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J F Flood

Publications and source records attributed to J F Flood.

At least 55 records · Page 3Linked to original sources
PubMed1994

Effect of competitive antagonism of NO synthetase on weight and food intake in obese and diabetic mice.

Recent studies have suggested a role for nitric oxide (NO) in the regulation of food intake. The present studies were undertaken to examine the effects of the administration of a nitric oxide synthetase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on food intake and weight loss. Two genetically obese mice, the ob/ob and db/db strains, and their lean heterozygote littermate controls, ob/c and db/c, served as subjects. In the first experiment, we demonstrated that L-NAME (100 micrograms/kg) given twice over a feeding period of 7 h/day produced a small but significant weight loss in ob/ob mice but not in their lean-genotype controls (P < 0.05). In the second experiment, a higher dose of L-NAME (100 mg/kg), given twice daily, produced a marked effect on body weight, with the ob/ob mice losing approximately 10% of their body weight in 9 days. The ob/c mice showed a lesser decrease in body weight. Food intake was decreased on all 9 days in the ob/ob mice (P < 0.01). A small decrease in body weight and food intake was seen in db/db and db/c mice receiving L-NAME. These studies provide further evidence for a role of nitric oxide in the modulation of food intake and weight gain.

Amino Acid Oxidoreductases↗
PubMed1994

Modulation of food intake by peripherally administered amylin.

Amylin has been demonstrated to produce anorexia in rodents. Its mechanism of action is unknown. We have studied the effect of amylin on food intake in mice in a variety of paradigms to determine whether it inhibits food intake by a peripheral mechanism of action. In addition, we determined its effect in genetically obese mice models and whether its effects differed in aged mice. Cholecystokinin is the prototypic satiety agent. The effects of amylin on reducing food intake were not attenuated by the cholecystokinin antagonist L-364718, suggesting that it does not produce its effect through the release of cholecystokinin. A number of gastrointestinal peptides produce anorexia by stimulating ascending vagal fibers. For this reason, we studied the effect of truncal vagotomy on the suppression of feeding induced by amylin. Vagotomy did not prevent amylin from inhibiting food intake. Amylin was equally effective at reducing food intake in genetically obese (ob/ob) and lean (ob/c) mice and in diabetic (db/db) and lean (db/c) mice. Amylin effectively suppressed food intake in mice over the age of 4-22 mo. These studies further support the role of the pancreatic hormone amylin as a peripherally acting satiety agent.

Amyloid↗
PubMed1993

Dose-response differences in the ability of ramipril to improve retention in diabetic mice.

Ramipril blocks the conversion of angiotensin I to II. The literature indicates that diabetes is often associated with mild impairment of learning and memory. The study reports the effects of ramipril on memory retention in diabetic and non-diabetic mice. Mice were made diabetic by an injection of streptozocin. After overt signs of diabetes were present, diabetic or vehicle-treated mice were partially trained on a footshock active avoidance task. Immediately after training, ramipril (0.5-1.5 mg/kg s.c.) was administered and retention was tested by continuing training one week later until mice avoided footshock on five out of six trails. The results indicate that ramipril enhanced retention of both diabetic and control mice but it required about 5 times as much ramipril in diabetic as control mice to achieve the same effect on retention. Increased sensitivity to angiotensin II may play a role in cognitive impairment in diabetes.

Angiotensin I↗
PubMed1993

Anorectic effects of amylin in rats over the life span.

Amylin is a pancreatic peptide hormone that has been demonstrated to antagonize a number of the effects of insulin. This study demonstrated that amylin, when administered IP, decreased food intake in 4-month-old rats at doses of 50, 75, and 100 micrograms/kg. Amylin was slightly more potent at suppressing food intake at 13 months of age and less potent at decreasing food intake in 21- and 25-month-old rats, but the difference was not significant. These studies show that amylin is another peripheral anorectic peptide. They do not implicate amylin in the pathogenesis of the anorexia of aging.

Aging↗
PubMed1992

Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycine receptor.

