Psychoneuroendocrinology, Vol.17,No.4. pp.391-399.1992
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EFFECTS OF PERIPHERAL H O R M O N E S O N MEMORY A N D INGESTIVE BEHAVIORS JOHN E. MORLEY, JAMES FLOOD and ANDREW J. SILVER Geriatric Research, Education, and Clinical Center, St. Louis Department of Veterans Affairs, and Division of Geriatric Medicine, St. Louis University School of Medicine, St. Louis, Missouri, U.S.A. (Received in final forrn 18 March 1992)
SUMMARY This article explores the mechanisms by which peripheral gastrointestinal hormones produce central nervous system effects on memory and feeding. Cholecystokinin produces its satiety effects and memory-enhancing effects by stimulating ascending vagal fibers. Hyperglycemia has been demonstrated to be a cause of memory dysfunction in persons with diabetes mellitus. A number of other hormones, such as amylin and bombesin, modulate both memory processing and feeding. The causes of the anorexia of aging are briefly reviewed.
INTRODUCTION THERE IS increasing evidence that gastrointestinal hormones can modulate central behavior, in particular, ingestive behaviors, memory, and locomotion (Morley, 1982; Morley & Blundell, 1988; Morley & Flood, 1991a). A number of mechanisms exist by which peptide hormones may alter behavior. These include the possibility that they (1) pass directly through the bloodbrain barrier, (2) produce their effects secondary to the release of pituitary hormones, (3) alter the blood levels of circulating metabolities, e.g., glucose or free fatty acids, (4) activate ascending fibers in the vagus or the sympathetic nervous system, (5) directly alter steroid hormone release from the adrenals, and (6) alter blood flow to the brain. With advancing age, it appears that alteration in receptor sensitivity or gastrointestinal hormone release is not uncommon. This article will review the evidence that gastrointestinal hormones modulate behavior and that changes in the responses to these hormones may play a role in some of the changes in behavior occurring with normal aging. FOOD, MEMORY AND CHOLECYSTOKININ Some years ago, we demonstrated that when mice were fed immediately after aversive Tmaze training, they remembered that task better than when access to food was delayed (Flood et al., 1987). Similarly, when humans are fed immediately after learning, they have better Address correspondence and reprint requests to: Dr. John E. Morley, School of Medicine, St. Louis University Medical Center, Division of Geriatric Medicine, 1402 South Grand Boulevard, Room M238, St. Louis MO 63104, USA. 391
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recall of a complex task 48 hr later. Children who have a 63% increase in the amount eaten at breakfast have enhanced short-term memory and decreased concentration (Simeon & GranthamMcGregor, 1989). Based on these findings we hypothesized that the enhanced memory retention associated with feeding is secondary to the release of gastrointestinal hormones. Cholecystokinin-octapeptide (CCK-8) is released from the duodenum in response to a meal. It is derived from CCK, a 33 amino-acid hormone, first isolated from the gastrointestinal tract. CCK-8 enhanced memory retention after being administered intraperitoneally (Flood et al., 1987). The effect of CCK-8 was less potent when administered subcutaneously, suggesting that its effect was mediated by a structure within the abdominal cavity. CCK-8 also reversed the amnesia produced by the anticholinergic drug, scopolamine, and by the protein synthesis inhibitor, anisomycin. The sulfated form of CCK-8 was more potent than the non-sulfated form, suggesting that CCK-8 was producing its effect through peripheral CCK-A receptors. We next demonstrated that the meal-associated enhancement in memory retention could be attenuated by the administration of the CCK-A receptor antagonist L-364,718 (Flood & Morley, 1989). Approximately 80% of the vagus nerve carries ascending fibers to the central nervous system (CNS). A number of studies have shown that stimulation of the vagus results in electrical activity in the central nucleus of the amygdala and in the hippocampus (Dell & Olson, 1951). In addition, CCK receptors have been demonstrated to be present in the vagus and in the nucleus tractus solitarius (Zarbin et al., 1981). We therefore hypothesized that CCK-8 produced its memory enhancing effect by stimulating ascending.vagal fibers. To confirm this, we examined the effect of CCK-8 on memory retention in vagotomized mice (Flood et al., 1987). CCK-8 could no longer enhance memory retention in vagotomized animals, confirming that the CCK effect is mediated through vagal fibers. The vagal fibers enter the midbrain at the level of the nucleus tractus solitarius (NTS). The NTS has a number of anatomical connections to the central nucleus of the amygdala (Morley & Flood, 1991c). The amygdala is an important area in the CNS which is involved in memory processing (Introini-Collison & McGaugh, 1991). Besides fibers going directly from the NTS to the amygdala, fibers go indirectly to the amygdala via the paraventricular nucleus of the hypothalamus and the bed nucleus of the stria terminalis, or through the parabrachial region (Morley & Flood, 1991). For these reasons we decided to test whether the amygdala played a role in the modulation of CCK-induced memory enhancement. Beta-endorphin (13-EP), an endogenous opioid, is a potent amnestic when administered centrally. When 13-EP was administered directly into the amygdala, it inhibited the ability of CCK-8 administered peripherally to enhance memory, and peripheral CCK-8 could not overcome the amnestic effect of intra-amygdally administered 13-EP. We next bilaterally lesioned the stria terminalis. The stria terminalis carries fibers entering the amygdala. Lesions of the stria-terminalis inhibited the ability of intraperitoneally administered CCK-8 to enhance memory. These studies confirm the concept that peripherally administered CCK-8 enhances memory function by stimulating ascending vagal fibers that course through the nucleus tractus solitarius and from there to the amygdala. AGING, MEMORY FUNCTION AND CCK
