Rebecca L. Corwin - US grants

One of the most devastating disorders of old age is osteoporosis, which increases fracture risk and reduces quality of life for tens of millions of Americans. Available evidence suggests that both the quality and the quantity of fat consumed can have important effects on bone integrity in the young. Little research, however, has examined these effects with age. The proposed research will use aged rats to determine the effects of moderate- and high-fat diets rich in specific fatty acids on calcium excretion, hormonal activity, and bone composition. The overall hypothesis guiding this research is that consumption of diets rich in fat will have adverse effects on bone integrity in older individuals. These effects will be due to alterations in calcium excretion and growth hormone (GH) responsiveness, which will be affected differentially by the type of fat consumed. Three experiments will address three specific aims designed to determine the effects of moderate- and high-fat diets containing saturated and trans-fatty acids or n-6 fatty acids on 1) calcium excretion, 2) GH responsiveness, and 3) bone density, volume, and mineral content. Old rats will be compared among six diet conditions: 10 percent, 40 percent, and 78 percent shortening (rich in saturated and trans fatty acids), and 10 percent, 40 percent, and 78 percent borage oil (rich in n-6 fatty acids). Caloric intakes will be yoked to assure that vitamin, mineral and protein intakes do not vary between groups. It is predicted that calcium excretion will increase, and GH responsiveness, bone density, bone volume, and bone mineral content will decrease, as the fat content of the diet increases. It is further predicted that these effects will be greatest when saturated and trans fats are consumed. Given the dietary fat consumption patterns of many Americans, the increasing size of the aged population, and the high prevalence of osteoporosis in the United States, there is an urgent need to examine the impact that dietary fats have on skeletal integrity with age.

DESCRIPTION (Adapted From The Applicant's Abstract): Binge eating is thought to involve significant alterations in brain serotonin levels and receptors that may serve to sustain overeat/restrict patterns of behavior. These changes may also contribute to associated comorbitidy such as depression, alcoholism and obesity. The neurochemical causes and consequences of repeated episodes of binge-type behavior, however, have been difficult to examine directly using human subjects. Furthermore, few animal models have been developed for use in this type of research. The purpose of the proposed research is to examine changes in serotonin levels, receptor density, and sensitivity to serotonergic agonist using a novel rat "binge-eating" procedure developed in my laboratory. In this procedure, nonfood deprived rats are allowed to "nibble" or "binge" on an optional source of fat or carbohydrate for four weeks. After the four-week period, discrete brain regions will be assayed before, during, and after a carbohydrate or fat "binge" and behavioral responses to selective serotonergic agonists will be determined. Three experiments will determine the affects of binge-type behavior on (1) levels of serotonin in discrete brain nuclei, (2) 5HT1B receptor density in discrete brain nuclei, (3) sensitivity to 5HT1B and 5HT2C receptor agonists. The independent contributions of consumption pattern and type of food consumed to changes in serotonin and its receptors will be systematically evaluated. These studies will provide important basic information relevant to understanding the neurobiological consequences of binge-type eating behavior.

DESCRIPTION (provided by applicant): Neurological mechanisms relevant to intermittent episodes of behavioral excess are not well understood, but bear investigation due to the contribution of this kind of behavior to health problems such as disordered eating, obesity and substance abuse. We have developed a unique rat bingeing protocol, which we have been using to examine the neurobiology associated with repeated intermittent excessive fat intake that is maintained over extended periods of time. Peptides that regulate fat intake under non-binge conditions are without effect when rats binge on fat. In contrast, recent results from my laboratory show that the GABA-B agonist baclofen reduces fat intake in our protocol, while having no effect in non-bingeing protocols. Others have reported that baclofen reduces self-administration of abused drugs. This suggests that the neurobiology of bingeing is different from that of non-binge behavior, but may share similarities with the neurobiology of substance abuse. Therefore, we will use baclofen to test the overall hypothesis guiding this research, i.e. that GABA-B receptors have a role in binge-type eating. The following Specific Aims will be addressed: AIM 1: To test the hypothesis that GABA-B ligands will differentially affect fat consumption in bingeing and non-bingeing rats. Hypotheses: a) Lower dosages of baclofen will reduce food intake to a greater extent in bingeing rats than in non-bingeing rats; Lower dosages of baclofen will reduce food intake to a greater extent in females than in males; b) Baclofen-induced reductions in binge intake will be mediated centrally; GABA-B receptor blockade will stimulate binge intake; c) Dosages of GABA-B ligands that affect food intake will not affect general behavioral activity in the bingeing rats. AIM 2: To test the hypothesis that baclofen-induced reductions in fat intake are enhanced with repeated bingeing. Hypothesis: Lower dosages of baclofen will reduce food intake to a greater extent in rats that have repeatedly binged than in rats that have engaged in fewer binge episodes. AIM 3: To test the hypothesis that the VTA is a sensitive site of action for baclofen-induced reductions in bingeing. Hypothesis: Lower doses of baclofen will reduce bingeing when infused into the VTA than when infused into the striatum or substantia nigra. These studies are the first to examine the contribution of GABA-B receptors to bingeing and will provide new insight into the neurobiology of bingeing-related disorders

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Binge eating is defined as consuming more food in a brief period of time than most individuals would consume under similar circumstances, and within the same time period. Binge eating threatens successful, sustained weight loss measures and is linked to weight regain and severe obesity. A number of psychotherapeutic, cognitive, and pharmotherapeutic methods have been used to treat bingeing with moderate success. However, small studies in rats and humans have shown that the GABA-B agonist baclofen can reduce craving and bingeing behavior. Thus, the purpose of this pilot study is to conduct a double-blind, placebo-controlled trial of bacolfen as a means to reducing craving and bingeing behaviors in adults with a significant history of bingeing. We hypothesize that the baclofen treatment will significantly reduce craving and the frequency of binge eating. Thirty adults who binge at least 3 times a week will be enrolled in the pilot study. Study involvement will last approximately 18 weeks for each participant.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Binge eating is defined as consuming more food in a brief period of time than most individuals would consume under similar circumstances, and within the same time period. Binge eating threatens successful, sustained weight loss measures and is linked to weight regain and severe obesity. A number of psychotherapeutic, cognitive, and pharmotherapeutic methods have been used to treat bingeing with moderate success. However, small studies in rats and humans have shown that the GABA-B agonist baclofen can reduce craving and bingeing behavior. Thus, the purpose of this pilot study is to conduct a double-blind, placebo-controlled trial of baclofen as a means to reducing craving and bingeing behaviors in adults with a significant history of bingeing. We hypothesize that the baclofen treatment will significantly reduce craving and the frequency of binge eating. Thirty adults who binge at least 3 times a week will be enrolled in the pilot study. Study involvement will last approximately 18 weeks for each participant.