Biomedical subjects

J F Flood

Publications and source records attributed to J F Flood.

At least 37 records · Page 2Linked to original sources

PubMed1996

Enhancement of hippocampal acetylcholine release by the neurosteroid dehydroepiandrosterone sulfate: an in vivo microdialysis study.

The effect of dehydroepiandrosterone sulfate (DHEAS) administered i.p. on the release of acetylcholine (ACh) from the hippocampus of anesthetized rats was examined using in vivo microdialysis. DHEAS significantly increased ACh release above the pre-treatment levels for all doses tested. The administration of 100 mg/kg significantly enhanced ACh release greater than 4-fold when compared to the saline-treated group 80 min following drug administration. This study is the first to demonstrate that the neurosteroid DHEAS, a negative allosteric modulator of the GABAA receptor, can enhance the release of ACh from neurons in the hippocampus.

Acetylcholine↗

PubMed1996

Inhibition of feeding by a nitric oxide synthase inhibitor: effects of aging.

Nitric oxide has been demonstrated to play a role in the modulation of food intake. With advancing age, there is a physiological decrease in food intake. The effect of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) on food intake in C57BL/6Nnia mice aged 3, 12 and 24 months was studied. L-NAME was more effective at decreasing food intake in 12- and 24-month-old mice than in the 3-month-old mice. NO synthase levels in the hypothalamus were increased in 16- and 25-month-old mice compared to 6-month-old mice (P < 0.01). NO synthase mRNA increased in 16- compared to 6-month-old mice, but decreased in 25-month-old mice. Overall, these studies may suggest that nitric oxide may play an increasingly important role in the feeding drive with advancing age.

Aging↗

PubMed1996

Isatin inhibits food intake in mice.

Isatin (2,3-dioxindole) is an endogenous compound which is distributed throughout the central nervous system. The studies reported here demonstrate that isatin decreased food intake in food deprived TAC (SW) male mice 12-16 weeks of age. Isatin was more effective at decreasing food intake when the mice had to work harder to obtain food. Isatin also decreased sucrose, milk and water intake. When hunger was reduced by prefeeding milk to the mice, isatin was more effective at decreasing food intake. Isatin did not alter spontaneous activity in an openfield. Behaviors observed in the home cage indicated that mice which received isatin approached the food more often without eating than the controls. Movement in the home cage was significantly reduced in mice receiving isatin. Drinking, grooming and resting were not significantly affected by administration of isatin. These studies suggest that isatin may be an endogenous modulator of food intake.

Animals↗

PubMed1996

Peripherally administered calcitonin gene-related peptide decreases food intake in mice.

Previously, calcitonin gene-related peptide (CGRP) decreased food intake when administered ICV but not when administered peripherally to rats. Amylin, which has a close structural homology to CGRP, reduced food intake administered IP at concentrations higher than those previously tested for CGRP. We examined the effects of higher doses of IP-administered CGRP on food intake. CGRP reduced food intake from 25 to 200 micrograms/kg in mice. CGRP did not reduce water intake and was not aversive in a two-bottle test. Using a lever press, CGRP was more effective at reducing milk consumption in prefed than in nonprefed mice. The effect of CGRP on food intake was not antagonized by the cholecystokinin A receptor antagonist, L364,718. These studies suggest a role for CGRP as a satiating factor.

Analysis of Variance↗

PubMed1995

Pregnenolone sulfate enhances post-training memory processes when injected in very low doses into limbic system structures: the amygdala is by far the most sensitive.

Immediate post-training, stereotactically guided, intraparenchymal administration of pregnenolone sulfate (PS) into the amygdala, septum, mammillary bodies, or caudate nucleus and of PS, dehydroepiandrosterone sulfate, and corticosterone into the hippocampus was performed in mice that had been weakly trained in a foot-shock active avoidance paradigm. Intrahippocampal injection of PS resulted in memory enhancement (ME) at a lower dose than was found with dehydroepiandrosterone sulfate and corticosterone. Intraamygdally administered PS was approximately 10(4) times more potent on a molar basis in producing ME than when PS was injected into the hippocampus and approximately 10(5) times more potent than when injected into the septum or mammillary bodies. ME did not occur on injection of PS into the caudate nucleus over the range of doses tested in the other brain structures. The finding that fewer than 150 molecules of PS significantly enhanced post-training memory processes when injected into the amygdala establishes PS as the most potent memory enhancer yet reported and the amygdala as the most sensitive brain region for ME by any substance yet tested.

Amygdala↗

PubMed1995

Localized injections of various compounds effecting neurotransmitter activity in the mammillary complex enhance (T-maze) avoidance retention.

