobiological underpinnings of these constructs in relation to the mesolimbic dopaminergic reward system, as related to information-seeking. Finally, we link creativity and aesthetic experience and discuss how stages of art viewing and making relate to curiosity. Thus, we argue that information-seeking, the key behavior attributed to curiosity, motivates both creative and aesthetic activities.

Chemogenetic inhibition of dopaminergic projections to the nucleus accumbens has sexually dimorphic effects in the rat gambling task.

Women and men can differ in their propensity to take risks and develop impulse control and addiction disorders. Sexual dimorphisms in behavioral control by the mesolimbic dopaminergic reward system may underlie these phenomena, given its sensitivity to gonadal hormones. However, this is hard to test experimentally using humans. Using the rat gambling task (rGT), we investigated what impact acute inhibition of accumbal dopamine had on decision-making and impulsivity in animals of both sexes. We expressed an inhibitory designer receptor exclusively activated by designer drugs (hM4D[Gi]) in the accumbal dopaminergic efferents of female and male transgenic (Tg) rats, engineered to selectively express cre recombinase in neurons synthesizing tyrosine hydroxylase. We then trained the rats to perform the rGT and assessed the effect of an acute clozapine-n-oxide (0-3 mg/kg) challenge. Chemogenetic inhibition of dopaminergic projections to the accumbens did not affect choice in females, perhaps due to low levels of risky choice in Tg+ animals at baseline, but induced a switch from risky to optimal decision-making in males performing the cued rGT. This manipulation also decreased motor impulsivity but only in females. These data support the hypothesis that cue-driven risky choice is mediated, at least in males, by activity of accumbal dopaminergic neurons. However, motor impulsivity is more sensitive to inhibition of accumbal dopamine neurons in female rats. These data may help explain differences in the manifestation of addictions across gender and reinforce the importance of examining both sexes when seeking to attribute control of behavior to specific monoaminergic pathways. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Oxytocin reduces the functional connectivity between brain regions involved in eating behavior in men with overweight and obesity.

Background:Oxytocin (OXT), shown to decrease food intake in animal models and men, is a promising novel treatment for obesity. We have shown that in men with overweight and obesity, intranasal (IN) OXT reduced the functional magnetic resonance imaging (fMRI) blood oxygenation level-dependent signal in the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic reward system, in response to high-calorie food vs. non-food images. Here, we employed functional connectivity fMRI analysis, which measures the synchrony in activation between neural systems in a context-dependent manner. We hypothesized that OXT would attenuate the functional connectivity of the VTA with key food motivation brain areas only when participants viewed high-calorie food stimuli.Methods:This randomized, double-blind, placebo-controlled crossover study of 24 IU IN OXT included 10 men with overweight or obesity (mean±SEM BMI: 28.9±0.8 kg/m2). Following drug administration, subjects completed an fMRI food motivation paradigm including images of high and low-calorie foods, non-food objects, and fixation stimuli. A psychophysiological interaction analysis was performed with the VTA as seed region.Results:Following OXT administration, compared with placebo, participants exhibited significantly attenuated functional connectivity between the VTA and the insula, oral somatosensory cortex, amygdala, hippocampus, operculum, and middle temporal gyrus in response to viewing high-calorie foods (Z≥3.1, cluster-corrected, p<0.05). There was no difference in functional connectivity between VTA and these brain areas when comparing OXT and placebo for low-calorie food, non-food, and fixation images.Conclusion:In men with overweight and obesity, OXT attenuates the functional connectivity between the VTA and food motivation brain regions in response to high-calorie visual food images. These findings could partially explain the observed anorexigenic effect of OXT, providing insight into the mechanism through which OXT ameliorates food cue-induced reward anticipation in patients with obesity. Additional studies are ongoing to further delineate the anorexigenic effect of OXT in obesity.