Both cross-sectional and longitudinal studies have demonstrated decrements in memory function with normal aging. Both primary and secondary memory declines with advancing age (Albert, 1990). Spatial abilities also decline with age, but to a lesser extent than the decline in
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memory. Advanced aging is associated with slowing of response time. Fluid intelligence declines more rapidly than does crystallized intelligence. Similar alterations in memory function have been found in aging rodents. Memory retention deficits exist in 24-mo-old mice compared to 2-mo-old mice, making them suitable animals for the study of age-related memory deficits (Flood & Morley, 1990). Cholinergic agonists have been demonstrated to reverse this memory deficit in older mice. In our studies, we found that CCK-8 also is effective at reversing the memory defect in the aversive T-maze training task seen in 24-mo-old mice. OTHER GASTROINTESTINALHORMONES AND MEMORY Bombesin, a frog skin peptide, and gastrin-releasing peptide, its mammalian analog, have been shown to enhance memory after peripheral administration (Flood & Morley, 1988). Bombesin has been demonstrated to release CCK under certain circumstances; the effects of bombesin on the sphincter of Oddi are mediated through CCK (Sievert et al., 1988). We therefore examined whether the effect of bombesin on memory was mediated through CCK release. The effect of bombesin on memory was inhibited by the CCK antagonist, L-364,718 (Flood & Morley, 1989). This strongly suggested that the effect of bombesin on memory is mediated through CCK release. Pancreastatin is a newly discovered pancreatic peptide hormone. It has been demonstrated to modulate glucose and fatty acid metabolism. Pancreastatin enhances memory with a bellshaped dose response curve, and its effects are time-dependent (Flood et al., 1988). The Cterminal amide fragment 33-49 of pancreastatin also has been demonstrated to enhance memory. Amylin is a pancreatic hormone (vide infra) which also appears to enhance memory when peripherally administered, while being amnestic after administration into the CNS (Flood & Morley, 1992). Overall these findings support the concept that memory processing is regulated during food ingestion secondarily to the release of gastropancreatic hormones. GLUCOSE, DIABETESMELLITUS,AND MEMORY Small increases in glucose levels, such as may occur after a meal, have been shown to enhance memory in rodents and humans (Hall et al., 1989). On the other hand, streptozotocininduced diabetic mice have both learning problems and amnesia (Flood et al., 1990). The memory retention problems of diabetic mice can be reversed by the administration of insulin immediately following training in an aversive T-maze paradigm. This suggests that the major cause of the memory retention deficit is the elevated glucose levels. Diabetes mellitus occurs in approximately 18% of persons between 65 and 75 yr of age, and 48% of all type II diabetics in the United States are over the age of 65 (Morley & Perry, 1991). A number of studies have shown that older humans with diabetes mellitus have cognitive deficits compared to age-matched persons without diabetes mellitus (Perlmutter et al., 1984; Mooradian et al., 1988). Diabetics have a much reduced ability to comprehend medication instructions than do age-matched non-diabetics. Preliminary studies indicate that lowering glucose in older persons with diabetes mellitus improves memory function. The biochemical basis of memory dysfunction in diabetes mellitus is poorly understood. Choline acetyltransferase activity is not changed in the brains of diabetic mice (Bitar et al., 1987). Both dopamine and serotonin synthesis are decreased in the brains of diabetic rodents (Morley & Flood, 1990). The levels of neuropeptide Y, which is a potent modulator of
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memory (Morley et al., 1987; Flood et al., 1989), are altered in the CNS in animals with experimental diabetes mellitus (Williams et al., 1989). It would appear that multiple neurotransmitters may be involved in the memory deficits occurring in rodents and humans with diabetes mellitus. APPETITE REGULATION It is now well accepted that appetite regulation consists of two components, viz. a central feeding drive and a peripheral satiety component (Morley, 1989). The central feeding drive system consists of a predominantly carbohydrate feeding drive system, i.e., neuropeptide Y and norepinephrine, and a fat feeding drive system, i.e., dynorphin and dopamine. Nitric oxide may be the primary intracellular mediator of the feeding system (Morley & Flood, 1991b). In addition, a variety of other neurotransmitters within the CNS appear to modulate the feeding drive systems (Morley, 1987). The peripheral satiety system acts as a brake on the central feeding system to limit the size of an individual meal. The major components of the peripheral satiety system are the gastrointestinal hormones that are released as food passes through the gut. The best studied of these peptide hormones is CCK. CCK limits the size of an individual meal in humans and many animal species. Based on studies with CCK antagonists, it appears that the effects of CCK on appetite regulation are physiological (Silver et al., 1989). Like its effects on memory regulation, CCK produces its effects on feeding by stimulating ascending