Randall R Sakai

• University of Cincinnati

Mood disorders such as major depressive disorder (MDD) affect a significant proportion of the population. Although progress has been made in the development of therapeutics, a large number of individuals do not attain full remission of symptoms and adverse side effects affect treatment compliance for some. In order to develop new therapies, there i...

Insulin receptors (IRs) are expressed in discrete neuronal populations in the central nervous system (CNS), including the hippocampus. To elucidate the functional role of hippocampal IRs independent of metabolic function, we generated a model of hippocampal-specific insulin resistance using a lentiviral vector expressing an IR antisense sequence (L...

This chapter discusses the importance of neuroethologically valid animal models of social stress, what information these models have produced, and how they may relate to the human condition. Interpersonal conflict, hostile work environments, perception of low socioeconomic status, or lack of social support can result in social stress exposure, whic...

During recovery from social stress in a visible burrow system (VBS), during which a dominance hierarchy is formed among the males, rats display hyperphagia and gain weight preferentially as visceral adipose tissue. By proportionally increasing visceral adiposity, social stress may contribute to the establishment of metabolic disorder. Amylin was ad...

Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are satiation factors secreted by the small intestine in response to lipid meals. Apo AIV and CCK-8 has an additive effect to suppress food intake relative to apo AIV or CCK-8 alone. In this study, we determined whether CCK-8 (1, 3, or 5 μg/kg ip) reduces food intake in fasted apo AIV knockout...

The prevalence of overweight and obesity has markedly increased during the past few decades. Stress has been suggested as one environmental factor that may contribute to the development of obesity. In this review, we discuss the role that exposure to chronic stress may play in the development of obesity, with particular attention to the effects of...

This study elucidates the neural circuits by which circulating angiotensin II (ANGII) acts in the brain to influence humoral and behavioral responses to psychological stressors. To test the hypothesis that systemic ANGII mediates stress responding via the subfornical organ (SFO), we first found that the timing of increased systemic ANGII in respons...

The prevalence of obesity has rapidly escalated and now represents a major public health concern. Although genetic associations with obesity and related metabolic disorders such as diabetes and cardiovascular disease have been identified, together they account for a small proportion of the incidence of disease. Environmental influences such as chro...

Considerable evidence implicates the renin-angiotensin system (RAS) in the regulation of energy balance. To evaluate the role of the RAS in the central nervous system regulation of energy balance, we used osmotic minipumps to chronically administer angiotensin II (Ang II; icv; 0.7 ng/min for 24 days) to adult male Long-Evans rats, resulting in redu...

Syrian hamsters, like many humans, increase food intake and body adiposity in response to stress. We hypothesized that glucocorticoids (cortisol and corticosterone) mediate these stress-induced effects on energy homeostasis. Because Syrian hamsters are dual secretors of cortisol and corticosterone, differential effects of each glucocorticoid on ene...

Life stress frequently occurs within the context of homeostatic challenge, requiring integration of physiological and psychological need into appropriate hormonal, cardiovascular, and behavioral responses. To test neural mechanisms underlying stress integration within the context of homeostatic adversity, we evaluated the impact of a pronounced phy...

The hypothalamic melanocortin system is known for its role in regulating energy homeostasis through it actions within hypothalamic brain centers. However, emerging evidence suggests that this system regulates addictive behaviors through signaling within mesolimbic neurons. Here, we hypothesized the melanocortin system modulates feeding behavior thr...

Individuals often eat calorically dense, highly palatable "comfort" foods during stress for stress relief. This article demonstrates that palatable food intake (limited intake of sucrose drink) reduces neuroendocrine, cardiovascular, and behavioral responses to stress in rats. Artificially sweetened (saccharin) drink reproduces the stress dampening...

Epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese and there is a growing appreciation that obesity affects the functional integrity of the central nervous system (CNS). We recently developed a lentivirus (LV) vector that produces an insulin receptor (IR) antisense RNA...

In the present study, we examined meal patterns during and after exposure to the visible burrow system (VBS), a rodent model of chronic social stress, to determine how the microstructure of food intake relates to the metabolic consequences of social subordination. Male Long-Evans rats were housed in mixed-sex VBS colonies (4 male, 2 female) for 2 w...

Fortunately, the majority of children conceived through assisted reproductive technologies (ARTs) appear healthy; however, metabolic abnormalities, including elevated glucose and increased and altered adipose tissue deposition, have been reported in adolescents. To parse out factors that may be responsible, we investigated the effects of two differ...