OR20-2 Oxytocin Significantly Attenuates the Functional Connectivity between Food Motivation Brain Areas in Overweight and Obese Men Exposed to High Caloric Food Images

Background: The hypothalamic neurohormone oxytocin (OXT), shown to decrease food intake in animal models and men, is a promising novel treatment for obesity. The mechanisms underlying OXT effects on caloric intake in humans are not well understood. We previously showed that in overweight and obese men, 24 IU intranasal (IN) OXT reduced fMRI activation in the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic reward system, in response to high-calorie food vs non-food visual stimuli. To provide further insight into the mechanisms by which OXT exerts its anorexigenic effects, we employed a dynamic method of fMRI analysis, functional connectivity, which refers explicitly to the influence that one neural system exerts over another in a context-dependent manner. We hypothesized that OXT would modulate the functional connectivity of the VTA with key brain areas known to be involved with food sensory and cognitive processing when participants viewed high-calorie foods compared to objects. Methods: In this randomized, double-blind, placebo-controlled crossover study of 24 IU IN OXT, 10 overweight/obese (mean±SD BMI 28.9±0.8 kg/m2), otherwise healthy men age 31.4±1.8 years presented after a 10-h overnight fast. Sixty min after drug administration, subjects started an established fMRI food motivation paradigm that included images of high and low-calorie foods, household objects, and fixation stimuli. Using psychophysiological interaction analysis, the VTA was anatomically defined as the seed region to explore effects of OXT on functional connectivity. Results: Following OXT administration, compared to placebo, participants showed significant attenuation of the functional connectivity between the VTA and insula, parietal operculum, amygdala, anterior and posterior cingulate, and hippocampus in response to viewing high-calorie food stimuli vs. objects (Z≥3.1, cluster corrected, P=0.05). Conclusion: Here we have shown in overweight/obese men that OXT attenuates functional connectivity between the VTA and brain regions associated with the cognitive, sensory and emotional processing of food images. This is particularly relevant to obese individuals, since previous studies have shown greater activation to palatable food images in these areas (e.g., amygdala, hippocampus and insula), and it has been proposed that this hyperactivity of the dopaminergic reward circuit renders obese individuals prone to overeating. Attenuated functional connectivity findings reported here could partially explain the clinically-observed anorexigenic effect of OXT, providing insight into the mechanism through which OXT ameliorates food-cue-induced, CNS-mediated reward anticipation in obese patients. Additional studies are ongoing to further delineate the neural connections underlying the anorexigenic effect of OXT in human obesity.

A short essay on the spirituality of placebo from an (evolutionary) psychiatric perspective

Different to spirituality, the placebo-effect is well operationalized. Against this background, an attempt is made to look at a possible phenomenological relationship between the therapeutic effectiveness of spirituality and placebo. Similar context influences as well as the possible common use of a phylogenetically well conserved protective route via the mesolimbic dopaminergic reward system are highlighted. For both phenomena, the clinical effectiveness seems to be ubiquitous, with that of the placebo effect being scientifically much more verified than this currently would be methodologically possible with the "spirituality effect". Both effects share their uncertain predictability and are Janus-headed (e. g., placebo effect vs. nocebo effect). Currently, for both, the placebo and spirituality-oriented approaches, there are attempts underway to maximize their clinical effectiveness by modulating the therapeutic framework and conversational content. The discussion ends with the reflexive question of whether the placebo effect could have in essence "spirituality-light" traits.

Effects of Intranasal Oxytocin on the Blood Oxygenation Level-Dependent Signal in Food Motivation and Cognitive Control Pathways in Overweight and Obese Men.

Recent research indicates that the hypothalamic neuropeptide hormone oxytocin is a key central nervous system factor in the regulation of food intake and weight. However, the mechanisms underlying the anorexigenic effects of oxytocin in humans are unknown and critical to study to consider oxytocin as a neurohormonal weight loss treatment. We performed a randomized, double-blind, placebo-controlled crossover study with single-dose intranasal oxytocin (24 IU) in ten overweight or obese, otherwise healthy men. Following oxytocin/placebo administration, participants completed an established functional magnetic resonance imaging food motivation paradigm. We hypothesized that oxytocin would reduce the blood oxygenation level-dependent (BOLD) signal to high-calorie food vs non-food visual stimuli in the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic reward system. Following oxytocin administration, compared to placebo, participants showed bilateral VTA hypoactivation to high-calorie food stimuli. A secondary exploratory whole-brain analysis revealed hypoactivation in additional hedonic (orbitofrontal cortex, insula, globus pallidus, putamen, hippocampus, and amygdala) and homeostatic (hypothalamus) food motivation and hyperactivation in cognitive control (anterior cingulate and frontopolar cortex) brain regions following oxytocin administration vs placebo. Oxytocin administration reduces the BOLD signal in reward-related food motivation brain regions, providing a potential neurobiological mechanism for the anorexigenic oxytocin effects in humans. Furthermore, our data indicate that oxytocin administration reduces activation in homeostatic and increases activation in cognitive control brain regions critically involved in regulating food intake and resolving affective conflict, respectively. Future studies are required to link these changes in brain activation to oxytocin effects on food intake and weight.