vagal fibers, particularly those in the gastric branch of the vagus (Smith et al., 1981; Morley et al., 1982). After the vagus fibers enter the nucleus tractus solitarius (NTS), pathways course from the NTS to the paraventricular nucleus of the hypothalamus. Although the data are controversial, it appears that the effect of CCK on appetite regulation is independent of its ability to slow gastric emptying (Shaw et al., 1985). Of particular relevance to older individuals is the fact that infections release a variety of cytokines, e.g., interleukin-1 and tumor necrosis factor (cachectin), which are anorexic. These cytokines appear to produce their anorexic effects by activating corticotropin releasing factor (CRF) in the hypothalamus (Uehara et al., 1990). CRF in turn releases oxytocin which is a potent anorexic agent (Olson et al., 1991). Many of the substances which modulate appetite also alter energy metabolism. In some cases, their effects on feeding are opposite to their effects on energy metabolism, e.g., neuropeptide Y and norepinephrine both increase feeding when administered centrally but cause weight loss when administered peripherally (Morley & Flood, 1987). Thus, the final effect of a neurotransmitter on body weight regulation is dependent upon the sum of its effects on feeding and weight loss. AGING, ANOREXIA, AND PEPTIDES Numerous studies have shown that low body weight in older persons is more closely related to mortality than is overweight. Anorexia, or a poor appetite, are common complaints in older persons (Morley & Silver, 1988). Sixteen percent of Americans over the age of 65 yr ingest less than 1000 calories per day. The causes of this anorexia in older persons are often multifactorial (Table). A number of older persons who are losing weight have unusual attitudes about food intake. and their body image (Morley, 1988). Some turn out to have had an episode of anorexia
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nervosa as a child and a lifelong pattem of food restriction. In others, these attitudes appear to be of new onset; this condition has been termed tardive anorexia. Depression is commonly associated with weight loss in older persons (Fitten et al., 1989). Older depressives are more likely to loose weight than younger depressives. Approximately two-thirds of depressed persons have elevated CRF levels. CRF is a potent anorexic agent which produces its effects within the paraventricular nucleus of the hypothalamus. It appears that the anorexia associated with depression is due to increased CRF (Morley & Levine, 1982). In addition, CRF activates the sympathetic nervous system and increases energy expenditure, further promoting weight loss. Besides the pathological causes of weight loss with advancing age, it is clear that older persons have a reduction in appetite. This appears to be in response to the .decreased metabolic rate and physical activity that accompany the aging process (Morley, 1986). A number of physiological processes appear to be involved in this resetting of the appetostat that occurs with aging. In part, the decreased food intake appears to be due to the reduction in hedonic qualities of food that occurs with aging, since the ability both to taste and to smell diminish. However, there also is evidence for direct alterations in the neurotransmitter system involvement with food regulation. Multiple opioid mediated responses decline with advancing age (Morley et al., 1990). This decrease in opioid function can be attributed to the decreases in opioid receptors and the concentrations of methionine- and leucine-enkephalin, as well as ~I-EP that occur with aging (Gambert et al., 1980; Ueno et al., 1986). Older rodents are only 1,100thas sensitive to the sup-
CAUSES OF ANOREXIA IN OLDER PERSONS
I. Potential peptide influences A. Decreased opioid effectiveness (decrease in central feeding drive) B. Increased effect of CCK (increase in satiety) C. Increased amylin secretion I1. Alterations in physiological processes A. Decrease in taste and smell B. Loss of adequate dentition C. Decrease in basal metabolic rate III. Pathological processes A. Depression B. Cognitive impairment C. Body image disturbances D. Inability to self feed (cerebrovascular accident, Parkinson's disease) IV. Other A. Financial constraints B. Medications (digitalis preparations, theophylline) C. Social isolation
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pressive effects of the opioid antagonist, naloxone, on food intake as are younger animals (Gosnell et al., 1983). Older rats also fail to have an appropriate feeding response to injections of the n-opioid receptor agonist, butorphanol tartrate. The ~c-opioid receptor is the receptor for the endogenous opioid peptide, dynorphin. These findings strongly implicate failure of the opioid feeding system in the pathogenesis of the anorexia of aging. Only one study has examined the role of the peripheral satiety system in aging (Silver et al., 1988). In this study, CCK demonstrated a greater suppressive effect on food intake in 25-moold mice compared to 8-mo-old mice (Silver et al., 1988). Bombesin and calcitonin also showed a tendency to be more potent in older mice. Glucagon suppressed food intake to a similar extent in both young and old mice. The markedly increased suppressive effect of CCK on food intake suggests that it may play a role in the pathogenesis of the anorexia of aging. The finding that CCK levels are often elevated in older individuals, particularly when they are malnourished, further supports a role for CCK in producing the malnutrition occurring in some older persons (Khalil et al., 1985; Velas et al., 1988). The decreased opioid feeding effect with aging may be linked to the increased satiety produced by CCK. CCK has been suggested to produce a physiological antagonism of endogenous opioids in many systems (Morley & Flood, 1991c). For example, CCK antagonizes tail pinch-induced feeding (a system which is dependent on endogenous opioid activation) and decreases analgesia produced by 13-EP and morphine (Levine & Morley, 1981). Proglumide, a CCK receptor antagonist, potentiates analgesia produced by endogenous opioids (Takeshige et al., 1991). Morphine analgesia was demonstrated to be increased in rats which were immunized against endogenously released CCK (Faris et al., 1984). In conclusion, the pathogenesis of the anorexia of aging appears to depend at least in part on an attenuation of the opioid feeding drive and an increase in the satiety effect of CCK with advancing age. AMYLIN A ND FEEDING
