Neuropeptide Y and memory processing.
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Alzheimer Disease↗
Biomedical subjects
J F Flood
Publications and source records attributed to J F Flood.
Characteristics of learning and memory in streptozocin-induced diabetic mice.
We demonstrated that mice with streptozocin-induced diabetes mellitus have normal acquisition for relatively simple tasks but show problems in learning more complex tasks such as shuttle box avoidance. Enhanced learning previously reported in simple passive avoidance tasks appears to be due to increased foot shock sensitivity. Diabetic mice show a marked memory retention deficit after learning an active avoidance T-maze task. This retention deficit was reversed by a single injection of insulin, suggesting that it may be related to hyperglycemia per se. Diabetic mice have a shift to the left in the inverted U-shaped dose-response curve for memory retention produced by the acetylcholine agonist arecoline. Based on a preliminary screening, responses to several other pharmacological memory enhancers are probably altered in diabetic mice. These studies suggest that this mouse model of diabetes mellitus demonstrates a deficit in memory retention and retrieval similar to that seen in humans with diabetes mellitus.
Animals↗
Modulation of memory processing by neuropeptide Y varies with brain injection site.
Neuropeptide Y (NPY) is a 36 amino acid peptide which was shown to enhance memory retention, recall and prevent amnesia induced by either scopolamine or anisomycin. In this study, we examined the effects of NPY administration into 6 areas of the mouse brain on memory retention for footshock avoidance training in a T-maze. NPY was injected into the rostral and caudal hippocampus, amygdala, caudate, septum and thalamus shortly after training. NPY improved retention when injected into the rostral portion of the hippocampus and septum, impaired retention in the caudal portion of the hippocampus and amygdala and had no effect in the thalamus and caudate. NPY was ineffective at either improving or impairing retention when injected 24 h after training, thus demonstrating that the effects of NPY on retention were time-dependent and not due to proactive effects on retention test performance per se. In addition, NPY had no effect on retention when injected into overlying cortical areas. NPY antibody impaired retention when administered into the rostral hippocampus and septum; it improved retention in the caudal hippocampus and amygdala. Thus NPY antibody had the opposite effect to that of NPY on memory retention suggesting that NPY has a physiological role as a modulator of memory processing within specific anatomical areas of the central nervous system.
Animals↗
The effect of neuropeptide Y on drinking in mice.
Neuropeptide Y (NPY) when administered intracerebroventricularly is a potent stimulator of feeding and drinking in rats. In these studies we demonstrated that, in contrast, in mice NPY inhibits drinking induced by water deprivation and that associated with food intake. In addition, we found that mice failed to respond to the rat dipsogen angiotensin II. Old mice demonstrated hypodipsia compared to young mice and NPY failed to inhibit drinking in older mice. Monosodium glutamate (MSG) administered neonatally produces lesions of the arcuate nucleus, an area rich in NPY cell bodies. NPY inhibited drinking and enhanced feeding in MSG treated mice. NPY also significantly inhibited the intake of water flavored with 8% sucrose and 0.1% quinine. NPY failed to alter ingestion of 0.2% or 5% saline. These studies support the contention that marked species differences exist in the regulation of water intake between rats and mice.
Aging↗
Evidence for a physiological role for CCK in the regulation of food intake in mice.
The effects of L-364,718, a cholecystokinin receptor antagonist, on cholecystokinin octapeptide-induced inhibition of food, and its effect on food intake when given alone, were studied in mice using several different feeding paradigms. In all studies, L-364,718 (100 micrograms/kg, 1.0 mg/kg) reversed the ability of cholecystokinin octapeptide to decrease food intake. L-364,718 enhanced food consumption compared with controls in nonfasted mice (100 microgram/kg) and in prefed mice (50, 100, 250 micrograms/kg). The number of reinforcements, using a lever press, was also enhanced by L-364,718 (100 micrograms/kg) compared with control. In other paradigms, L-364,718 failed to enhance food intake. These results are compatible with the suggestion that cholecystokinin may play a physiological role in the regulation of food intake.
Animals↗
Relationship between behavioral and motor responses of mature and old mice and cerebellar beta-adrenergic receptor density.
