Genetic Variations in the Dopamine Reward System Influence Exercise Reinforcement and Tolerance for Exercise Intensity

Background: Exercise is a reinforcing behavior and finding exercise highly reinforcing is characteristic of habitual exercisers. Genotypes related to dopamine metabolism moderate the reinforcing value of behaviors, but genetic moderators of exercise reinforcement have not been established. Purpose: Determine whether singular nucleotide polymorphisms (SNPs) that moderate central reward pathways and pain neurotransmission are associated with exercise reinforcement, tolerance for exercise intensity, and usual physical activity. Methods: Adults (n = 178) were measured for the reinforcing value of exercise relative to sedentary activities (RRVexercise), minutes of moderate-to-vigorous physical activity (MVPA) and completed the Preference for and Tolerance of the Intensity of Exercise Questionnaire. Genotyping of 23 SNPs known to influence central dopamine tone, pain, or physical activity was performed. ANOVA tested differences in RRVexercise, tolerance, and MVPA among genotype groups. Linear regression controlling for BMI, sex, and liking of exercise was used to further predict the association of genotype on RRVexercise, tolerance, and MVPA. Results: Having at least one copy of the G allele for the DRD2/ANKK1 polymorphism (rs1800497) conferred greater RRVexercise. Greater tolerance for exercise intensity was observed among those homozygous for the T allele for the CNR1 polymorphism (rs6454672), had at least one copy of the G allele for the GABRG3 polymorphism (rs8036270), or had at least one copy of the T allele for the LPR polymorphism (rs12405556). Homozygous individuals for the T allele at rs6454672 exhibited greater MVPA. Conclusion: Similar to other reinforcing behaviors, there is a genetic contribution to exercise reinforcement, tolerance for exercise intensity, and MVPA

The role of the dopaminergic system in the regulation of physical activity in mice

Physical activity (PA) is important to human health, and the genetic and biological regulating factors of physical activity are only beginning to be understood. The dopamine (DA) system has been shown to regulate motivation, and locomotor behavior in animals, and this research was designed to understand the dopaminergic factors important in regulating voluntary physical activity in mice. First, the repeatability of measuring exercise endurance vs. wheel running (WR) in different inbred strains of mice was investigated. It was found that WR behavior is a highly repeatable measurement, while exercise capacity measurements showed low repeatability in Balb/cJ mice. Next, expression levels of the five DA receptors, Tyrosine hydroxylase (TH), and the dopamine transporter (DAT) in the nucleus accumbens and striatum were studied in mice with or without wheel access in differentially active inbred strains of mice. No differences in expression levels of any DA receptors were found within strain between group, suggesting level of PA did not affect DA receptor expression. High active C57L/J mice had significantly decreased expression of Drd1 and TH compared to low active C3H/HeJ mice indicating DA receptor, and enzyme expression/function may act independently to control level of PA. Pharmacological studies showed C57L/J mice significantly decrease WR in response to a D1 agonist, and C3H/HeJ mice significantly increase WR in response to a DAT inhibitor. These results suggest genetic differences in the DA system may mediate differences in PA behavior between inbred strains of mice

Brain opioid and endocannabinoid systems as risk factors for obesity. Positron emission tomography studies of μ-opioid and CB1 receptors with glucose uptake analysis