Islet of Langerhans cells from persons with type II diabetes mellitus contain interstitial amyloid deposits. Amylin is a 37 amino-acid peptide which was isolated from these amyloid deposits (Cooper et al., 1989). Amylin is co-released with insulin, in a molar ratio of 1:100. Amylin levels increase in the circulation following a meal or oral glucose ingestion. Amylin antagonizes a number of effects of insulin including some of the effects of insulin on the liver and on muscle. It has been suggested that amylin may play a role in the development of insulin resistance. We have demonstrated that amylin decreased food intake in food-deprived mice (Morley & Flood, 1991d). The amylin effect on food intake was more potent in diabetic than in nondiabetic mice. Amylin also inhibited insulin-induced feeding. The amylin effect was more potent when it was administered intraperitoneally than when it was administered intracerebroventricularly. These data suggest that the increased amylin secretion occurring with advancing age may also play a partial role in the pathogenesis of the anorexia of aging. Further studies on the role of amylin in the modulation of food intake are needed. GROWTH HORMONE, WEIGHT LOSS A N D AGING
Growth hormone (GH) secretion decreases with advancing age (Kelijman, 1991). In addition, insulin growth factor-1 (IGF-1 or somatomedin-C), which is the liver end-organ hor-
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mone responsive to GH, also decreases with advancing age. This decrease in IGF-1 is more dramatic in malnourished, institutionalized older persons (Rudman et al., 1987). The decrease in GH with aging appears to be predominantly secondary to an increase in somatostatin which inhibits GH release from the pituitary. It has been suggested that the decrease in GH and IGF-1 leads to a GH " m e n o p a u s e " (Rudman, 1985). This would result in a variety of potentially deleterious effects, including an increase in adipose tissue, a decrease in muscle mass as a percentage of body weight, a decrease in albumin synthesis, and a decrease in cancellous bone density. Many of these effects are similar to the physical changes of aging. This led Rudman et al. (1990) to suggest that GH replacement may result in a decreased rate of aging. Their studies suggest that in healthy older persons, administration of recombinant GH results in a decrease in body fat and an increase in skin thickness. However, neither of these findings could be considered dramatic. We took a different approach and gave recombinant GH to malnourished older persons (Kaiser et al., 1991). We found that GH stimulated IGF-1, enhanced nitrogen retention, and produced weight gain. Control patients continued to lose weight. The persons receiving GH tended to increase their caloric intake. A study carried out in the Netherlands also has demonstrated similar positive effects of GH administration to malnourished older persons (Binnert et al., 1988). Overall, these findings support the concept that recombinant GH may be useful in the management of malnutrition in selected older individuals. CONCLUSION It is clear that a number of gastrointestinal hormones are capable of modulating behavior. In the case of older persons, they appear to have potentially dramatic effects on both cognitive function and appetite regulation. The concept of gut-brain interactions is one which should be of increasing importance over the next decade.
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Morley JE, Levine AS, Kneip J, Grace M (1982) The effect of vagotomy on the satiety effects of neuropeptides and naloxone. Life Sci 30" 1943-1947. Morley JE, Hernandez EN, Flood JF (1987) Neuropeptide Y increases food intake in mice. Am J Physiol 253: R516-R522. Morley JE, Flood JF, Silver AJ (1990) Opioid peptides and aging. Ann NYAcad Sci 579: 123-132. Olson BR, Drutarosky MD, Stricker EM, Verbalis JG (1991) Brain oxytocin receptor antagonism blunts the effects of anorexigenic treatments in rats: evidence for central oxytocin inhibition of food intake. Endocrinology 129: 785-791. Perlmuter LC, Hakami MK, Hodgson-Harrington C, Ginsberg J, Katz J, Singer DE, Nathan DM (1984) Decreased cognitive function in aging non-insulindependent diabetic patients. Am J Med 77: 1043-1048. Rudman D (1985) Growth hormone, body composition and aging. J A m Geriatr Soc 33: 800-807. Rudman D, Nagraj HS, Mattson DE, Jackson DC, Rudman IW, Boswell J, Pucci DC (1987) Hyposomatomedinemia in men of a Veterans Administration nursing home: prevalence and correlates. Gerontology 33: 307314. Rudman D, Feller AJ, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE (1990) Effects of human growth hormone in men over 60 yrs old. N Engl J Med 323: 1-6. Shaw MJ, Hughes JJ, Morley JE, Levine AS, Silvis SE, Shafer RB (1985) Cholecystokinin octapeptide action on gastric emptying and food intake in normal and vagotomized man. Ann NY Acad Sci 448: 640-641. Sievert CE, Potter TJ, Levine AS, Morley JE, Silvis SE, Vennes JA (1988) Effect of bombesin and gastrin