Glycine has been shown to modulate N-methyl-D-aspartate (NMDA) subclass of acidic amino acid receptors which have been implicated in learning and memory. We report that d-cycloserine (DCS) which has a high affinity for the glycine modulatory site in the NMDA receptor complex modulated memory processing in a dose-dependent manner. Mice were trained on a footshock avoidance task. Immediately after training DCS was administered (2.5 to 50 mg/kg s.c.). When retention was tested a week later, 20 mg/kg facilitated retention the best with lower and higher doses be less effective in weakly trained young mice. DCS also facilitated retention in 'senescence-accelerated mice' in which impairment of learning and memory increases with age. DCS had to be administered at higher doses to improve retention as impairment of learning and memory increased.

Age Factors↗
PubMed1992

Evidence that cholecystokinin-enhanced retention is mediated by changes in opioid activity in the amygdala.

Mice, partially trained to avoid footshock in a T-maze, showed enhanced retention relative to vehicle-injected mice when treated peripherally with arecoline, D-amphetamine, cholecystokinin octapeptide (CCK-8), epinephrine or naloxone. Both intra-amygdaloid and intraventricular injections of beta-endorphin resulted in amnesia. D-amphetamine and arecoline blocked the amnestic effect of beta-endorphin administered into the amygdala but it required higher doses for CCK-8, epinephrine and naloxone to block the amnestic effect of beta-endorphin. The effects of CCK-8, epinephrine and naloxone showed a differential ability to block amnesia induced by beta-endorphin intraventricularly with epinephrine and naloxone preventing amnesia but CCK-8 not improving retention. This data suggests that the memory enhancement produced by peripherally administered CCK-8 involves the amygdala and that both CCK-8 and epinephrine interact with opioid amnestic mechanisms within the amygdala to alter memory processing.

Amygdala↗
PubMed1992

Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it.

Immediate post-training intracerebroventricular administration to male mice of pregnenolone (P), pregnenolone sulfate (PS), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, dihydrotestosterone, or aldosterone caused improvement of retention for footshock active avoidance training, while estrone, estradiol, progesterone, or 16 beta-bromoepiandrosterone did not. Dose-response curves were obtained for P, PS, DHEA, and testosterone. P and PS were the most potent, PS showing significant effects at 3.5 fmol per mouse. The active steroids did not show discernible structural features or known membrane or biochemical effects that correlated with their memory-enhancing capacity. The above, together with the findings that DHEA acted even when given at 1 hr after training and that P, PS, and DHEA improved retention over a much wider dose range than do excitatory memory enhancers, led to the suggestion that the effects of the active steroids converge at the facilitation of transcription of immediate-early genes. P and PS, for which receptors have not yet been demonstrated, may exert their effects by serving as precursors for the formation of a panoply of different steroids, ensuring near-optimal modulation of transcription of immediate-early genes required for achieving the plastic changes of memory processes. Low serum levels of P in aging and the increases of cancer and behavioral disorders in individuals receiving drugs that block synthesis of cholesterol, the immediate precursor of P, suggest possible clinical utility for P.

Animals↗
PubMed1992

Age-related changes in LFA-1 expression, cell adhesion, and PHA-induced proliferation by lymphocytes from senescence-accelerated mouse (SAM)-P/8 and SAM-R/1 substrains.

Accelerated senescence-prone mice of the SAM-P/8jf series were compared with senescence-resistant SAM-R/1 controls in terms of age-related changes in phytohemagglutinin (PHA) proliferative responses and lymphocyte function-associated antigen-1 (LFA-1) utilization by non-adherent splenocytes. Advancing age was associated with a reduction in cell proliferative responses to PHA in both substrains, although the rate of decline was significantly more rapid in the senescence-prone animals. Conversely, in both substrains there was a progressive age-related increase in the proportion of splenocytes expressing high levels of LFA-1, and a parallel increase in the degree of LFA-1-dependent cell aggregation induced by phorbol ester. Age-matched SAM-P/8jf and SAM-R/1 mice did not differ in terms of LFA-1 expression or LFA-1-dependent cell aggregation. Two-color cytofluorometric analysis demonstrated the enhanced expression of LFA-1 expression by cells bearing the Pgp-1hi phenotype characteristic of memory lymphocytes. These results suggest that age-associated changes in lymphocyte adhesion are attributable to alterations in the relative numbers of memory cells expressing high levels of LFA-1, but are unlikely to contribute to the reduced proliferative response to mitogen in aged mice.