Aging alters motor performance. Changes in adrenergic systems also occur and may be involved in altered motor function. Since beta-adrenergic input is prominently involved in cerebellar control, the current study investigated the relationship between cerebellar beta-adrenergic status and motor function in old (27 month) and mature (10 month) C57BL mice. Plank balance, photocell box activity and novelty-induced locomotion were all greater in mature compared to old mice (P less than 0.01) as was beta-adrenergic receptor density. Beta-adrenergic receptor density, but not receptor affinity for antagonist, was highly correlated to these measures of motor function when results from both groups of animals were analyzed: Plank balance (R = 0.80, P less than 0.01); locomotion in an open field (R = 0.60, P less than 0.01) and in a photocell box (R = 0.59, P less than 0.02). Aging alters cerebellar motor function and part of this dysfunction is correlated with beta-adrenergic receptor density.
Aging↗
Effects of bombesin and gastrin-releasing peptide on memory processing.
We have previously shown that feeding mice immediately following training enhances memory retention and that one of the gastrointestinal hormones released during a meal, cholecystokinin, also enhances retention after peripheral administration. In the studies reported here we demonstrate that another gastrointestinal peptide, gastrin-releasing peptide (GRP), enhances retention after peripheral administration, as does its amphibian counterpart, bombesin. GRP had the same effect as the intact peptide, while GRP was ineffective at enhancing retention. The dose-response curves showed a characteristic inverted U-shape with high doses of both GRP and bombesin being amnestic. The effect of both peptides was time-dependent and both reversed amnesia induced by the anticholinergic, scopolamine. I.c.v. administration of the peptides required higher doses to produce an effect on memory retention, suggesting that the effect was mediated predominantly through a peripheral mechanism. Doses of the peptides that enhanced memory retention after peripheral administration failed to increase serum glucose, suggesting that glucose modulation was not the mechanism by which GRP and bombesin modulate memory processing. Vagotomy inhibited the memory-enhancing effects of both GRP and bombesin, suggesting that these peptides produced their effect by stimulating ascending vagal pathways. These studies, together with our previous study with cholecystokinin, suggest the existence of a gastrointestinal hormonal system, which is activated by the passage of food through the intestine, that enhances memory retention.
Animals↗
Dehydroepiandrosterone sulfate improves memory in aging mice.
Middle-aged (18 month old) and old (24 month old) mice showed poorer retention of footshock active avoidance training (FAAT) than young mice (2 month old). Immediate post-training subcutaneous injection of dehydroepiandrosterone sulfate (DHEAS) improved retention of FAAT in middle-aged and old mice to the high levels observed in young mice. DHEAS, a major naturally occurring adrenal steroid that decreases in blood serum with age, could be rate-limiting in achievement of retention of learning.
Aging↗
Dehydroepiandrosterone and its sulfate enhance memory retention in mice.
Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), major naturally occurring precursors of both androgenic and estrogenic steroids, were shown in the present study to have convincing memory enhancing effects in mice. Post-training intracerebroventricular (i.c.v.) administration of DHEA in dimethylsulfoxide (2 microliters) prevented the amnesia for footshock active avoidance training (FAAT) caused by the same volume of dimethylsulfoxide alone. DHEAS significantly enhanced retention of FAAT in weakly trained mice whether injected i.c.v. or s.c. immediately post-training or given in the drinking water for a 2-week period. In the latter instance DHEAS was shown to facilitate retention of FAAT without enhancing acquisition. The maximally effective doses were: i.c.v., 162 ng/mouse; s.c., 700 micrograms/mouse; and oral, 1.45 mg/mouse/day. DHEAS administered i.c.v. occluded the amnestic effects of anisomycin (inhibitor of protein synthesis) and scopolamine (muscarinic cholinergic antagonist). There was a time-dependence of the facilitatory effects of post-training i.c.v. administration of DHEAS on retention of FAAT, significant enhancement of retention being observed when it was given either immediately (within 2 min) or at 30 and 60 min after training, but not at 90 or 120 min. DHEAS given i.c.v. also improved retention for step-down passive avoidance. In all instances, dose-dependent inverted U curves were obtained in a manner typical for memory enhancing substances. At a practical level, these experiments open new possibilities for the development of substances that may help in alleviating amnesic disorders in man.
Administration, Oral↗
Two-drug combinations of memory enhancers: effect of dose ratio upon potency and therapeutic window, in mice.