Humor, laughter, learning, and health! A brief review

Human emotions, such as anxiety, depression, fear, joy, and laughter, profoundly affect psychological and physiological processes. These emotions form a set of basic, evolved functions that are shared by all humans. Laughter is part of a universal language of basic emotions that all humans recognize. Health care providers and educators may utilize the power of laughter to improve health and enhance teaching and learning. This is an important consideration because teaching is not just about content: it is also about forming relationships and strengthening human connections. In this context, when used effectively, humor is documented to build relationships and enhance performance. Specifically, humor improves student performance by attracting and sustaining attention, reducing anxiety, enhancing participation, and increasing motivation. Moreover, humor stimulates multiple physiological systems that decrease levels of stress hormones, such as cortisol and epinephrine, and increase the activation of the mesolimbic dopaminergic reward system. To achieve these benefits, it is important to use humor that is relevant to the course content and not disparaging toward others. Self-effacing humor illustrates to students that the teacher is comfortable making mistakes and sharing these experiences with the classroom. In this brief review, we discuss the history and relationship between humor, laughing, learning, and health with an emphasis on the powerful, universal language of laughter.

Amphetamines: Potent Recreational Drug of Abuse

Amphetamines are central nervous system (CNS) stimulants and belong to psychoactive drugs that affect chemicals in the brain, nerves and exert a constant contribution to hyperactivity and impulse control. The communal group of amphetamines comprises amphetamine, dextroamphetamine and methamphetamine. Amphetamines show its action on the mesolimbic dopaminergic reward system by inducing release of dopamine and to some extent norepinephrine, in the synaptic clefts of the nucleus accumbens and other terminal areas. They offer not only a sense of euphoric state, but also addiction. Amphetamines are frequently prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults, narcolepsy and obesity. At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, improved cognitive control, etc. The balance of benefit/risk is the main challenge for its clinical use. When overused these medications can be highly addictive, are often diverted from the user to be used as recreational drugs. Adverse effects include anxiety, aggression, headache, insomnia, hyperactivity, palpitations, increased breathing rate, increased blood pressure, tachycardia, arrhythmia, dilated pupils, paranoia, etc. However, at large doses, these drugs may impair cognitive function and induce rapid muscle breakdown. Even higher doses may give rise to hallucinations, paranoia, psychosis and potentially lifethreatening conditions such as convulsions, stroke, kidney failure, etc. The furthermost serious health implications of amphetamine resulting from chronic use are dependence, considered by compulsive drug-seeking and drug use and a phenomenon notorious as amphetamine psychosis. Therefore the objective of this study was to explore the functions of the amphetamines as recreation drug of abuse.

Inhibition of the reward system by antipsychotic treatment

The mesolimbic dopaminergic reward system is responsible for the negative affective symptomatology of schizophrenia, which may be related to a low dopamine tonus within the ventral striatum. The monetary incentive delay (MID) task can be used to study the response of the ventral striatum to incentive stimuli. We show that activation of the ventral striatum is low in patients with schizophrenia, and that this low activation is related to primary and secondary negative symptoms induced by neuroleptics, also known as antipsychotics. Switching from first-(typical) to second-generation (atypical) antipsychotics increased activation of the ventral striatum due to less blocking of dopamine D2 receptors. This and similar studies show that functional magnetic resonance imaging (fMRI) tasks are suitable to investigate important aspects of antipsychotic mechanisms.

Selective modulation of GABAergic tonic current by dopamine in the nucleus accumbens of alcohol-dependent rats