Mineralocorticoids and glucocorticoids are steroid hormones that are released by the adrenal cortex in response to stress and hydromineral imbalance. Historically, adrenocorticosteroid actions are attributed to effects on gene transcription. More recently, however, it has become clear that genome-independent pathways represent an important facet of...

This study investigated the role of post-ingestive signals in the satiation of thirst or salt appetite. Post-ingestive signals, defined as those arising from the passage of fluid into the duodenum and proximal jejunum, were manipulated by implanting rats with gastric fistulas. After recovery, rats were water deprived and the following day gastric f...

Weight gain and adiposity are often attributed to the overconsumption of unbalanced, high-fat diets however, the pattern of consumption can also contribute to associated body weight and compositional changes. The present study explored the rapid alterations in meal patterns of normal-weight rats given continuous access to high-fat diet and examined...

Increasing evidence suggests that the renin-angiotensin-system contributes to the etiology of obesity. To evaluate the role of the renin-angiotensin-system in energy and glucose homeostasis, we examined body weight and composition, food intake, and glucose tolerance in rats given the angiotensin-converting enzyme inhibitor, captopril ( approximatel...

Apolipoprotein E (apoE) is a satiation factor, playing an important role in the regulation of food intake and body weight. We previously reported that apoE was present in the hypothalamus, but it is unclear which type of the cells in this brain area expressing apoE. In addition, hypothalamic apoE mRNA levels were significantly reduced in both genet...

Risk-taking behavior is a vital aspect mediating the formation of social structure in animals. Here, we utilized the visible burrow system (VBS), a model in which rats form dominance hierarchies, to test the hypothesis that dominant rats in the VBS are natural risk takers and display an increased motivational state after VBS exposure. In particular...

Circulating angiotensin II (ANGII) elicits water intake and activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating angiotensin type 1 receptors (AT1Rs) within circumventricular organs. The subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) are circumventricular organs that express AT1Rs that bind bloo...

CCK acts peripherally as a satiating peptide released during meals in response to lipid feeding and centrally functions in the modulation of feeding, exploratory, and memory activities. The present study determined metabolic parameters, food intake, anxiety-like behaviors, and cognitive function in mice lacking the CCK gene. We studied intestinal f...

The visible burrow system (VBS) is a model used to study chronic social stress in colony-housed rats. A hierarchy develops among the males resulting in dominant (DOM) and subordinate (SUB) animals. Hierarchy-associated changes in body weight, body composition, behavior, and neuroendocrine measures have been observed. After 14 d of VBS housing, SUB...

Social stress resulting from dominant-subordinate relationships is associated with body weight loss and altered body composition in subordinate (SUB) male rats. Here, we extend these findings to determine whether stress-induced changes in energy homeostasis persist when the social stress is removed, and the animal is allowed to recover. We examined...

Regulation of feeding behavior and energy balance are among the central effects of insulin. For example, intracerebroventricular administration of insulin decreases food intake and body weight, whereas antisense oligodeoxynucleotide downregulation of insulin receptors (IRs) produces hyperphagia. To further examine the role of IRs in the central act...

Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are peptides that act both peripherally and centrally to reduce food intake by decreasing meal size. The present study examined the effects of intraperitoneally administered bolus doses of recombinant apo AIV, CCK-8, and a combination of subthreshold doses of apo AIV and CCK on 4-h food intake...

Nearly three-quarters of a century ago, Curt Richter removed the adrenal glands from rats and noted that the animal's vitality was dependent on its increased consumption of sodium chloride. In doing so, Richter revealed an innate behavioral mechanism that serves to maintain the hydromineral balance of an animal faced with sodium deficit. This exper...

Social stress is prevalent in many facets of modern society. Epidemiological data suggest that stress is linked to the development of overweight, obesity and metabolic disease. Although there are strong associations between the incidence of obesity with stress and elevated levels of hormones such as cortisol, there are limited animal models to allo...

In the visible burrow system (VBS) model of chronic social stress male rats are housed with females resulting in a dominance hierarchy with one dominant (DOM) and three subordinate (SUB) males. Previous work has described behavioral, physiological and neuroendocrine changes during VBS stress and subsequent recovery. Specifically, SUB animals displa...

Apolipoprotein A-IV (apo A-IV) is a satiety factor involved in the control of food intake and body weight. Our previous studies demonstrated that apo A-IV is present in areas of the hypothalamus where leptin acts to influence energy homeostasis. In the present studies, we found that leptin-deficient obese (ob/ob) mice have significantly reduced hyp...

