Dysregulation of the dopamine system is linked to various aberrant behaviors, including addiction, compulsive exercise, and hyperphagia leading to obesity. The goal of the present experiments was to ...determine how dopamine contributes to the expression of opposing phenotypes, excessive exercise and obesity. We hypothesized that similar alterations in dopamine and dopamine-related gene expression may underly obesity and excessive exercise, as competing traits for central reward pathways. Moreover, we hypothesized that selective breeding for high levels of exercise or obesity may have influenced genetic variation controlling these pathways, manifesting as opposing complex traits. Dopamine, dopamine-related peptide concentrations, and gene expression were evaluated in dorsal striatum (DS) and nucleus accumbens (NA) of mice from lines selectively bred for high rates of wheel running (HR) or obesity (M16), and the non-selected ICR strain from which these lines were derived. HPLC analysis showed significantly greater neurotransmitter concentrations in DS and NA of HR mice compared to M16 and ICR. Microarray analysis showed significant gene expression differences between HR and M16 compared to ICR in both brain areas, with changes revealed throughout the dopamine pathway including D1 and D2 receptors, associated G-proteins (e.g.,
Golf), and adenylate cyclase (e.g.,
Adcy5). The results suggest that similar modifications within the dopamine system may contribute to the expression of opposite phenotypes in mice, demonstrating that alterations within central reward pathways can contribute to both obesity and excessive exercise.
Running and Addiction Kanarek, Robin B; D'Anci, Kristen E; Jurdak, Nicole ...
Behavioral neuroscience,
08/2009, Letnik:
123, Številka:
4
Journal Article
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Exercise improves cardiovascular health, strengthens muscles and bones, stimulates neuroplasticity, and promotes feelings of well-being. However, when taken to extremes, exercise can develop into an ...addictive-like behavior. To assess the addictive potential of exercise, withdrawal symptoms following injections of 1.0 mg/kg naloxone were compared in active and inactive male and female rats. Active and inactive rats were given food for 1 hr or 24 hr/day. Additionally, a group of inactive rats was pair-fed the amount of food consumed on the previous day by food-restricted active rats. Rats fed for 1 hr/day decreased food intake and lost weight. Additionally, food-restricted active rats increased wheel running. There was a direct relationship between the intensity of running and the severity of withdrawal symptoms. Active food-restricted rats displayed the most withdrawal symptoms, followed by active rats given 24-hr access to food. Only minimal withdrawal symptoms were observed in inactive rats. These findings support the hypothesis that exercise-induced increases in endogenous opioid peptides act in a manner similar to chronic administration of opiate drugs.
Objective: To examine the literature on binge eating to gain a better understanding of its biological foundations and their role in eating disorders. Method: Literature review and synthesis. Results: ...Research using animal models has revealed several factors that contribute to the development and maintenance of binge eating. These factors, including stress, food restriction, the presence of palatable foods, and environmental conditioning, parallel many of the precursory circumstances leading to binge eating in individuals with bulimia nervosa and binge eating disorder. Discussion: The animal literature has opened a new avenue to aid in the understanding of the neurobiological basis of binge eating. Future endeavors examining the genetic and environmental correlates of binge eating behavior will further contribute to the understanding of the biological foundations of binge eating and assist with establishing diagnostic criteria and the development of novel treatments for eating disorders marked by binge eating.
Obesity has reached epidemic proportions and is recognised as a significant global health problem. Increased food intake and decreased physical activity are traditionally to blame for the development ...of obesity; however, many variables such as behaviour, diet, environment, social structures and genetics also contribute to this multifactorial disease. Complex interactions among these variables (for example, gene–environment, gene–diet and gene–gene) contribute not only to individual differences in the development of obesity, but also in treatment response. Mouse models have historically played valuable roles in understanding the genetics of traits related to energy balance and obesity. In the present review, we survey past use and examine new advances in mouse models designed to uncover the genetic architecture of obesity and its component traits. We discuss traditional models such as inbred strains and selectively bred lines and their contributions and shortcomings. We consider the evolution of mouse models into more informative resources such as outbred crosses and the Hybrid Mouse Diversity Panel, as well as novel next-generation approaches such as the Collaborative Cross. Moreover, the genetic architecture of voluntary exercise and the interactive relationship between host genetics and the gut microbiome are presented as novel phenotypes that augment studies using body weight and body fat percentage as endpoints. Understanding the intricate network of phenotypic, genotypic and environmental variables that predispose individuals to obesity will elucidate biological networks involved in the development of obesity. Knowledge obtained from advances in mouse models will inform human health and provide insight into inter-individual variability in the aetiology of obesity-related diseases.
Interspecies genetics of eating disorder traits Kas, Martien J.H.; Kaye, Walter H.; Foulds Mathes, Wendy ...
American journal of medical genetics. Part B, Neuropsychiatric genetics,
5 April 2009, Letnik:
150B, Številka:
3
Journal Article
The effects of intraperitoneal (ip) d-glucose administration on antinociception were studied in male Long–Evans rats. Rats were assessed for antinociception using the hot-water tail-withdrawal ...procedure (54±0.2°C) to determine if peripheral administration of d-glucose (300, 560, or 720mg/kg) would enhance morphine-mediated antinociception (MMA) (1.0, 3.0, 4.2, 5.6, and 10.0mg/kg cumulative-dosing regime) and if d-glucose (560, 720, or 1000mg/kg) alone could produce antinociceptive activity that was naloxone (0.32mg/kg) reversible. Additionally, the actions of d-glucose on MMA were compared with a stereoisomer, l-glucose, which is not metabolized. The results of these studies demonstrate that peripheral administration of d-glucose significantly enhances MMA and that d-glucose alone produces antinociceptive actions that are potentially mediated by the endogenous opioid system. Furthermore, l-glucose failed to have an effect on MMA suggesting that the alterations in antinociception seen with d-glucose are not due to stressors such as osmolality or injection. The current studies provide evidence that d-glucose alteration of antinociception is not simply a response to taste or gustation.