The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Alterations in glutamatergic and GABAergic signaling were recently demonstrated in the NAcc of rats after chronic intermittent ethanol (CIE) treatment, a model of alcohol dependence. Here we studied dopamine (DA) modulation of GABAergic signaling and how this modulation might be altered by CIE treatment. We show that the tonic current (I(tonic)) mediated by extrasynaptic γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc core is differentially modulated by DA at concentrations in the range of those measured in vivo (0.01-1 μM), without affecting the postsynaptic kinetics of miniature inhibitory postsynaptic currents (mIPSCs). Use of selective D1 receptor (D1R) and D2 receptor (D2R) ligands revealed that I(tonic) potentiation by DA (10 nM) is mediated by D1Rs while I(tonic) depression by DA (0.03-1 μM) is mediated by D2Rs in the same MSNs. Addition of guanosine 5'-O-(2-thiodiphosphate) (GDPβS) to the recording pipettes eliminated I(tonic) decrease by the selective D2R agonist quinpirole (5 nM), leaving intact the quinpirole effect on mIPSC frequency. Recordings from CIE and vehicle control (CIV) MSNs during application of D1R agonist (SKF 38393, 100 nM) or D2R agonist (quinpirole, 2 nM) revealed that SKF 38393 potentiated I(tonic) to the same extent, while quinpirole reduced I(tonic) to a similar extent, in both groups of rats. Our data suggest that the selective modulatory effects of DA on I(tonic) are unaltered by CIE treatment and withdrawal.

Plasticity of GABAAreceptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats

Chronic alcohol exposure-induced changes in reinforcement mechanisms and motivational state are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Here we describe the long-lasting alterations of γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc after chronic intermittent ethanol (CIE) treatment, a rat model of alcohol dependence. CIE treatment and withdrawal (>40 days) produced decreases in the ethanol and Ro15-4513 potentiation of extrasynaptic GABA(A)Rs, which mediate the picrotoxin-sensitive tonic current (I(tonic)), while potentiation of synaptic receptors, which give rise to miniature inhibitory postsynaptic currents (mIPSCs), was increased. Diazepam sensitivity of both I(tonic) and mIPSCs was decreased by CIE treatment. The average magnitude of I(tonic) was unchanged, but mIPSC amplitude and frequency decreased and mIPSC rise time increased after CIE treatment. Rise-time histograms revealed decreased frequency of fast-rising mIPSCs after CIE treatment, consistent with possible decreases in somatic GABAergic synapses in MSNs from CIE rats. However, unbiased stereological analysis of NeuN-stained NAcc neurons did not detect any decreases in NAcc volume, neuronal numbers, or neuronal cell body volume. Western blot analysis of surface subunit levels revealed selective decreases in α1 and δ and increases in α4, α5, and γ2 GABA(A)R subunits after CIE treatment and withdrawal. Similar, but reversible, alterations occurred after a single ethanol dose (5 g/kg). These data reveal CIE-induced long-lasting neuroadaptations in the NAcc GABAergic neurotransmission.

Anti-Anhedonic Effect of Deep Brain Stimulation of the Prefrontal Cortex and the Dopaminergic Reward System in a Genetic Rat Model of Depression: An Intracranial Self-Stimulation Paradigm Study

BackgroundOne of the two core symptoms of major depression (MD), whether uni- or bipolar, is the inability to experience pleasure, suggested to be triggered by dysregulation within the brain reward system. In recent years, deep brain stimulation (DBS) has evolved as a potential tool to modulate pathological neural activity; stimulation of the subgenual cingulate (Cg25) has been shown to reduce depressive symptoms, including anhedonia. In rodents, the ventromedial prefrontal cortex (vmPFC) is likely to represent the correlate of Cg25 and accordingly, stimulation of vmPFC reduces anhedonia-like behavior in rats. Objective/hypothesisThe present study addresses the question of whether the anti-anhedonic effect of vmPFC-DBS is mediated by the brain reward system. MethodsRats of the Flinders Sensitive Line (FSL), a validated genetic animal model of depression, and its controls, the Flinders Resistant Line (FRL), were stimulated in the vmPFC and tested in the forced swim test (FST), sucrose consumption test (SCT) and the intracranial self-stimulation (ICSS) paradigm. The curve-shift paradigm of ICSS was used in combination with vmPFC-DBS, d-amphetamine and fluoxetine to quantify reward-facilitating or -attenuating treatment effects. ResultsOur findings support anti-depressive efficacy of vmPFC-DBS with respect to despair- and anhedonia-like behavior, as shown in the FST and SCT, respectively. However, DBS did not elicit reward-facilitating or reward-attenuating effects on ICSS behavior. ConclusionThese data suggest that it is unlikely that the anti-anhedonic effect of vmPFC-DBS depends on the mesolimbic dopaminergic reward system.