Cloning from adult somatic cells has been successful in at least ten species. Although generating viable cloned mammals from adult cells is technically feasible, prenatal and perinatal mortality is high and live cloned offspring have had health problems. This chapter summarizes the health consequences of cloning in mice and discusses possible mecha...

Many gastrointestinal meal-related signals are transmitted to the central nervous system via the vagus nerve and thereby control changes in meal size. The c-Fos-positive neuron has been used as a marker of neuronal activation after lipid meals to examine the contribution of a selective macronutrient on brain neurocircuit activity. In rats fed Intra...

Group-housed male rats form social hierarchies, and under these conditions, it has been reported that subordinate (SUB) rats consume more alcohol than dominant (DOM) rats. We tested the hypothesis that a history of drinking alcohol would cause SUB rats to consume even greater amounts of alcohol. Male Long-Evans rats were trained to drink 10% alcoho...

The human population has slowly transformed from the "hunter-gatherer" period to the current environment of high energy consumption, minimal physical activity and a lifestyle that includes stress and anxiety. Modeling the current environment in the laboratory can help to elucidate mechanisms responsible for the development of obesity, diabetes and,...

Recently, prolactin was shown to inhibit the development of stress-induced ulcers. However, the mechanism for suppression of gastric ulcers by prolactin has not been clarified. Hatano high-avoidance (HAA) and low-avoidance (LAA) strains of rats were originally selected and bred from Sprague-Dawley rats based on shuttle-box tasks. The present study...

Prolonged social subjugation produces physiological indices of chronic stress in rats. In the current study, we examined the impact of social stress on glutamic acid decarboxylase (GAD) isoforms, corticotropin-releasing hormone (CRH) and vasopressin mRNA expression in forebrain stress circuitry, using the visible burrow system model of dominance-su...

Stress response is an important neuroendocrine function. Overt or prolonged stress hormone secretion can lead to various disease states. The hippocampus plays an important role in the negative feedback onto the major player in the stress response, the hypothalamo-pituitary-adrenal axis. The transcription factor c-Fos is activated in the hippocampus...

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi: 10.1016/j.appet.2006.03.001 . The duplicate article has therefore been withdrawn.

This chapter reviews several animal models of social stress with a focus on those involving social hierarchy. The chapter describes an appreciation of the different types of laboratory animal models available for social stress research. Manipulations of an animal's environment or the animal itself to elicit a desired response may, appear to be an a...

The purpose of this study was to determine the effect of chronic food restriction and reduced dietary fat on feeding behavior and body weight. Young female rats were fed ad lib or food restricted on a low-fat (LF) or a fat-free (FF) diet for 4 weeks. Rats then received 24-h free access to 2 diets, the maintenance diet (LF or FF) plus a novel high-f...

Under acute stress conditions in the rat, there is rapid and transient increase in circulating prolactin (PRL). This leads to an elevated expression of the long form of PRLR (PRLR-L) first in the hypothalamus and the choroid plexus. This increase in PRL is involved in the inhibition of stress-induced hypocalcemia and gastric erosion. In this study...

Over the past 40 years, our increased understanding and development of cell and molecular biology has allowed even greater advances in reproductive biology. This is most evident by the development of various aspects of assisted reproductive techniques (ART), generation of transgenic animals, and most recently generation of mammals through somatic c...

Social stress is associated with development of many psychological and physiological disturbances in humans. Animal models are needed to determine the etiology of these diseases and to develop rational clinical therapies to treat those afflicted. Rodent and non-human primate models of social stress have been developed to address these needs and con...

To further investigate the role of intestinal aplipoprotein A-IV (apo A-IV) in the management of daily food intake, we examined the diurnal patterns in apo A-IV gene and protein expression in freely feeding (FF) and food-restricted (FR; food provided 4 h daily for 4 wk) rats that were killed at 3-h intervals throughout the 24-h diurnal cycle. In FF...

Apolipoprotein A-IV (apo A-IV) is a satiety protein synthesized in the small intestine and hypothalamus. To further understand the roles of central apo A-IV in the management of daily food intake, we have examined the diurnal patterns of hypothalamic apo A-IV gene and protein expression in freely feeding and food-restricted (food provided 4 h daily...

Stress causes hypocalcemia and ulcerogenesis in rats. In rats under stressful conditions, a rapid and transient increase in circulating prolactin (PRL) is observed, and this enhanced PRL induces PRL receptors (PRLR) in the choroid plexus of rat brain. In this study we used restraint stress in water to elucidate the mechanism by which PRLR in the ra...

The visible burrow system (VBS) is an ethologically relevant model of social stress, which has been used to study the aggression of male rats in a social context. Previous studies using the VBS have established physiological, endocrine, and neurochemical characteristics associated with chronic social stress in dominant and subordinate animals. A cr...