The prevalence of obesity is increasing globally. Obesity is a major threat to public health since it predisposes individuals to multiple non-communicable diseases. Obesity is difficult to treat or prevent. The modern environment has been blamed for the obesity epidemic, due to the abundance of energy-dense and aggressively advertised foods. The brain is the most important organ controlling energy homeostasis and feeding. However, we do not know which brain pathways render some individuals susceptible to the obesity development in the current environment. The aim of this thesis was to examine whether variation in the brain opioid and endocannabinoid pathways explains differences in the risk for obesity development. Two receptor systems associated with food intake and reward processing were investigated: μ-opioid receptors (MOR) and cannabinoid CB1 receptors (CB1R). MORs were measured with [11C]carfentanil, and CB1Rs with [18F]FMPEP-d2. In addition, brain glucose uptake (BGU) was quantified with [18F]FDG. Healthy, non-obese humans were studied with positron emission tomography in four studies investigating I) the effects of demographic factors on MORs, II) the associations of obesity risk factors on MORs, CB1Rs and BGU, III) the physical fitness and MOR function, and IV) how MORs and CB1Rs associate with feeding behavior. Age, sex and smoking influenced MOR availability, which may contribute to obesity development in specific populations. Familial obesity risk associated with increased BGU but low neuroreceptor availability, suggesting that vulnerability to obesity may be mediated by disruption of these interconnected pathways. Impulsive feeding was associated with reduced MOR availability, which may underlie excessive food intake and weight gain. Central capacity for releasing endogenous MOR ligands was dependent on aerobic fitness, suggesting that the MOR function may be critical in habitual exercise and weight maintenance. Obesity risk factors and circulating cannabinoids associated with reduced CB1R availability, suggesting that an overactive cannabinoid system may facilitate weight gain. In conclusion, multiple neurochemical alterations previously associated with obesity are already present in a number of non-obese individuals, which may increase their risk for future obesity.Aivojen opioidi- ja endokannabinoidijärjestelmät lihavuuden riskitekijöinä. Positroniemissiotomografiatutkimuksia μ-opioidi- ja CB1-reseptoreista sekä glukoosin otosta Lihavuus yleistyy ympäri maailmaa. Lihavuus on yksi merkittävimmistä uhista väestön terveydelle, sillä painon kertyminen altistaa useille kansansairauksille. Lihavuutta on vaikea hoitaa tai ehkäistä. Nykyistä elinympäristöä on syytetty lihavuusepidemiasta, sillä ympäristö on täynnä energiatiiviitä ja voimakkaasti markkinoituja ruokatuotteita. Aivot ovat tärkein energiatasapainoa ja syömistä säätelevä elin. Emme kuitenkaan tiedä, mitkä muutokset aivojen toiminnassa saavat osan ihmisistä lihomaan tässä ympäristössä. Väitöskirjan tavoitteena oli selvittää, selittävätkö aivojen opioidi- ja endokannabinoidijärjestelmän muutokset eroja ihmisten välisessä lihomisriskissä. Tutkimme kahta aivojen välittäjäainejärjestelmää, jotka säätelevät syömisen palkkiokokemuksia: μ-opioidireseptoreja (MOR) ja CB1-kannabinoidireseptoreja (CB1R). MOR-sitoutumista mitattiin [11C]karfentaniililla, ja CB1R-sitoutumista [18F]FMPEP-d2-merkkaineella. Aivojen glukoosinottoa mitattiin lisäksi [18F]FDG-merkkiaineella. Tutkimme terveitä, ei-lihavia ihmisiä positroniemissiotomografialla neljässä tutkimuksessa, joissa selvitettiin: I) väestömuuttujien vaikutusta MOR-sitoutumiseen, II) lihavuuden riskitekijöiden vaikutusta MOR- ja CB1R-sitoutumiseen sekä aivojen glukoosinottoon, III) fyysistä kuntoa ja MOR-toimintaa, ja IV) MOR- ja CB1R-sitoitumisen yhteyttä syömiskäyttäytymiseen. Ikä, sukupuoli ja tupakointi vaikuttivat MOR-sitoutumiseen, mikä voi selittää eroja lihavuuden kehittymisessä eri väestöryhmissä. Perheeseen liittyvä lihomisriski oli yhteydessä aivojen glukoosinottoon ja reseptorimääriin, ja näiden järjestelmien häiriintyminen saattaa altistaa lihavuudelle. Impulsiivinen syömiskäyttäytyminen liittyi alentuneeseen MOR-sitoutumiseen, mikä voi altistaa liialliselle syömiselle ja painon nousulle. Sisäsyntyisten opioidien vapauttamiskyky oli yhteydessä fyysiseen kuntoon, viitaten MOR-toiminnan merkitykseen liikuntaharrastuksen ylläpidossa ja painonhallinnassa. Lihavuuden riskitekijät ja verenkierron kannabinoidit liittyivät alentuneeseen CB1R-sitoutumiseen, mikä viittaa siihen, että yliaktiivinen kannabinoidijärjestelmä voi altistaa lihomiselle. Osalla terveistä ihmisistä on siis havaittavissa useita aivokemiallisia muutoksia, jotka saattavat altistaa lihavuudelle