Ventral Striatal Activation during Reward Processing in Subjects with Ultra-High Risk for Schizophrenia

Background: Early dysfunction of the brain reward system in schizophrenia might be already recognized in the prodromal phase of this illness. We used functional magnetic resonance imaging to assess the blood oxygen level-dependent response in the ventral striatum (VS) of subjects with ultra-high risk for psychosis during the presentation of reward-indicating and loss-indicating stimuli. Methods: Thirteen prodromal patients (mean age: 25.5 ± 4.6 years) and 13 age-matched healthy volunteers participated in an incentive monetary delay task, in which visual cues predicted that a rapid response to a subsequent target stimulus will gain money, avoid losing money or have no consequence. Results: Compared with the neutral condition, anticipation of reward loss-avoidance elicited significant activation of the VS in both healthy subjects and subjects with ultra-high risk for psychosis, but there was only a statistical tendency for less activation during loss-avoidance anticipation in prodromal compared to healthy subjects. Discussion: This study provides a first weak hint, as revealed by functional magnetic resonance imaging, for impaired activation of a central area of the mesolimbic dopaminergic brain reward system, the VS, already in subjects with ultra-high risk for psychosis, which is in line with results of patients with full-blown schizophrenic psychosis. This pilot study has, however, strong limitations, and its results need to be replicated first before they can be used e.g. for early recognition of patients in the schizophrenic prodrome.

CS04-01 - Starving instead of eating as a reward: the case of anorexia nervosa

Anorexia nervosa is characterized by severe emaciation, amenorrhea and hyperactivity. Aetiology of the disorder is unknown however evidence grows that factors that maintain the core symptoms are important for the understanding of the chronicity of the disorder. Theories based on research on self-starvation in animals emphasise the interaction of stress and feeding behaviour, since under certain dietary conditions and possibility for non-forced physical activity, self-starvation through excessive wheel running until death is seen in rodents. Results of these studies suggest a pivotal role for the mesolimbic dopaminergic reward system of the brain in self-starvation in the animal. The activity level of this system with the ventral striatum as a core structure is modulated by expectation or receipt of rewards. There is also growing evidence referring to reward related processes in patients with anorexia nervosa with the mesolimbic dopaminergic reward system being essential in mediating maintenance of the disorder. It is suggested that alterations in the dopaminergic neurotransmission could affect the evaluation of reward stimuli in the patients, resulting in reduced responsiveness towards disease-unspecific rewarding stimuli, and obsessive and increased reaction towards disease-specific stimuli, like cues for emaciation or experience of the own cachectic body. The present study examined activity in the ventral striatal system in response to disease specific stimuli in acute anorexia patients. During functional magnetic resonance imaging 14 patients with anorexia nervosa and 14 healthy control women evaluated images of a BMI-standardized female body depicting features of under-, normal- and overweight. Photorealistic textures were used to give a familiar presentation of specific features according to the particular BMI. Subjects were asked to process the stimuli in a self-referring way (task “feel”: Imagine you have the same body shape as this woman. How would you feel?), and to give ratings by four buttons on a keyboard (scaling from 1 “very bad” to 4 “very good”). In the control task “weight” subjects had to estimate the weight of the images as one out of four categories (30 - 45 - 60 - 75 kg). Behaviourally, patients with anorexia nervosa rated underweight stimuli as the most preferred, while healthy control women preferred normal weight stimuli. The groups did not differ with regard to correctness or decision times in the control task. Functionally, ventral striatal activity demonstrated a highly significant group-by-stimulus interaction for underand normal weight stimuli during self-referred processing of the stimuli: In patients activation was higher during processing of underweight compared to normal weight stimuli. The reversed pattern was observed in controls. Differential responses on overweight stimuli did not substantially contribute to the overall effect either behaviourally or functionally in either task This pattern of activation is in good agreement with previous assumptions concerning differential responsiveness upon disease-specific and -unspecific stimulation in patients with anorexia nervosa. Results also align with predictions derived from animal studies on the pivotal role of the human dopaminergic reward system, and thereby support theories of starvation-dependence to account for the maintenance of the disease.