Substantial progress has been made over the last 50 years in studies examining the neural and hormonal basis of thirst and salt appetite. We now understand much about the physiological systems that are engaged in response to perturbations of water and electrolyte balance, including the brain areas that are activated to elicit the appropriate behavi...

The visible burrow system (VBS) is a chronic social stress paradigm in which a dominance hierarchy forms among male rats housed with females. Males in the VBS undergo behavioral and physiological changes thought to be manifestations of chronic social stress. Since it is unclear whether chronic social stress affects motivation and reward behavior, b...

Cloning technology has potential to be a valuable tool in basic research, clinical medicine, and agriculture. However, it is critical to determine the consequences of this technique in resulting offspring before widespread use of the technology. Mammalian cloning using somatic cells was first demonstrated in sheep in 1997 and since then has been ex...

Responses to stressors serve to adjust physiology and behavior to increase short-term survival at the potential expense of increasing susceptibility to disease over the long term. We show that glucagon-like peptide-1 (7-36) amide (GLP-1) increases levels of the stress-activated hormones ACTH and corticosterone when administered directly into the ra...

Glucocorticoid hormones bind both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) exerting a broad spectrum of actions in various tissues. The concentrations of glucocorticoid hormones in the target cells are regulated by 11 beta-hydroxysteroid dehydrogenases, type 1 (11 beta-HSD1) and type 2 (11 beta-HSD2). 11 beta-HSD2 is a unidi...

The lateral hypothalamus (LH) has a critical role in the control of feeding and drinking. Melanin-concentrating hormone (MCH) is an orexigenic peptidergic neurotransmitter produced primarily in the LH, and agouti-related protein (AgRP) is an orexigenic peptidergic neurotransmitter produced exclusively in the arcuate (ARC), an area that innervates t...

Tachykinins are a family of neuropeptides that inhibit salt appetite. Although decreased tachykinin-mRNA levels are observed in natriorexic sodium-deplete rats, no decrease is seen in natriorexic sodium-replete rats that are administered the aldosterone-mimetic deoxycorticosterone acetate (DOCA). Since reduced synthesis of tachykinins could not acc...

Stress in socially subordinate male rats, associated with aggressive attacks by dominant males, was studied in a group-housing context called the visible burrow system (VBS). It has been established that subordinate males have reduced serum testosterone (T) and higher corticosterone (CORT) relative to dominant and singly housed control males. The r...

Mammalian cloning using somatic cells has been accomplished successfully in several species, and its potential basic, clinical and therapeutic applications are being pursued on many fronts. Determining the long-term effects of cloning on offspring is crucial for consideration of future application of the technique. Although full-term development of...

Previous studies in female rats have shown that estrogen treatment attenuates angiotensin II (AngII)-induced water intake. The mechanism underlying this attenuation may be decreased responsiveness to AngII, as revealed by a reduction in AngII binding to the angiotensin type 1 (AT1) receptor in the subfornical organ (SFO). It has not been determined...

Male rats housed in mixed-sex groups in a visible burrow system (VBS) form a dominance hierarchy in which subordinate animals show stress-related changes in behavior, endocrine function and neurochemistry. Dominants also appear to be moderately stressed compared to controls, although these animals do not develop the more pronounced behavioral and p...

BACKGROUND.: Mineralocorticoids act on the brain to influence sodium intake, and they do so via intracellular type I receptors and possibly also via a direct membrane action, as they do in the kidney. One brain area implicated by lesion studies investigating the regulation of sodium appetite aroused by adrenal steroids is the amygdala. To examine t...

The localization in the brain and metabolism of 3H-labeled corticosterone (B) and 11-dehydrocorticosterone (A) of high specific radioactivity was determined after stereotaxic injection into the hippocampus of anesthetized rats. [3H]B was cleared very rapidly with, on average, only about 7% being recovered after 5 min and 0.5% after 30 min. Most of...

The angiotensin II type 1 (AT1) receptor plays a pivotal role in the regulation of blood pressure and electrolyte balance, and is involved in the control of specific ingestive behaviours. Irbesartan (SR 47436/BMS 186295) is a recently developed angiotensin AT1 receptor antagonist, chemically described as 2-butyl-3-([2′-{1H-tetrazol-5-yl}biphenyl-4-...

Estrogen has been shown to modulate angiotensin II (AngII)-regulated behaviors, such as thirst, and may do so by influencing the central renin-angiotensin system (RAS). While numerous studies have attempted to correlate changes in AngII receptors or other components of the RAS with estrogen treatment, the low abundance of these genes has made compa...