releasing peptide on the canine sphincter of oddi. Am J Physio1254: G361-G365. Silver AJ, Flood JF, Morley JE (1988) Effect of gastrointestinal peptides on ingestion in young and old mice. Peptides 2: 221-226. Silver AJ, Flood JF, Song AM, Morley JE (1989) Evidence for a physiological role for CCK in the regulation of food intake in mice. Am J Physio1256: R646-R652. Simeon DT, Grantham-McGregor S (1989) Effects of missing breakfast on the cognitive functions of school children of differing nutritional status. Am J Clin Nutr 49: 646-653. Smith GP, Jerome C, Cushin BJ, Eterno R, Simansky KJ (1981) Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat. Science 213: 1036-1037. Takeshige C, Mera H, Hisamitru T, Tanaka M, Hishida F (1991) Inhibition of the analgesia inhibitory system by D-phenylalanine and proglumide. Brain Res Ball 26: 385-391. Uehora Y, Shimizu H, Shimomura Y (1990) Effect of recombinant human interleukins on food intake of previously food-deprived rats. Proc Soc Exper Biol Med 195: 197-201. Ueno E, Lui DD, Hoikhoskins B (1986) Opiate receptor characteristics in brains from young, mature and aged mice. NeurobiolAging 9: 279-283. Velas B, Balas D, Moureau J, Bouisson M, Seregas-Balas F, Guidet M, Rebet A (1988) Title? Int J Pancreatol 3: 497-502. Williams G, Steel JH, Polak JM, Bloom G (1989) Neuropeptide Y in the hypothalamus. In: Mutt V, Fuxe K, Hokfeldt T, Lundberg JM (Eds) Neuropeptide Y. Raven Press, New York, pp 243-251. Zarbin MA, Wamsley JK, Innis RB (1981) Cholecystokinin receptors: presence and axonal flow in rat vagus nerve. Life Sci 29: 697-701.
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EFFECTS OF PERIPHERAL H O R M O N E S O N MEMORY A N D INGESTIVE BEHAVIORS JOHN E. MORLEY, JAMES FLOOD and ANDREW J. SILVER Geriatric Research, Education, and Clinical Center, St. Louis Department of Veterans Affairs, and Division of Geriatric Medicine, St. Louis University School of Medicine, St. Louis, Missouri, U.S.A. (Received in final forrn 18 March 1992)
SUMMARY This article explores the mechanisms by which peripheral gastrointestinal hormones produce central nervous system effects on memory and feeding. Cholecystokinin produces its satiety effects and memory-enhancing effects by stimulating ascending vagal fibers. Hyperglycemia has been demonstrated to be a cause of memory dysfunction in persons with diabetes mellitus. A number of other hormones, such as amylin and bombesin, modulate both memory processing and feeding. The causes of the anorexia of aging are briefly reviewed.
INTRODUCTION THERE IS increasing evidence that gastrointestinal hormones can modulate central behavior, in particular, ingestive behaviors, memory, and locomotion (Morley, 1982; Morley & Blundell, 1988; Morley & Flood, 1991a). A number of mechanisms exist by which peptide hormones may alter behavior. These include the possibility that they (1) pass directly through the bloodbrain barrier, (2) produce their effects secondary to the release of pituitary hormones, (3) alter the blood levels of circulating metabolities, e.g., glucose or free fatty acids, (4) activate ascending fibers in the vagus or the sympathetic nervous system, (5) directly alter steroid hormone release from the adrenals, and (6) alter blood flow to the brain. With advancing age, it appears that alteration in receptor sensitivity or gastrointestinal hormone release is not uncommon. This article will review the evidence that gastrointestinal hormones modulate behavior and that changes in the responses to these hormones may play a role in some of the changes in behavior occurring with normal aging. FOOD, MEMORY AND CHOLECYSTOKININ Some years ago, we demonstrated that when mice were fed immediately after aversive Tmaze training, they remembered that task better than when access to food was delayed (Flood et al., 1987). Similarly, when humans are fed immediately after learning, they have better Address correspondence and reprint requests to: Dr. John E. Morley, School of Medicine, St. Louis University Medical Center, Division of Geriatric Medicine, 1402 South Grand Boulevard, Room M238, St. Louis MO 63104, USA. 391
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recall of a complex task 48 hr later. Children who have a 63% increase in the amount eaten at breakfast have enhanced short-term memory and decreased concentration (Simeon & GranthamMcGregor, 1989). Based on these findings we hypothesized that the enhanced memory retention associated with feeding is secondary to the release of gastrointestinal hormones. Cholecystokinin-octapeptide (CCK-8) is released from the duodenum in response to a meal. It is derived from CCK, a 33 amino-acid hormone, first isolated from the gastrointestinal tract. CCK-8 enhanced memory retention after being administered intraperitoneally (Flood et al., 1987). The effect of CCK-8 was less potent when administered subcutaneously, suggesting that its effect was mediated by a structure within the abdominal cavity. CCK-8 also reversed the amnesia produced by the anticholinergic drug, scopolamine, and by the protein synthesis inhibitor, anisomycin. The sulfated form of CCK-8 was more potent than the non-sulfated form, suggesting that CCK-8 was producing its effect through peripheral CCK-A receptors. We next demonstrated that the meal-associated enhancement in memory retention could be attenuated by the administration of the CCK-A receptor antagonist L-364,718 (Flood & Morley, 1989). Approximately 80% of the vagus nerve carries ascending fibers to the central nervous system (CNS). A number of studies have shown that stimulation of the vagus results in electrical activity in the central nucleus of the amygdala and in the hippocampus (Dell & Olson, 1951). In addition, CCK receptors have been demonstrated to be present in the vagus