•d-glucose enhanced morphine-mediated antinociception.•d-glucose demonstrated naloxone reversible antinociceptive actions.•The stereoisomer of d-glucose, l-glucose, had no antinociceptive action.•d-glucose has antinociception actions in the absence of gustation.
The Collaborative Cross (CC) is a mouse recombinant inbred strain panel that is being developed as a resource for mammalian systems genetics. Here we describe an experiment that uses partially inbred ...CC lines to evaluate the genetic properties and utility of this emerging resource. Genome-wide analysis of the incipient strains reveals high genetic diversity, balanced allele frequencies, and dense, evenly distributed recombination sites-all ideal qualities for a systems genetics resource. We map discrete, complex, and biomolecular traits and contrast two quantitative trait locus (QTL) mapping approaches. Analysis based on inferred haplotypes improves power, reduces false discovery, and provides information to identify and prioritize candidate genes that is unique to multifounder crosses like the CC. The number of expression QTLs discovered here exceeds all previous efforts at eQTL mapping in mice, and we map local eQTL at 1-Mb resolution. We demonstrate that the genetic diversity of the CC, which derives from random mixing of eight founder strains, results in high phenotypic diversity and enhances our ability to map causative loci underlying complex disease-related traits.
The hypothalamus plays a central role in the integrated regulation of energy homeostasis and body weight, and a number of hypothalamic neuropeptides, such as neuropeptide Y (ref. 1), galanin, CRH ...(ref. 3) and GLP-1 (ref. 4), have been implicated in the mediation of these effects. To discover new hypothalmic peptides involved in the regulation of body weight, we used differential display polymerase chain reaction to identify messenger RNAs that are differentially expressed in the hypothalamus of ob/+ compared with ob/ob C57B1/6J mice. We show here that one mRNA that is overexpressed in the hypothalamus of ob/ob mice encodes the neuropeptide melanin-concentrating hormone (MCH). Fasting further increased expression of MCH mRNA in both normal and obese animals. Neurons containing MCH are located in the zona incerta and in the lateral hypothalamus. These areas are involved in regulation of ingestive behaviour, but the role of MCH in mammalian physiology is unknown. To determine whether MCH is involved in the regulation of feeding, we injected MCH into the lateral ventricles of rats and found that their food consumption increased. These findings suggest that MCH participates in the hypothalamic regulation of body weight.
Food intake and body weight are determined by a complex interaction of regulatory pathways. To elucidate the contribution of the endogenous peptide cholecystokinin, mice lacking functional ...cholecystokinin-A receptors were generated by targeted gene disruption. To explore the role of the cholecystokinin-A receptor in mediating satiety, food intake of cholecystokinin-A receptor-/- mice was compared with the corresponding intakes of wild-type animals and mice lacking the other known cholecystokinin receptor subtype, cholecystokinin-B/gastrin. Intraperitoneal administration of cholecystokinin failed to decrease food intake in mice lacking cholecystokinin-A receptors. In contrast, cholecystokinin diminished food intake by up to 90% in wild-type and cholecystokinin-B/gastrin receptor-/- mice. Together, these findings indicate that cholecystokinin-induced inhibition of food intake is mediated by the cholecystokinin-A receptor. To explore the long-term consequences of either cholecystokinin-A or cholecystokinin-B/gastrin receptor absence, body weight as a function of age was compared between freely fed wild-type and mutant animals. Both cholecystokinin-A and cholecystokinin-B/gastrin receptor-/- mice maintained normal body weight well into adult life. In addition, each of the two receptor-/- strains had normal pancreatic morphology and were normoglycemic. Our results suggest that although cholecystokinin plays a role in the short-term inhibition of food intake, this pathway is not essential for the long-term maintenance of body weight.
Chronic exercise in a running wheel increases baseline pain sensitivity while attenuating the antinociceptive effects of peripherally administered opiate agonists in laboratory rodents. To determine ...if these effects are due to exercise-induced changes in the central nervous system (CNS) or an artifact of exercise-induced alterations in peripheral physiology, the present study evaluated the antinociceptive actions of centrally administered opiate agonists in active and inactive female rats. Rats were implanted with cannula into the right periaqueductal gray (PAG) area of the midbrain. After the completion of the surgery, the animals were allowed ad libitum access to running wheels or housed in standard cages for three weeks. Pain sensitivity was measured on the tail flick test before and immediately following microinjections of either morphine (0, 2.5, 5.0, 10.0, 20.0 μg/rat) or the more potent morphine metabolite, morphine-6-glucuronide (M6G) (0, 0.03, 0.1, 0.3, 1.0 μg/rat). Baseline tail flick latencies were significantly shorter in active than in inactive rats. Additionally, active animals were less sensitive to the antinociceptive effects of morphine and M6G than inactive rats. These findings provide evidence for the involvement of the CNS in exercise-mediated alterations in pain sensitivity and opiate drug actions.
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