Wendy Foulds Mathes

The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance 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.

The biology of binge eating.

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.

Dopaminergic Dysregulation in Mice Selectively Bred for Excessive Exercise or Obesity

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: Precipitated Withdrawal in a Rat Model of Activity-Based Anorexia

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.

Chronic running-wheel activity decreases sensitivity to morphine-induced analgesia in male and female rats

The effects of exercise on morphine-induced analgesia were examined in male and female Long-Evans rats. In Experiment 1, 10 male rats were housed in standard laboratory cages, and 10 in activity wheels for 20 days prior to nociceptive testing. Pain thresholds were assessed using a tail-flick (TF) procedure. Morphine sulfate was administered using a cumulative dosing procedure (2.5, 5.0, 7.5, 10.0, 12.5, and 15.0 mg/kg). TF latencies were measured immediately prior to and 30 min following each injection. In Experiment 2, morphine-induced analgesia was examined in females in an identical manner to that of Experiment 1. Additionally, to determine if the attenuation of morphine-induced analgesia was permanent or reversible, after the initial test nociceptive test, previously active female rats were placed in standard cages, and previously inactive females placed in running wheels for 17 days prior to a second nociceptive test. Baseline TF latencies were significantly shorter in active male rats than in inactive animals. Additionally, both active male and female rats displayed decreased morphine-induced analgesia relative to inactive controls. Moreover, females that had been inactive and then were permitted to run showed a suppression in morphine-induced analgesia relative to presently inactive rats, and to their own nociceptive responses when sedentary. In contrast, morphine-induced analgesia in initially active females who were housed in standard cages during part 2 of Experiment 2 was enhanced relative to their first nociceptive test and to presently active rats. Experiment 3 examined the effects of short-term (24 h) running on antinociception. Baseline TF latencies were shorter in active rats than inactive rats. However, no differences in morphine-induced analgesia were observed as a function of short-term exposure to exercise. Experiment 4 investigated whether differences in body weight contributed to the differences in morphine-induced analgesia between chronically active and inactive animals. %MPEs did not vary among male rats maintained at 100, 85, or 77% of their free-feeding body weight. These results indicate that chronic activity can decrease morphines analgesic properties. These effects may be due to crosstolerance between endogenous opioid peptides released during exercise and exogenous opioids.

Wheel running attenuates the antinociceptive properties of morphine and its metabolite, morphine-6-glucuronide, in rats

Recent work has shown that chronic exercise is associated with a reduction in the pain-relieving actions of opioid drugs in experimental animals. To determine whether this reduction represents an interaction between exogenously administered opioids and the endogenous opioid system, or is the result of altered drug pharmacokinetics, the antinociceptive actions of morphine and its metabolite, morphine-6-glucuronide (M6G), were compared in active and inactive female Long-Evans rats. Active animals were housed in running wheels and inactive animals in standard laboratory cages for 3 weeks preceding determinations of antinociception using the tail-flick test. At the end of the 3-week period, active rats were running the equivalent of 9-11 km a day. Antinociceptive responses, determined following subcutaneous injections of either morphine (0.625-20 mg/kg) or M6G (0.3-10.0 mg/kg), were significantly reduced in active rats relative to inactive rats. This reduction was manifested by both a lower magnitude of antinociception, and a shorter duration of antinociception after drug administration in active compared to inactive rats. This reduction was not associated with alterations in the estrous cycle or with differences in body weight between the active and inactive animals. The present results support the hypothesis that cross-tolerance develops between endogenous opioid peptides released in response to exercise and exogenously administered opioid drugs.

Prior Exposure to Palatable Solutions Enhances the Effects of Naltrexone on Food Intake in Rats

Previous research has suggested that chronic intake of palatable foods and fluids enhances the activity of the endogenous opioid system. To examine this suggestion, the effect of naltrexone on food intake was examined in male Long-Evans rats with or without prior exposure to palatable solutions. In Experiment 1, rats were fed laboratory chow alone or laboratory chow and a 32% sucrose solution, and in Experiment 2, were fed chow alone, chow and a 32% Polycose solution, or chow and a 0.15% saccharin solution for three weeks. The sucrose, Polycose, and saccharin solutions were removed 18 h prior to drug administration. Rats then received injections of naltrexone hydrochloride (0.0, 0.3 or 3.0 mg/kg. sc) and chow intakes were measured during the subsequent 1, 2, 4, 6 and 24 h. Naltrexone injections had minimal effects on intakes of animals which previously had consumed only chow. In contrast, naltrexone led to significant dose-related decreases in chow intakes in rats which had previously consumed the sucrose, Polycose, or saccharin solutions. These results provide confirmation for the suggestion that chronic intake of palatable solutions alters the activity of the endogenous opioid system.

Architecture of energy balance traits in emerging lines of the Collaborative Cross

The potential utility of the Collaborative Cross (CC) mouse resource was evaluated to better understand complex traits related to energy balance. A primary focus was to examine if genetic diversity in emerging CC lines (pre-CC) would translate into equivalent phenotypic diversity. Second, we mapped quantitative trait loci (QTL) for 15 metabolism- and exercise-related phenotypes in this population. We evaluated metabolic and voluntary exercise traits in 176 pre-CC lines, revealing phenotypic variation often exceeding that seen across the eight founder strains from which the pre-CC was derived. Many phenotypic correlations existing within the founder strains were no longer significant in the pre-CC population, potentially representing reduced linkage disequilibrium (LD) of regions harboring multiple genes with effects on energy balance or disruption of genetic structure of extant inbred strains with substantial shared ancestry. QTL mapping revealed five significant and eight suggestive QTL for body weight (Chr 4, 7.54 Mb; CI 3.32-10.34 Mb; Bwq14), body composition, wheel running (Chr 16, 33.2 Mb; CI 32.5-38.3 Mb), body weight change in response to exercise (1: Chr 6, 77.7Mb; CI 72.2-83.4 Mb and 2: Chr 6, 42.8 Mb; CI 39.4-48.1 Mb), and food intake during exercise (Chr 12, 85.1 Mb; CI 82.9-89.0 Mb). Some QTL overlapped with previously mapped QTL for similar traits, whereas other QTL appear to represent novel loci. These results suggest that the CC will be a powerful, high-precision tool for examining the genetic architecture of complex traits such as those involved in regulation of energy balance.

Chronic running wheel activity attenuates the antinociceptive actions of morphine and morphine-6-glucouronide administration into the periaqueductal gray in rats.

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 microg/rat) or the more potent morphine metabolite, morphine-6-glucuronide (M6G) (0, 0.03, 0.1, 0.3, 1.0 microg/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.

Advances in comparative genetics: influence of genetics on obesity.

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.