An analysis of the relationship between obesity, over-eating and addiction behaviours

Introduction: Obesity is a modifiable risk factor with an ever-increasing impact on morbity and mortality worldwide. Efforts to prevent obesity and promote weight loss, like the Direcção-Geral de Saúde’s (National Board of Health - DGS) Programa Nacional para a Promoção da Alimentação Saudável (National Program for the Promotion of Healthy Eating - PNPAS), have yet to prove their effectiveness. This dissertation reviews recent studies on the impact of food, over-eating and obesity on known neuroanatomical structures of addiction and how the concept of food addiction and addictive processes in eating could impact clinical practice. What is addiction? The definition of addiction has been broadened, both by scientific literature and popular media to accommodate for new “addictive disorders”. Known addiction disorders act on the limbic system, whose dopaminergic circuitry is responsible for prediction of reward and reward value. In these disorders, reduction of dopamine receptors DRD2/3 availability and of dopamine release has been described and could translate into a blunted response of the emotional reinforcement circuitry and justify symptoms of withdrawal and tolerance (SRAD pharmacological criteria 10 and 11). Observing these alterations in obese and over-eating individuals could provide significant evidence to the concept of food addiction and provide a new therapeutical target for the treatment and prevention of obesity. Evidence for food addiction: Several types of studies have been found: 1) Neuroimaging studies testing DA release and/or DRD2/3/4 availability; 2) studies using neuroimaging and DA agonists or antagonists; 3) genetic testing on DRD2 like receptors genes; 4) studies using self-assessment reports and/or scales in different populations. Across the first 3 types of studies small sample sizes were used and results were inconsistent between each study, making it difficult to describe a consistent model for addiction-like behaviour in eating and to validate the concept of food addiction. However, the constant differences observed in dopaminergic pathways between either obese and non-obese or over-eaters and normal eaters, show an undeniable influence of reward and emotion on feeding behaviours and how such mechanisms could undermine motivation and ability to regulate diet and lose weight. Clinical Implications: The Yale Food Addiction Scale was developed as a diagnostic tool, based on the DSM-5 criteria for SRAD. Studies using the YFAS across different populations showed inconsistent results, supporting the findings of the previously mentioned studies. Additionally, Riva et al developed a therapeutic approach based on addiction and compared it in a clinical trial with two other medically managed intensive inpatient obesity treatments. No differences were observed in the effectiveness of the three approaches. However, they all showed greater weight loss than the control group, indicating that obese patients could largely benefit from an intensive medically and psychologically managed therapeutic approach. Conclusion: Further research is needed to clarify if and how addiction could impact eating behaviour. Even though, self-assessment scoring scales like the YFAS are greatly put into question, the development of a new, non-addiction-based tool could help differentiate which patients would benefit from a more classical approach of dietary and nutritional counselling,and which patients would benefit from specific psychological counselling, targeting the emotional and behavioural aspects of eating.Introdução: A obesidade é um factor de risco modificável com crescente impacto global na morbilidade e mortalidade. A eficácia de medidas para prevenir e tratar a obesidade, como o Programa Nacional para a Promoção da Alimentação Saudável da Direcção-Geral de Saúde, está ainda por estabelecer. Esta tese revê literatura recente sobre o impacto de alimentos, alimentação compulsiva e obesidade em estruturas neuroanatómicas associadas a processos de dependência e como o conceito de dependência/compulsão alimentar pode influenciar a prática clínica. O que é dependência? A definição de dependência tem sido alargada para incluir novas perturbações de dependência, tanto pela comunidade científica como pela comunicação social. Perturbações de dependência associadas ao uso de substâncias atuam no sistema límbico, cujos circuitos dopaminérgicos estão associados à previsão de recompensa e do seu valor subjetivo. Nestas perturbações de dependência, foi observada a diminuição da expressão dos recetores de dopamina DRD2/3 e da libertação de dopamina, o que pode indicar uma resposta diminuída dos circuitos de reforço emocional e justificar sintomas de abstinência e tolerância (Critérios farmacológicos de SRAD 10 e 11). A observação destas alterações em indivíduos obesos ou com alimentação compulsiva poderia contribuir para a validação da existência de dependência em alimentação excessiva/compulsiva e demonstrar novas áreas de intervenção terapêutica na obesidade. Evidências científicas para dependência em alimentação excessiva/compulsiva: Vários tipos de estudo foram encontrados: 1) estudos da libertação de dopamina e da disponibilidade de receptores DRD2/3 em estruturas límbicas, especialmente no estriado ventral e núcleos da base, através de neuroimagiologia; 2) estudos dos efeitos de agonistas e antagonistas dopaminérgicos; 3) estudos de polimorfismos genéticos em receptores dopaminérgicos; 4) estudos com escalas e questionários de auto-avaliação de sintomas de dependência/compulsão alimentar. Os três primeiros tipos de estudo usaram maioritariamente amostras de pequenas dimensões e apresentaram resultados inconsistentes entre si, dificultando a definição de um modelo neuropatológico de dependência associado a obesidade. Contudo, estudos que compararam populações com e sem obesidade ou populações com e sem alimentação compulsiva, mostraram diferenças significativas nas vias dopaminérgicas, o que indica uma forte influência de mecanismos emocionais e de recompensa em comportamentos alimentares, nomeadamente na motivação e capacidade de controlar dieta e peso. Implicações clínicas: A Yale Food Addiction Scale foi desenvolvida como ferramenta de diagnóstico, baseada nos critérios de Substance-Related Addictive Disorders do DSM-5. Estudos com a aplicação desta ferramenta entre diferentes populações demonstraram resultados inconsistentes entre si, corroborando o padrão observado nos estudos acima mencionados. Adicionalmente, Riva et al, desenvolveram um programa terapêutico baseado em tratamentos de perturbações de dependência e compararam-no num ensaio clínico com outros dois tratamentos de acompanhamento médico intensivo. Embora não tenham sido observadas diferenças estaticamente significativas entre os três tratamentos, todos resultaram em maior perca de peso que no grupo de controlo (grupo com aconselhamento nutricional e de exercício, sem acompanhamento médico), indicando que alguns pacientes obesos poderão ter melhores resultados com um tratamento médico e psicológico continuado. Conclusão: São necessários mais estudos para esclarecer a relação entre distúrbios de dependência e comportamento alimentar. Ainda que a validade de ferramentas de auto-avaliação como a YFAS seja incerta, o desenvolvimento de novas ferramentas de diagnóstico, não baseadas em modelos de dependência, poderia contribuir para a diferenciação de pacientes de acordo com a etiologia da sua obesidade e distinguir quais beneficiariam mais de acompanhamento médico e psicológico especializado

