Amanda L. Sharpe, Ph.D. - US grants

The co-use of alcohol and nicotine is positively correlated in man, with people who drink alcohol having an increased probability of smoking and vice versa. Although alcohol and nicotine are known to be one of the most common combinations of drugs abused by man, little is known about the relationship between these two drugs. The experiments proposed will examine the interaction between these drugs in rats by investigating the effect of self-administration of one drug on the subsequent self-administration of the other drug as well as the concurrent administration of both. The hypothesis being tested predicts that alcohol and nicotine are interacting by a pharmacological mechanism and that self-administration of one drug will be affected only when the other drug is present. These experiments are unique because the rats will be able to self-administer both nicotine (intravenously) and alcohol (orally) during daily operant sessions. Examination of the relationship between alcohol and nicotine using this procedure will develop a model that can be used for further determination of the mechanism of the interaction between these two drugs.

DESCRIPTION (provided by applicant): The goal of the proposed studies is to investigate the relationship between corticotropin-releasing hormone type 2 receptors (CRH-R2) in the ventromedial hypothalamus (VMH) and ethanol intake. Alcoholism has been hypothesized as an inability to regulate appetite for and consumption of alcohol, resulting in increased intake of alcohol. Central administration of CRH receptor agonists, such as corticotropin-releasing hormone and urocortin, decreases intake of food, water and ethanol. The VMH is implicated in regulation of appetite and consumption of food by studies reporting a decrease in food intake following electrical stimulation or injection of CRH into the VMH. The studies contained in the first aim examine the effect of injection of CRH-R2 agonists and antagonists into the VMH on alcohol consumption in a limited access procedure in mice. Results from these studies will determine if activity at CRH-R2 in the VMH play a role in regulation of alcohol self-administration. The second aim attempts to correlate alcohol intake and preference with basal levels of CRH-R2 and urocortin III, an endogenous CRH-R2 agonist, in the VMH using several different strains of alcohol preferring versus non-preferring mice.

Obesity is a major concern for our society, and development of strategies to help decrease body weight is important in the battle against obesity and comorbid health conditions. As the major endogenous mechanism responsible for combating obesity, understanding how proopiomelanocortin (POMC) mediates feeding and reward learning, and how this may change following obesity is essential for rational development of therapeutics to treat obesity. Neurons containing POMC are found in the arcuate nucleus and project to many areas such as the nucleus accumbens and hypothalamus. Beta-endorphin (b-END) and alpha-melanocyte stimulating hormone (a-MSH) are neuropeptide products of POMC, and have well-established central roles in reward (food, drugs of abuse, sex) and learning. Despite their hypothesized co-release from terminals, studies to date have overwhelmingly looked at the role of either b-END or a-MSH alone in feeding and reward, and results from these studies have suggested opposing roles for these peptides in feeding which is perplexing. The overall objective for this application is to 1) determine sensitivity of nucleus accumbens projecting POMC neurons to leptin and insulin (known simulators of POMC neuron firing), and 2) establish the physiological and behavioral role of co- released b-END and a-MSH in the nucleus accumbens in feeding and reward learning. These two objectives will be assessed in energy neutral state and following diet induced obesity to assess if adaptations to the system occur following obesity. The central hypothesis is that POMC signaling in the nucleus accumbens is important in the regulation of feeding and learning about food reward, and that this role for POMC is impaired following development of obesity. These studies will, for the first time, delineate the behavioral role of POMC signaling from the arcuate nucleus to the nucleus accumbens on reward learning and feeding both in normal energy state and after the development of obesity.

Cognitive decline is a common sequela of mammalian aging, from rodents to humans. As it often results in the inability to live independently, slowing or preventing the loss of cognition with age would significantly increase the quality of life for older adults. While the etiology of age-related cognitive impairment is unknown, there is increasing evidence that age-related changes in neurotransmitters may play an important role. Neurotransmitters produced from proopiomelanocortin (POMC) are of particular interest because they modulate cognition, metabolic rate and other age-related phenotypes, and their levels are known to decrease with age. Furthermore, when administered systemically, or into the brain, they improve memory, attention, and cognition and delay the decline in cognition in mouse models of Alzheimer?s disease. However, which POMC- producing neurons are responsible for the age-related decline in brain POMC, the mechanism by which this occurs, and its contribution to age-dependent cognitive decline are not known. Our studies will yield insight into mechanisms responsible for age-related changes in POMCHipp neurons and reveal whether interventions that delay aging act, in part, by modulating these neurons. Filling these gaps in knowledge is essential f or development of interventions to reverse cognitive aging. The proposed work is enabled by a novel combination of technology including retrograde labeling of POMCHipp neurons and mouse genetic models that together allow us to specifically target these neurons. This will allow us to analyze age-dependent changes in the number and projection density (Aim 1) and gene expression (Aim 2) of POMCHipp neurons that may provide insight into the decline in cognition with age. We will further determine whether these changes can be reversed by treatment with rapamycin, a drug that increases lifespan in mice while ameliorating age-related declines in cognition, as well the age-related dysfuncton of Arc POMCPVN neurons. Finally, in Aim 3 we will specifically activate or inhibit the function of Arc POMCHipp neurons and measure the impact on cognition. Our approach is highly innovative and will define the role POMCHipp neurons in the mechanisms responsible for cognitive decline with age, and provide a framework for studies to develop interventions to reduce age-related cognitive decline. This JPI project will provide the preliminary data, mentorship, and resources for the development of a competitive, independent research grant proposal in the field of geroscience.