Motivated behaviors, including sodium (Na) appetite, are correlated with increased dopamine (DA) transmission in the nucleus accumbens (NAc). DA transporter (DAT) modulation affects DA transmission and may play a role in motivated behaviors. In vivo Na depletion, which reliably induces Na appetite, was correlated with robust decreases in DA uptake...

Spontaneous water intake as well as thirst elicited by ANG II has been shown to be influenced by the stage of the estrous cycle in the female rat. In these experiments, the contribution of each of the ovarian steroid hormones to the regulation of water intake was examined. Ovariectomized female rats were given replacement doses of estrogen, progest...

Adrenal steroids and neurotrophic factors are important modulators of neuronal plasticity, function, and survival in the rat hippocampus. Adrenal steroids act through two receptor subtypes, the glucocorticoid receptor (GR) and the mineralocorticoid receptor, and activation of each receptor subtype has distinct biochemical and physiological conseque...

Adrenal steroids can have prodigious effects on the structure, function, and survival of hippocampal neurons. In the rat hippocampus, the actions of adrenal steroids are mediated by two receptor types, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Using in situ hybridization, we have examined the regulation of the messen...

Adult male rats showed very high levels of crouching when exposed to a cat, with suppression of the nondefensive behaviors (e.g., lying, locomotion, rearing) that were shown by toy cat-exposed controls. The crouching of cat-exposed rats declined slightly but reliably with increasing time within daily 60-min exposure sessions. However, the lack of a...

Antisense experiments are often complicated by the lack of reliable methods for selecting effective antisense sequences. Chimeric oligodeoxynucleotide (ODN) libraries and ribonuclease H (RNase H) were used to identify regions on the 1253 nucleotide angiotensin type-1 receptor (AT1) mRNA that are accessible to hybridization with antisense ODNs. Phos...

Subordination constitutes a natural and often chronic stress condition for males of virtually all species of social mammals. Subordinate male rats of mixed-sex groups maintained in visible burrow systems show high-magnitude changes in adrenal and gonadal steroid hormones and, in a subpopulation, disruptions in hypothalamic pituitary adrenal axis fu...

Investigations in the area of behavioral neuroendocrinology have typically employed traditional approaches to discerning the sites of action of these hormones in the brain. These techniques used in examining the mechanisms governing thirst and sodium appetite have included selective electrolytic and chemical lesions, electrophysiological recording...

The anterior ventral third ventricle (AV3V) region of the brain contains high concentrations of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) that are important in the maintenance of body fluid and electrolyte balance as well as other physiological processes. Daily intracerebroventricular pulse injections of MR antisense oligon...

In the visible burrow system model of chronic social stress, male rats housed in mixed-sex groups quickly form a dominance hierarchy in which the subordinates appear to be severely stressed. A subgroup of subordinates have an impaired corticosterone response after presentation of a novel restraint stressor, leading to their designation as nonrespon...

Long-term treatment (21 days) of male rats with corticosterone in the drinking water caused a significant increase in the activity of the NADP-dependent form of 11β-hydroxysteroid dehydrogenase (11-HSD1) in the pituitary, thymus, and spleen, (marginally in the hippocampus, amygdala and lymph nodes), without having any effect in a number of other ce...

Previous studies have shown that preweanling rats do not express an endogenous sodium appetite until postnatal day 12. The present studies tested the hypothesis that prior to 12 days of age sodium appetite, induced by either central administration of angiotensin II (AngII) or adrenalectomy, is inhibited by endogenous oxytocin (OT). After 9- or 10-d...

The amygdala contains mineralocorticoid (MR) and glucocorticoid receptors (GR) involved in the arousal of salt appetite. In the present investigation, MR antisense oligonucleotides injected into the amygdala inhibited salt appetite induced by systemic desoxycorticosterone (DOCA) but not adrenalectomy (ADX). In contrast, GR antisense or scrambled ol...

Removal of the adrenal glands, the main site for the synthesis of aldosterone, produces an intake of sodium that is essential for survival. Using central blockade of angiotensin II (Ang II) receptors with SarIle Ang II, previous studies have shown that this intake depends on the stimulation of the brain angiotensin system. In the present study, usi...

The peptide hormone angiotensin II (Ang II) is an important regulator of cardiovascular and body fluid homeostasis. Circulating Ang II mediates its physiological actions by activating Ang II receptors in both the periphery and the brain. Previous studies have demonstrated that Ang II receptor expression is high in neonates and decreases to adult le...