and in the nucleus tractus solitarius (Zarbin et al., 1981). We therefore hypothesized that CCK-8 produced its memory enhancing effect by stimulating ascending.vagal fibers. To confirm this, we examined the effect of CCK-8 on memory retention in vagotomized mice (Flood et al., 1987). CCK-8 could no longer enhance memory retention in vagotomized animals, confirming that the CCK effect is mediated through vagal fibers. The vagal fibers enter the midbrain at the level of the nucleus tractus solitarius (NTS). The NTS has a number of anatomical connections to the central nucleus of the amygdala (Morley & Flood, 1991c). The amygdala is an important area in the CNS which is involved in memory processing (Introini-Collison & McGaugh, 1991). Besides fibers going directly from the NTS to the amygdala, fibers go indirectly to the amygdala via the paraventricular nucleus of the hypothalamus and the bed nucleus of the stria terminalis, or through the parabrachial region (Morley & Flood, 1991). For these reasons we decided to test whether the amygdala played a role in the modulation of CCK-induced memory enhancement. Beta-endorphin (13-EP), an endogenous opioid, is a potent amnestic when administered centrally. When 13-EP was administered directly into the amygdala, it inhibited the ability of CCK-8 administered peripherally to enhance memory, and peripheral CCK-8 could not overcome the amnestic effect of intra-amygdally administered 13-EP. We next bilaterally lesioned the stria terminalis. The stria terminalis carries fibers entering the amygdala. Lesions of the stria-terminalis inhibited the ability of intraperitoneally administered CCK-8 to enhance memory. These studies confirm the concept that peripherally administered CCK-8 enhances memory function by stimulating ascending vagal fibers that course through the nucleus tractus solitarius and from there to the amygdala. AGING, MEMORY FUNCTION AND CCK
Both cross-sectional and longitudinal studies have demonstrated decrements in memory function with normal aging. Both primary and secondary memory declines with advancing age (Albert, 1990). Spatial abilities also decline with age, but to a lesser extent than the decline in
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memory. Advanced aging is associated with slowing of response time. Fluid intelligence declines more rapidly than does crystallized intelligence. Similar alterations in memory function have been found in aging rodents. Memory retention deficits exist in 24-mo-old mice compared to 2-mo-old mice, making them suitable animals for the study of age-related memory deficits (Flood & Morley, 1990). Cholinergic agonists have been demonstrated to reverse this memory deficit in older mice. In our studies, we found that CCK-8 also is effective at reversing the memory defect in the aversive T-maze training task seen in 24-mo-old mice. OTHER GASTROINTESTINALHORMONES AND MEMORY Bombesin, a frog skin peptide, and gastrin-releasing peptide, its mammalian analog, have been shown to enhance memory after peripheral administration (Flood & Morley, 1988). Bombesin has been demonstrated to release CCK under certain circumstances; the effects of bombesin on the sphincter of Oddi are mediated through CCK (Sievert et al., 1988). We therefore examined whether the effect of bombesin on memory was mediated through CCK release. The effect of bombesin on memory was inhibited by the CCK antagonist, L-364,718 (Flood & Morley, 1989). This strongly suggested that the effect of bombesin on memory is mediated through CCK release. Pancreastatin is a newly discovered pancreatic peptide hormone. It has been demonstrated to modulate glucose and fatty acid metabolism. Pancreastatin enhances memory with a bellshaped dose response curve, and its effects are time-dependent (Flood et al., 1988). The Cterminal amide fragment 33-49 of pancreastatin also has been demonstrated to enhance memory. Amylin is a pancreatic hormone (vide infra) which also appears to enhance memory when peripherally administered, while being amnestic after administration into the CNS (Flood & Morley, 1992). Overall these findings support the concept that memory processing is regulated during food ingestion secondarily to the release of gastropancreatic hormones. GLUCOSE, DIABETESMELLITUS,AND MEMORY Small increases in glucose levels, such as may occur after a meal, have been shown to enhance memory in rodents and humans (Hall et al., 1989). On the other hand, streptozotocininduced diabetic mice have both learning problems and amnesia (Flood et al., 1990). The memory retention problems of diabetic mice can be reversed by the administration of insulin immediately following training in an aversive T-maze paradigm. This suggests that the major cause of the memory retention deficit is the elevated glucose levels. Diabetes mellitus occurs in approximately 18% of persons between 65 and 75 yr of age, and 48% of all type II diabetics in the United States are over the age of 65 (Morley & Perry, 1991). A number of studies have shown that older humans with diabetes mellitus have cognitive deficits compared to age-matched persons without diabetes mellitus (Perlmutter et al., 1984; Mooradian et al., 1988). Diabetics have a much reduced ability to comprehend medication instructions than do age-matched non-diabetics. Preliminary studies indicate that lowering glucose in older persons with diabetes mellitus improves memory function. The biochemical basis of memory dysfunction in diabetes mellitus is poorly understood. Choline acetyltransferase activity is not changed in the brains of diabetic mice (Bitar et al., 1987). Both dopamine and serotonin synthesis are decreased in the brains of diabetic rodents (Morley & Flood, 1990). The levels of neuropeptide Y, which is a potent modulator of