The mammillary complex is implicated in the amnesic syndrome associated clinically with Korsakoff's syndrome, Alzheimer's disease and experimentally with lesions in animals. There is however no direct evidence that the mammillary bodies are involved in long term memory processing. Mice were partially trained on a footshock avoidance task. Immediately after training drugs were injected into the mammillary complex. Retention was tested 1 week later by continuing training until each mouse made five avoidance responses in six trials. The results indicated that muscarine, nicotine, dopamine, glutamine and adrenoceptor agonists as well as GABA and 5-HT receptor antagonists and neuropeptide Y improved retention test performance relative to the control. Injection of the same drugs 1 mm above the injection site for the mammillary complex failed to significantly improve retention test performance. It is concluded that the mammillary complex, with its important connections to other areas of the limbic system, is involved in memory processing events that occur shortly after training.

Animals↗

PubMed1995

The memory enhancing effects of cholecystokinin octapeptide are dependent on an intact stria terminalis.

Cholecystokinin is a gastrointestinal peptide which is released from the duodenum during eating. Cholecystokinin octapeptide (CCK-8) has been found to improve retention when administered intraperitoneally in intact mice but not in vagotomized mice. This suggested that CCK-8 improves retention by stimulating vagal afferents to the nucleus of the solitary tract in the brainstem. In this study, we tested whether nerve fibers in the stria terminalis which project from the NTS to the amygdala need to be intact for CCK-8 to enhance retention. Three groups of mice were used: nonoperated, bilateral cortical control lesioned, and bilateral stria terminalis lesioned. The lesions were performed 1 week prior to footshock avoidance training in a T-maze. Saline, CCK-8 (0.5 microgram/kg, ip), epinephrine (100 micrograms/kg, sc), or arecoline (1.5 mg/kg, sc) were administered immediately after training. Retention was tested 1 week later. Neither bilateral stria terminalis lesions nor cortical control lesions significantly altered acquisition of the task compared to the nonoperated group. Whether the groups received a saline injection after training or received no injection did not affect retention test performance. CCK-8 and epinephrine enhanced retention in the mice with cortical lesions but not in mice with stria terminalis lesions. Arecoline enhanced retention in both groups. Possible pathways and neurotransmitters mediating the effect are discussed.

Afferent Pathways↗

PubMed1995

Age-related decrease of plasma testosterone in SAMP8 mice: replacement improves age-related impairment of learning and memory.

Corticosterone increases with aging but pregnenolone, dehydroepiandrosterone, and testosterone decrease. The marked decrease in hormones that occurs with aging may contribute to the age-related deficit in learning and memory. Administration of these hormones after training was found to improve long-term memory processing in normal young mice. SAMP8 (P8) mice show an age-related loss of learning and memory for a variety of tasks whereas age-matched control mice of the closely related SAMR1 (R1) strain do not. In this study, we found an age-related decrease in serum testosterone levels of 71% between P8 mice 4 and 12 months of age, but only a 26% decrease between R1 mice of the same ages. The difference between the P8 mice was significant (p < 0.01) and the difference between the R1 mice was not. The decrease in testosterone in 12-month-old P8 mice was not accompanied by gross morphological change in the testes. A SC testosterone implant, sufficient to increase plasma testosterone levels to 414 +/- 25 ng/dl, alleviated impaired learning and memory of a foot shock avoidance task in P8 mice. Castration of 4-month-old P8 mice did not produce a deterioration in learning and memory, indicating that low levels of testosterone per se are not responsible for the impairment seen in 12-month-old P8 mice. This suggests that impaired cognitive functioning of the older P8 mice was due to an interaction of aging and reduced testosterone levels.

Aging↗

PubMed1995

Effect of ovarian steroids on footshock avoidance learning and retention in female mice.

Mice were trained to avoid footshock in a T-maze, with retention tested one week later. Adult male CD-1 mice made their first avoidance during acquisition after fewer trials than random cycling females and with less variability. Female mice in diestrus, when plasma levels of progesterone are low, learned to avoid footshock faster than females in estrus. Ovariectomized (OVX) mice learned in fewer trials than intact random cycling mice. Similar differences, though of a smaller magnitude, were found on the retention tests (i.e. males had better retention than females, mice in diestrus showed better retention 8 days later when in the same part of the estrous cycle than those in estrus, and OVX mice had better retention than cycling females). OVX mice with estrogen implants learned faster than those with progesterone implants or progesterone plus estrogen implants. Hormonal status did not affect sensitivity to acoustic or footshock stimuli as measured by a startle reflex, nor did it affect activity. Pretraining administration of amphetamine, picrotoxin and strychnine attenuated the impairing effect of progesterone on acquisition. The possibility that progesterone may impair learning and to some extent, retention by facilitating the GABAergic activity and thereby reducing arousal level is discussed.

Animals↗

PubMed1995

Age-related changes in learning, memory, and lipofuscin as a function of the percentage of SAMP8 genes.