Aging↗
PubMed1992

Competitive antagonism of nitric oxide synthetase causes weight loss in mice.

These studies demonstrate that the competitive antagonist of nitric oxide synthesis, L-NG-nitro-arginine methyl ester (NO Arg ME), produces an L-arginine reversible decrease in food intake in mice. NO Arg ME also blocked the feeding effect of the potent orexigenic peptide, neuropeptide Y. NO Arg ME produced weight loss when administered over 5 days. The studies suggest that nitric oxide is a physiological modulator of food intake and that nitric oxide synthetase inhibitors may be useful in the management of obesity.

Amino Acid Oxidoreductases↗
PubMed1992

Early onset of age-related impairment of aversive and appetitive learning in the SAM-P/8 mouse.

SAM-P/8 (P/8if) mice, trained on aversive and appetitive training tasks, showed age-related impairment of learning on more difficult tasks. Using aversive training tasks, acquisition of step-down passive avoidance did not differ between 4- and 12-month-old mice. T-maze footshock avoidance acquisition detected impairment from 9 to 12 months of age. On the appetitive tasks, 12-month-old mice required significantly more trails than 4-month-old mice to learn to press a lever for milk reinforcement or to learn a specific sequence of 10 black-white, left-right discriminations. However, learning a simple black-white discrimination in the same 10-unit maze did not discriminate between the performance of 4- and 12-month-old mice. A lack of age-related changes in food, water, and milk consumption suggests that changes in motivation do not account for the decline in learning in older P/8if mice. The results suggest an early onset of impaired learning relative to the 17.2-month median life span of the P/8if mice.

Aging↗
PubMed1991

Amnestic effects in mice of four synthetic peptides homologous to amyloid beta protein from patients with Alzheimer disease.

Immediate post-training intracerebroventricular administration of a synthetic peptide homologous to beta protein of brain amyloid, [Gln11]beta-(1-28), caused amnesia for footshock active avoidance training in mice in a dose-dependent fashion. This effect was specific to memory processing since the peptide did not cause amnesia when injected 24 hr after training nor did it disturb storage or retrieval of older memories. Shorter fragments of the amyloid beta protein consisting of residues 12-28, 18-28, and 12-20 also were amnestic when given intracerebroventricularly, residues 12-20 being least effective. The hippocampus, a brain structure importantly involved in learning and memory, consistently shows severe pathological changes and deposition of amyloid in patients with Alzheimer disease. Immediate post-training bilateral intrahippocampal injection of [Gln11]beta-(1-28) produced amnesia at much lower doses than did [Gln11]beta-(1-28) injected intracerebroventricularly. Thus these experimental results suggest a possible direct role of amyloid beta protein or fragments thereof in an aspect of the spectrum of cognitive deficit in Alzheimer disease.

Alzheimer Disease↗
PubMed1991

Evidence that nitric oxide modulates food intake in mice.

Nitric oxide (NO) may be an intercellular modulator within the central nervous system. L-arginine, which results in NO synthesis, increased food intake in mice while the inhibitor of NO synthesis, L-NG-nitro arginine (L-NO Arg) inhibited food intake in food deprived mice. L-arginine, but not D-arginine, partially reversed the inhibitory effect of L-NO Arg on food intake. These findings suggest the possibility that NO may be a physiological modulator of food intake and that the possibility of exploring the utility of L-NO arg in the treatment of obesity should be explored.

Animals↗
PubMed1991

Effect of aging on fluid ingestion in mice.