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memory (Morley et al., 1987; Flood et al., 1989), are altered in the CNS in animals with experimental diabetes mellitus (Williams et al., 1989). It would appear that multiple neurotransmitters may be involved in the memory deficits occurring in rodents and humans with diabetes mellitus. APPETITE REGULATION It is now well accepted that appetite regulation consists of two components, viz. a central feeding drive and a peripheral satiety component (Morley, 1989). The central feeding drive system consists of a predominantly carbohydrate feeding drive system, i.e., neuropeptide Y and norepinephrine, and a fat feeding drive system, i.e., dynorphin and dopamine. Nitric oxide may be the primary intracellular mediator of the feeding system (Morley & Flood, 1991b). In addition, a variety of other neurotransmitters within the CNS appear to modulate the feeding drive systems (Morley, 1987). The peripheral satiety system acts as a brake on the central feeding system to limit the size of an individual meal. The major components of the peripheral satiety system are the gastrointestinal hormones that are released as food passes through the gut. The best studied of these peptide hormones is CCK. CCK limits the size of an individual meal in humans and many animal species. Based on studies with CCK antagonists, it appears that the effects of CCK on appetite regulation are physiological (Silver et al., 1989). Like its effects on memory regulation, CCK produces its effects on feeding by stimulating ascending vagal fibers, particularly those in the gastric branch of the vagus (Smith et al., 1981; Morley et al., 1982). After the vagus fibers enter the nucleus tractus solitarius (NTS), pathways course from the NTS to the paraventricular nucleus of the hypothalamus. Although the data are controversial, it appears that the effect of CCK on appetite regulation is independent of its ability to slow gastric emptying (Shaw et al., 1985). Of particular relevance to older individuals is the fact that infections release a variety of cytokines, e.g., interleukin-1 and tumor necrosis factor (cachectin), which are anorexic. These cytokines appear to produce their anorexic effects by activating corticotropin releasing factor (CRF) in the hypothalamus (Uehara et al., 1990). CRF in turn releases oxytocin which is a potent anorexic agent (Olson et al., 1991). Many of the substances which modulate appetite also alter energy metabolism. In some cases, their effects on feeding are opposite to their effects on energy metabolism, e.g., neuropeptide Y and norepinephrine both increase feeding when administered centrally but cause weight loss when administered peripherally (Morley & Flood, 1987). Thus, the final effect of a neurotransmitter on body weight regulation is dependent upon the sum of its effects on feeding and weight loss. AGING, ANOREXIA, AND PEPTIDES Numerous studies have shown that low body weight in older persons is more closely related to mortality than is overweight. Anorexia, or a poor appetite, are common complaints in older persons (Morley & Silver, 1988). Sixteen percent of Americans over the age of 65 yr ingest less than 1000 calories per day. The causes of this anorexia in older persons are often multifactorial (Table). A number of older persons who are losing weight have unusual attitudes about food intake. and their body image (Morley, 1988). Some turn out to have had an episode of anorexia
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nervosa as a child and a lifelong pattem of food restriction. In others, these attitudes appear to be of new onset; this condition has been termed tardive anorexia. Depression is commonly associated with weight loss in older persons (Fitten et al., 1989). Older depressives are more likely to loose weight than younger depressives. Approximately two-thirds of depressed persons have elevated CRF levels. CRF is a potent anorexic agent which produces its effects within the paraventricular nucleus of the hypothalamus. It appears that the anorexia associated with depression is due to increased CRF (Morley & Levine, 1982). In addition, CRF activates the sympathetic nervous system and increases energy expenditure, further promoting weight loss. Besides the pathological causes of weight loss with advancing age, it is clear that older persons have a reduction in appetite. This appears to be in response to the .decreased metabolic rate and physical activity that accompany the aging process (Morley, 1986). A number of physiological processes appear to be involved in this resetting of the appetostat that occurs with aging. In part, the decreased food intake appears to be due to the reduction in hedonic qualities of food that occurs with aging, since the ability both to taste and to smell diminish. However, there also is evidence for direct alterations in the neurotransmitter system involvement with food regulation. Multiple opioid mediated responses decline with advancing age (Morley et al., 1990). This decrease in opioid function can be attributed to the decreases in opioid receptors and the concentrations of methionine- and leucine-enkephalin, as well as ~I-EP that occur with aging (Gambert et al., 1980; Ueno et al., 1986). Older rodents are only 1,100thas sensitive to the sup-
CAUSES OF ANOREXIA IN OLDER PERSONS
I. Potential peptide influences A. Decreased opioid effectiveness (decrease in central feeding drive) B. Increased effect of CCK (increase in satiety) C. Increased amylin secretion I1. Alterations in physiological processes A. Decrease in taste and smell B. Loss of adequate dentition C. Decrease in basal metabolic rate III. Pathological processes A. Depression B. Cognitive impairment C. Body image disturbances D. Inability to self feed (cerebrovascular accident, Parkinson's disease) IV. Other A. Financial constraints B. Medications (digitalis preparations, theophylline) C. Social isolation