A Behavioural Genetic Model of the Mechanisms Underlying the Link Between Obesity and Dimensional Measures of Attention-Deficit/Hyperactivity Disorder (ADHD)

Objective: The purpose of this study was to investigate genetic and psycho-behavioural mechanisms contributing to the strong ADHD symptom-obesity association. Genetic variants associated with hypo-dopaminergic functioning have been implicated in ADHD, particularly the 7-repeat allele of a VNTR located on the DRD4 gene, likely due to the receptor’s predominance in the prefrontal cortex. Based on this evidence, some experts have suggested that a shared aetiology of a dysfunctional dopamine (DA) system is responsible for the link. However, this conflicts with accumulating evidence that it is actually an amplified DA signal that increases the risk for overeating and weight gain due to a stronger appetitive response to food cues. It seems plausible that individuals with ADHD symptoms who are predisposed overeat are those who also possess a high sensitivity to, and greater motivation to seek out, rewarding stimuli, as reflected by increased DA availability in the brain reward pathways. Accordingly, the current study tested the hypothesis that symptoms of ADHD, predicted by hypo-dopaminergic functioning in the prefrontal cortex, in combination with an enhanced appetitive drive, predict hedonic eating, and in turn, higher BMI. Methods: Functional markers of the DRD2 and DRD4 were genotyped to determine their contributions to ADHD symptoms and various indices of hedonic eating, respectively. The model was tested using Structural Equation Modeling procedures in a general population sample (n=421 adults) representing a broad range of body mass index (BMI) values. Results: Overall, the fit indices indicated that the proposed model was a good fit to the data. Controlling for education level, all parameter estimates were in the expected direction and statistically significant with the exception of the pathway from the DRD4 marker to ADHD symptoms. The indirect effect was significant, indicating that overeating mediated the association between ADHD symptoms and BMI. Conclusions: Results lend support to the hypothesis that overeating and an elevated DA signal in the ventral striatum – representative of a greater reward response – are responsible for the link between ADHD symptoms and obesity. The current study was the first to connect the most prominent and supported theories of ADHD with evidence-based models of hedonic eating