Two-drug combinations have been reported to enhance retention more effectively than when either drug was administered alone at the same dose. Some combinations of cholinergic drugs enhance retention even though the total drug dosage is reduced by as much as 97% compared to the dose needed to improve retention when the same drugs are administered singly. The choice of dose ratio is usually arbitrary or based on empirical results. The present study systematically varied the ratio of two drugs in a combination and at the same time varied the dosage of each drug. The drug combinations were administered to mice immediately after training on T-maze footshock avoidance task. Retention was tested one week later. Three two-drug combinations were selected for presentation because they differed considerably as to (a) the lowest effective total dose that improved memory-retention, (b) the optimal ratio that improved retention and (c) the width of the therapeutic window. The effect of a drug combination on retention was found to be dependent on the particular drugs in the combination, the ratio and the dose administered.
Animals↗
Memory enhancement in mice: role of drug dose and training-testing interval.
Pharmacologic probes are useful for studying memory mechanisms. For eight drug treatments affecting a variety of transmitter systems [arecoline, piribedil, clonidine, fluoxetine, naloxone, ACTH (4-10)], we determined how long memory retention would remain improved with a dose sufficient to improve 3-hour retention. While all 6 treatments enhanced 3-hour retention test performance at p less than 0.05, only 5 treatments significantly enhanced retention 24 hour after training and none of the treatments significantly affected retention at 168 hours. A detailed analysis of the dose and retention interval interaction for arecoline indicated that at low doses retention decreased as the retention interval increased while higher doses improved retention up to 3 hours and only the highest dose tested enhanced retention at 3 and 24 hours. Drug doses that enhance short-term retention (3 hours) were not adequate to enhance long term retention (168 hours). The 6 drug treatments had no significant or systematic effect on activity or on acquisition. We conclude that short-term retention performance was better because of enhanced memory processing or recall and not because of performance effects per se.
Adrenocorticotropic Hormone↗
Effect of acute arecoline, tacrine, and arecoline + tacrine post-training administration on retention in late middle-aged mice.
The amnesias characteristic of Alzheimer's disease and other age-related dementias are refractory to conventional pharmacotherapy. A recent treatment strategy is to combine drugs, particularly cholinergic drugs, to improve their memory enhancing effect. We previously reported that in young, weakly trained mice, the combination of arecoline and tacrine was more effective on a mg/kg basis than either drug administered alone. This was true whether the route of administration was intracerebroventricular, subcutaneous, or oral. These drug treatments have also been found to improve retention in 24-month-old mice. Mice 24 months of age show very poor recall one week after training. Failing memory must develop over time but may only be detected in mice younger than 24 months of age when the retention test interval is substantially longer. We now report that 18-month-old mice trained to avoid footshock in a T-maze show poor retention when tested two months after training and drug administration. Subcutaneous administration of arecoline, tacrine, and arecoline plus tacrine all enhanced retention of 18-month-old mice compared to the saline-injected control. The combination was as effective as the single drug treatments even though 96% less arecoline and 99.7% less tacrine were administered.
Age Factors↗
An investigation of tolerance to the actions of leptogenic and anorexigenic drugs in mice.
This study compared the effects of chronic administration of anorexigenic drugs on weight loss in mice. Tolerance to the effects of peripheral anorexigenic peptides, viz. cholecystokinin-octapeptide and bombesin, developed rapidly. Morphine, cocaine and dehydroepiandrosterone-sulfate caused weight loss and appeared similar to d-amphetamine in mechanisms of action. A high dose of fluoxetine (25 mg/kg) proved to be a potent leptogenic agent but was also associated with death in some animals. A lower dose of fluoxetine (5 mg/kg) was associated with the development of tolerance. Calcitonin, a potent anorexigenic agent, did not produce weight loss and tolerance to its anorectic effect had developed by 10 days. Animals varied widely in their individual responsiveness to a given drug. Peripheral administration of peptide YY caused weight loss. We conclude that acute or chronic effects of agents on food intake do not necessarily predict effects on body weight. However, neurotransmitters that enhance feeding centrally appear to cause weight loss when administered peripherally.
Amphetamine↗
Antagonism of endogenous opioids modulates memory processing.