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pressive effects of the opioid antagonist, naloxone, on food intake as are younger animals (Gosnell et al., 1983). Older rats also fail to have an appropriate feeding response to injections of the n-opioid receptor agonist, butorphanol tartrate. The ~c-opioid receptor is the receptor for the endogenous opioid peptide, dynorphin. These findings strongly implicate failure of the opioid feeding system in the pathogenesis of the anorexia of aging. Only one study has examined the role of the peripheral satiety system in aging (Silver et al., 1988). In this study, CCK demonstrated a greater suppressive effect on food intake in 25-moold mice compared to 8-mo-old mice (Silver et al., 1988). Bombesin and calcitonin also showed a tendency to be more potent in older mice. Glucagon suppressed food intake to a similar extent in both young and old mice. The markedly increased suppressive effect of CCK on food intake suggests that it may play a role in the pathogenesis of the anorexia of aging. The finding that CCK levels are often elevated in older individuals, particularly when they are malnourished, further supports a role for CCK in producing the malnutrition occurring in some older persons (Khalil et al., 1985; Velas et al., 1988). The decreased opioid feeding effect with aging may be linked to the increased satiety produced by CCK. CCK has been suggested to produce a physiological antagonism of endogenous opioids in many systems (Morley & Flood, 1991c). For example, CCK antagonizes tail pinch-induced feeding (a system which is dependent on endogenous opioid activation) and decreases analgesia produced by 13-EP and morphine (Levine & Morley, 1981). Proglumide, a CCK receptor antagonist, potentiates analgesia produced by endogenous opioids (Takeshige et al., 1991). Morphine analgesia was demonstrated to be increased in rats which were immunized against endogenously released CCK (Faris et al., 1984). In conclusion, the pathogenesis of the anorexia of aging appears to depend at least in part on an attenuation of the opioid feeding drive and an increase in the satiety effect of CCK with advancing age. AMYLIN A ND FEEDING
Islet of Langerhans cells from persons with type II diabetes mellitus contain interstitial amyloid deposits. Amylin is a 37 amino-acid peptide which was isolated from these amyloid deposits (Cooper et al., 1989). Amylin is co-released with insulin, in a molar ratio of 1:100. Amylin levels increase in the circulation following a meal or oral glucose ingestion. Amylin antagonizes a number of effects of insulin including some of the effects of insulin on the liver and on muscle. It has been suggested that amylin may play a role in the development of insulin resistance. We have demonstrated that amylin decreased food intake in food-deprived mice (Morley & Flood, 1991d). The amylin effect on food intake was more potent in diabetic than in nondiabetic mice. Amylin also inhibited insulin-induced feeding. The amylin effect was more potent when it was administered intraperitoneally than when it was administered intracerebroventricularly. These data suggest that the increased amylin secretion occurring with advancing age may also play a partial role in the pathogenesis of the anorexia of aging. Further studies on the role of amylin in the modulation of food intake are needed. GROWTH HORMONE, WEIGHT LOSS A N D AGING
Growth hormone (GH) secretion decreases with advancing age (Kelijman, 1991). In addition, insulin growth factor-1 (IGF-1 or somatomedin-C), which is the liver end-organ hor-
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mone responsive to GH, also decreases with advancing age. This decrease in IGF-1 is more dramatic in malnourished, institutionalized older persons (Rudman et al., 1987). The decrease in GH with aging appears to be predominantly secondary to an increase in somatostatin which inhibits GH release from the pituitary. It has been suggested that the decrease in GH and IGF-1 leads to a GH " m e n o p a u s e " (Rudman, 1985). This would result in a variety of potentially deleterious effects, including an increase in adipose tissue, a decrease in muscle mass as a percentage of body weight, a decrease in albumin synthesis, and a decrease in cancellous bone density. Many of these effects are similar to the physical changes of aging. This led Rudman et al. (1990) to suggest that GH replacement may result in a decreased rate of aging. Their studies suggest that in healthy older persons, administration of recombinant GH results in a decrease in body fat and an increase in skin thickness. However, neither of these findings could be considered dramatic. We took a different approach and gave recombinant GH to malnourished older persons (Kaiser et al., 1991). We found that GH stimulated IGF-1, enhanced nitrogen retention, and produced weight gain. Control patients continued to lose weight. The persons receiving GH tended to increase their caloric intake. A study carried out in the Netherlands also has demonstrated similar positive effects of GH administration to malnourished older persons (Binnert et al., 1988). Overall, these findings support the concept that recombinant GH may be useful in the management of malnutrition in selected older individuals. CONCLUSION It is clear that a number of gastrointestinal hormones are capable of modulating behavior. In the case of older persons, they appear to have potentially dramatic effects on both cognitive function and appetite regulation. The concept of gut-brain interactions is one which should be of increasing importance over the next decade.
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