Acute physical exercise improves shifting in adolescents at school: evidence for a dopaminergic contribution

The executive function of shifting between mental sets demands cognitive flexibility. Based on evidence that physical exercise fostered cognition, we tested whether acute physical exercise can improve shifting in an unselected sample of adolescents. Genetic polymorphisms were analyzed to gain more insight into possibly contributing neurophysiological processes. We examined 297 students aged between 13 and 17 years in their schools. Physical exercise was manipulated by an intense incremental exercise condition using bicycle ergometers and a control condition which involved watching an infotainment cartoon while sitting calm. The order of conditions was counterbalanced between participants. Shifting was assessed by a switching task after both conditions. Acute intense physical exercise significantly improved shifting as indicated by reduced switch costs. Exercise-induced performance gains in switch costs were predicted by a single nucleotide polymorphism (SNP) targeting the Dopamine Transporter (DAT1/SLCA6A3) gene suggesting that the brain dopamine system contributed to the effect. The results demonstrate the potential of acute physical exercise to improve cognitive flexibility in adolescents. The field conditions of the present approach suggest applications in schools

Master of Science

thesisThe purpose of this study was to assess the influence of an acute bout of cardiovascular exercise on selective and sustained attention in preadolescent children. Secondary aims included determining if gender, baseline physical activity level, or intensity of exercise moderates the relationship between acute exercise and attentional processes. A within-subjects design was used to measure performance on the Conners' Continuous Performance Test (CPT II) following 20 min of sedentary activity (passively viewing a video) and 20 min of cardiovascular (CV) exercise. The CPT II was administered on two different testing days to 26 preadolescent children (age = 10.4 ± 1.16 years; 13 females). Participants wore ActiGraph GT1M accelerometers at the waist during the exercise session, which consisted of a 10-station aerobic circuit, designed to elicit and maintain a cardiovascular response. Testing began once heart rate returned to within 10% of preexercise levels. The Physical Activity Questionnaire for Children (PAQ-C) was administered as a baseline measure of physical activity levels. Average exercise intensities met national guidelines of spending greater than 50% exercise time at moderate to vigorous physical activity (MVPA). Results indicated that CV exercise had no adverse effects on selective or sustained attentional processes. Neither gender nor baseline physical activity level influenced this relationship. To meet daily recommended levels of MVPA, opportunities for CV exercise may be incorporated in the school day without adversely affecting student attention

The overlap between binge eating disorder and substance use disorders: Diagnosis and neurobiology

Background and aims: Binge eating disorder (BED) is a relatively common condition, especially in young adult females, and is characterized by chronic over-consumption of food resulting in embarrassment, distress, and potential health problems. It is formally included as a disorder in DSM-5 for the first time, an acknowledgement to its debilitating nature. This article explores the overlap between binge eating disorder and substance use disorders (SUD). Methods: The bibliographic search was a computerized screen of PubMed databases from January 1990 to the present. Binge eating disorder, substance use disorder, binging, obesity, food addiction, comorbidity, dopamine, opioid, serotonin, glutamate, and pharmacological treatment were the keywords used in searching. Results: BED shares similar phenomenology to SUD, including significant urges to engage in binging episodes, resulting in distress and impairment. Similar neurobiological pathways are found in both BED and SUD and medications based on similar neurobiology have been examined for both disorders. A subset of individuals with BED may have a “food addiction”, but there is no clinical agreement on the meaning of “food addiction”. Exploring the relationship between BED and obesity may also shed light on the extent to which BED can be viewed as an addiction. Conclusions: Overall, nascent research regarding BED and SUD suggests an overlap between these disorders, but there are discrepancies between these two disorders that need further exploration