The studies reported here demonstrate that opioid antagonism enhances memory in two classes of animals viz. Aves and Mammalia. In mice, immediate posttraining administration of naloxone produces a time-dependent improvement in retention tested one week later. This effect is stereospecific. As naloxone was approximately 1000-fold more potent when administered intracerebroventricularly compared to subcutaneously, it appears that it produces its effect within the central nervous system. Pretest administration of naloxone, at a dose that failed to alter acquisition, also improved test performance, suggesting that naloxone also improved recall. Similar improvement in retention was demonstrated with the more potent opioid antagonist, nalmefene, at a 500-fold lower dose. The dose response to naloxone in both the mouse and the chick and to nalmefene in the mouse had the characteristics of an inverted U, with high doses either being ineffective or suppressing memory retention. In mice, naloxone demonstrated anti-amnestic properties against both anisomycin, a protein synthesis inhibitor, and scopolamine, an acetylcholine receptor blocker. Administration of beta-funaltrexamine (B-FNA) 72 h prior to training did not alter acquisition but did enhance retention. In studies where the mu-opioid receptor was blocked with B-FNA, naloxone was unable to enhance retention. B-FNA failed to impair the memory enhancing properties of arecoline, fluoxetine or clonidine. This demonstrates specificity of the B-FNA ability to prevent naloxone from enhancing memory and suggests that the opioid antagonist effects on memory are mediated by the mu-receptor.
Animals↗
Modulation of memory processing by neuropeptide Y.
Neuropeptide Y (NPY) is a 36 amino acid peptide which occurs in high concentrations in the amygdala and the hippocampus. The studies reported here demonstrate that administration of porcine NPY into the third ventricle of the brain enhanced memory retention for T-maze footshock avoidance and step-down passive avoidance training in mice. Human NPY at 5 micrograms enhanced retention but the inactive free acid form for NPY did not. NPY at 5 micrograms administered subcutaneously did not enhance retention. Post-training administration of NPY produced a dose-dependent, inverted U-shaped dose-response curve for retention of both passive and active avoidance conditioning. NPY enhanced retention in a time-dependent manner. NPY was also found to alleviate the amnesia caused by anisomycin, a protein synthesis inhibitor, and scopolamine, an anticholinergic. Pre-test administration of NPY improved recall but did not affect acquisition. These data support the concept that NPY is a modulator of memory processes.
Amnesia↗
Modulation of memory processing by cholecystokinin: dependence on the vagus nerve.
Allowing mice access to food immediately after an aversive training session enhances memory retention. Cholecystokinin-octapeptide (CCK-8), which is a gastrointestinal hormone released during feeding, also enhances memory retention when administered intraperitoneally. This memory-enhancing effect of CCK-8 is blocked when the vagus nerve is cut, indicating that CCK-8 may produce its effect on memory retention by activating ascending fibers in the vagus nerve. Thus, CCK-8, a peripherally acting peptide, may mediate the memory-enhancing effects of feeding.
Animals↗
Effects of dehydroepiandrosterone and its sulfate on brain tissue in culture and on memory in mice.
Low concentrations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) enhanced neuronal and glial survival and/or differentiation in dissociated cultures of 14-day mouse embryo brain. Posttrial intracisternal injection into the brains of mice undergoing active avoidance training alleviated amnesia and enhanced long-term memory. By minimizing degenerative changes in injured nerve tissue and facilitating plastic changes, DHEA and DHEAS may be of use in treatment of neurodegenerative and memory disorders in man.
Animals↗
Fluoxetine enhances memory processing in mice.
Fluoxetine (FLU) increases brain concentrations of serotonin by blocking its uptake, without appreciably affecting the dopamine or norepinephrine systems. The present experiments provide evidence that a subcutaneous injection of FLU enhanced post-memory processing ("consolidation") and retrieval, but not acquisition in young adult mice. FLU (15 mg/kg) enhanced 1-week memory retention when injected 2 min post-training. Similar enhancement was obtained with intracerebroventricular injection (20 micrograms per mouse). FLU enhanced retention when administered prior to training (1-5 mg/kg). FLU (2.5 mg/kg) enhanced recall scores when injected 1 h before the 1-week retention test, indicating an enhancing effect on memory retrieval. Neither the pre-training nor pre-testing effects depended on improved acquisition, since FLU did not improve acquisition of T-maze foot-shock avoidance over the dose range 0.5-35 mg/kg. The sensitive period for post-training enhancement by FLU (15 mg/kg) was less than 90 min, as shown by the temporal gradient typical of memory-enhancing drugs. The amnesia induced by a protein synthesis inhibitor anisomycin, or by an anticholinergic drug scopolamine, was blocked by FLU (15 mg/kg) injected post-training. Finally, FLU (15 mg/kg) injected after one-trial passive avoidance training enhanced 1-week retention, demonstrating effectiveness in this task as well as in the active avoidance task.
Animals↗