Long-Lasting Alterations in Membrane Properties, K+ Currents, and Glutamatergic Synaptic Currents of Nucleus Accumbens Medium Spiny Neurons in a Rat Model of Alcohol Dependence

Chronic alcohol exposure causes marked changes in reinforcement mechanisms and motivational state that are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system. Although the NAcc plays an important role in mediating alcohol-seeking behaviors, little is known about the molecular mechanisms underlying alcohol-induced neuroadaptive changes in NAcc function. The aim of this study was to investigate the effects of chronic intermittent ethanol (CIE) treatment, a rat model of alcohol withdrawal and dependence, on intrinsic electrical membrane properties and glutamatergic synaptic transmission of medium spiny neurons (MSNs) in the NAcc core during protracted withdrawal. We show that CIE treatment followed by prolonged withdrawal increased the inward rectification of MSNs observed at hyperpolarized potentials. In addition, MSNs from CIE-treated animals displayed a lower input resistance, faster action potentials (APs), and larger fast afterhyperpolarizations (fAHPs) than MSNs from vehicle-treated animals, all suggestive of increases in K+-channel conductances. Significant increases in the Cs+-sensitive inwardly rectifying K+-current accounted for the increased input resistance, while increases in the A-type K+-current accounted for the faster APs and increased fAHPs in MSNs from CIE rats. We also show that the amplitude and the conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated mEPSCs were enhanced in CIE-treated animals due to an increase in a small fraction of functional postsynaptic GluA2-lacking AMPARs. These long-lasting modifications of excitability and excitatory synaptic receptor function of MSNs in the NAcc core could play a critical role in the neuroadaptive changes underlying alcohol withdrawal and dependence.

NTS GLP-1 projections to the mesolimbic dopaminergic reward system reduce food intake

NTS GLP-1 projections to the mesolimbic dopaminergic reward system reduce food intake

S14-03 - Dysfunctional reward processing in alcohol addiction

Alcohol dependence is one of the most fatal mental diseases amongst men in western industrialized nations and is the major risk factor for the development of more than 60 chronic illnesses. With no further intervention, relapse rates in detoxified alcoholics are high and usually exceed 85% of all detoxified patients. It has been suggested that stress and exposure to priming doses of alcohol and to alcohol-associated stimuli (cues) contribute to the relapse risk after detoxification.In the last decades there has been substantial progress in scientific research of the neurobiological principles of alcohol-related disorders. Recent studies using multi modal imaging techniques like functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) observed dysfunctions of the mesolimbic dopaminergic brain reward system (ventral striatum including the nucleus accumbens): Functional brain activation is increased during the processing of alcohol-associated cues and decreased during the confrontation with other non-alcoholic reward-indicating stimuli. This alcohol-associated “hijacking” of the reward system is associated with craving and the prospective relapse risk.Moreover, the reward-associated learning seems to be disturbed in alcohol-dependent patients, so that addicted persons have problems to integrate informations about positive and negative consequences of their actions and to adapt their behavior accordingly. Personality traits like impulsiveness seem to be relevant in this context as well.These findings about the different neurobiological mechanisms of addiction and relapse raise hope for new psychotherapeutic and pharmacological treatment approaches of alcohol dependence that is adapted to individual relapse mechanisms and needs.

S.24.02 High and low anxiety rat and mouse models: behaviour and neuropeptides

One of the two core symptoms of major depression (MD), whether uni- or bipolar, is the inability to experience pleasure, suggested to be triggered by dysregulation within the brain reward system. In recent years, deep brain stimulation (DBS) has evolved as a potential tool to modulate pathological neural activity; stimulation of the subgenual cingulate (Cg25) has been shown to reduce depressive symptoms, including anhedonia. In rodents, the ventromedial prefrontal cortex (vmPFC) is likely to represent the correlate of Cg25 and accordingly, stimulation of vmPFC reduces anhedonia-like behavior in rats.The present study addresses the question of whether the anti-anhedonic effect of vmPFC-DBS is mediated by the brain reward system.Rats of the Flinders Sensitive Line (FSL), a validated genetic animal model of depression, and its controls, the Flinders Resistant Line (FRL), were stimulated in the vmPFC and tested in the forced swim test (FST), sucrose consumption test (SCT) and the intracranial self-stimulation (ICSS) paradigm. The curve-shift paradigm of ICSS was used in combination with vmPFC-DBS, d-amphetamine and fluoxetine to quantify reward-facilitating or -attenuating treatment effects.Our findings support anti-depressive efficacy of vmPFC-DBS with respect to despair- and anhedonia-like behavior, as shown in the FST and SCT, respectively. However, DBS did not elicit reward-facilitating or reward-attenuating effects on ICSS behavior.These data suggest that it is unlikely that the anti-anhedonic effect of vmPFC-DBS depends on the mesolimbic dopaminergic reward system.