The amount of fluid consumed by C57BL/6Nnia male mice 3, 12, and 25 months of age under various paradigms was studied. The old mice consumed less water during the dark cycle but not during the light cycle (12 h lights off; 12 h lights on). When thirst was induced by providing dry food pellets or after overnight fluid deprivation, old mice consumed significantly less water than younger mice over a one-hour period. When thirst was induced by administration of hypertonic saline, there were no age-related effects. Naloxone 7.5 mg/kg IP significantly suppressed drinking in 3- and 12-month-old mice, while 25-month-old mice did not show suppression. Dehydration-induced thirst is impaired in old mice, as it is in older humans. This may be related to the alteration in opioid mechanisms modulating thirst.

Aging↗
PubMed1990

Modulation of memory processing by glutamic acid receptor agonists and antagonists.

Recent hypotheses suggesting a critical role of glutamate receptors in hippocampal long-term potentiation and memory processing suggested a closer examination of this transmitter's effect on memory processing in an in vivo setting. New pharmacological antagonists allow for a separation and examination of various glutamate receptors and their role in memory processing. Mice were trained on a shock avoidance learning paradigm and injected intracerebroventricularly after training with agonists and antagonists of various classes of glutamate receptors. Retention was tested 1 week after training. N-Methyl-D-aspartate (NMDA) receptor agonists enhanced retention in a dose-dependent manner. The enhancement of retention by the non-NMDA agonist kainic acid and quisqualic acid was dose-dependent. L-Glutamic acid, but not D-glutamic acid, enhanced retention. Both NMDA and non-NMDA receptor antagonists produced dose-dependent impairment of retention for footshock training. Administration of the antagonists 24 h after training did not impair memory retention.

Animals↗
PubMed1990

Modulation of memory retention by neuropeptide K.

Neuropeptide K (NPK) is one of the structures in beta-preprotachykinin which also includes substance P. NPK, a 36 amino acid peptide, contains the sequence of neurokinin A as amino acids 27-36 of its C-terminus. Neurokinin A is also contained separately in the gamma-preprotachykinin precursor. Both NPK (2.5-10 micrograms) and neurokinin A administered intracerebroventricularly after footshock avoidance training in the T-maze enhanced memory retention in CD-1 male mice. Local microinjections of NPK enhanced memory retention when injected into the rostral and caudal portions of the hippocampus (0.25 and 0.50 microgram) and the amygdala (1.0 microgram), but were without effect when injected into the septum and the caudate. The differential effects of NPK on memory retention across brain regions differed from those previously reported for substance P and neuropeptide Y. These studies suggest that NPK, acting through discrete anatomical areas, modulates memory processing. The functional significance of co-localization of neuropeptides with classical neurotransmitters and other transmitter peptides in the same neurons is not well understood, but recent studies have indicated that the neuropeptides modulate the release of the primary transmitter. Since NPK occurs in the same precursor molecule as substance P, NPK may be co-released with the putative neurotransmitter substance P and act with it, in a synergistic manner, to enhance memory processing. These studies provide further evidence that the hippocampus is an anatomical structure involved in memory processing that occurs shortly after training.

Amino Acid Sequence↗
PubMed1990

Pharmacological enhancement of long-term memory retention in old mice.

This study examined memory retention deficits in 24-month-old mice as compared to 4-month-old mice and if they were related to an altered functional state of neurotransmitters or hormones that modulate memory. We administered to 24-month-old C57BL/6Nnia mice pharmacological compounds known to improve retention in young mice. Eleven of the pharmacological agents improved retention in old mice at the dose previously shown to be optimal in young mice. Clonidine and ST 587, the two alpha noradrenergic agonists tested, failed to enhance retention at the optimum dose for young mice. A dose response study with clonidine found that a lower dose (1 mg/kg) improved retention in old mice rather than the optimal dose (3 mg/kg) for young mice. These data suggest that memory retention in old C57BL/6Nnia mice is similar to that of young mice, with the exception of alpha noradrenergic receptors.

Aging↗