SAMP8 (P8) mice are characterized by impaired learning and memory relatively early in their life, while CD-1 mice show impairment later in life. A series of paternal backcross strains were developed from a CD-1 dame and P8 sire. Siblings from each backcross were bred to establish strains with 50% to 97% P8 genes. F4 mice, 4 or 12 mo of age, were trained to avoid foot shock in a T-maze with retention tested 1 wk later. After testing, brain sections were examined for lipofuscin autofluorescence. At 4 mo of age, all strains, including the CD-1 and P8 strains, showed no significant differences in learning, retention or lipofuscin deposits. At 12 mo of age, groups with 94%, 97% P8 genes or P8 mice (100%) required significantly more trials to learn the task or relearn the task 1 wk later than groups with 88% or fewer P8 genes. Lipofuscin deposits increased in the hippocampus as the percentage of P8 genes increased suggesting that many genes control aging of the brain. However, the sudden appearance of impaired learning in the 94% strain suggests that the mechanism(s) responsible for the impairment involves a few recessive genes and are independent of the mechanisms controlling the general aging of the brain.

Aging↗

PubMed1995

Nitric oxide synthase inhibition and food intake: effects on motivation to eat and in female mice.

Recent studies have demonstrated that nitric oxide may play an important role in the regulation of food intake. The studies reported here extend these findings by demonstrating that NG-nitro-arginine-methylester, N-Arg(ME), a nitric oxide synthase inhibitor, decreased intake of a highly palatable substance (i.e., milk), though at a higher dose than necessary for decreasing consumption of food pellets. N-Arg(ME) failed to inhibit lever press for milk reward in nonprefed mice, but decreased lever pressing in prefed mice. N-Arg(ME) decreased food intake in female mice, being most potent in proestrus. These studies suggest that nitric oxide synthase inhibition decreases food intake without inducing aversion or illness.

Amino Acid Oxidoreductases↗

PubMed1995

Age-related impairment in learning but not memory in SAMP8 female mice.

Four-month and 12-month-old SAM (Senescence Accelerated Mouse)-P8 and -R1 female mice, either intact or ovariectomized, were trained to avoid foot shock in a T-maze. Mice were trained until they made their first avoidance. Memory retention of this task was then tested 1 week later. The results indicated that P8, but not R1, female mice whether intact or ovariectomized, showed an age-related learning impairment. This impairment was more apparent in ovariectomized mice, as ovariectomy was associated with a significant reduction in the mean trials to make an avoidance in all groups except 12-month P8 females. Of greatest interest was the absence of any age-related impairment of retention in P8 females. In several previous studies, SAM-P8, but not R1, males showed an age-related impairment of learning and memory. These results indicate that age-related impairment of memory in P8 mice may be inherited in a sex-related manner, and suggests that the mechanisms involved in the development of impaired learning and memory are different.

Aging↗

PubMed1995

Effects of amylin on appetite regulation and memory.

Amylin has been demonstrated to decrease food intake in mice and rats. Amylin is effective when delivered both peripherally and directly into the central nervous system. Amylin's effect on food intake is not aversive. Amylin may produce its effect on food intake by modulating nitric oxide synthesis. Calcitonin gene related peptide also decreases food intake after peripheral and central administration. In addition, amylin has been demonstrated to modulate memory at both peripheral and central sites.

Amyloid↗

PubMed1994

An amyloid beta-protein fragment, A beta[12-28], equipotently impairs post-training memory processing when injected into different limbic system structures.

Previously, amyloid beta-protein (A beta) fragments 1-28, 12-28 and 12-20 were found to impair retention in mice when injected intracerebroventricularly after footshock active avoidance training. We now have measured the dose-dependence of amnestic effects of peptide 12-28 stereotactically injected into amygdala, caudate, hippocampus, mammillary bodies and septum, which limbic structures are known to be involved in memory processing and into the medial thalamus, which largely is involved in sensory processing during training. Peptide 12-28 impaired retention with remarkably similar efficacy when injected into limbic structures but was not at all amnestic upon thalamic injection. Present results together with those in the literature lead us to suggest that A beta may exert dysregulatory cognitive effects by incoordination of K(+)-channel function in neurons, glia and endothelial cells.

Amino Acid Sequence↗

PubMed1994

Topography of a binding site for small amnestic peptides deduced from structure-activity studies: relation to amnestic effect of amyloid beta protein.

Four peptides homologous to amyloid beta protein containing the Val-Phe-Phe (VFF) sequence administered intracerebroventricularly after training caused amnesia for footshock active avoidance training in mice. Results with VFF and other peptides containing VFF or portions thereof were used to generate a topographic map for a hypothetical binding surface for amnestic peptides, termed Z. Effects on retention of footshock active avoidance training were rationalized in terms of fit to Z, making possible design of potential memory-modulating peptidic and nonpeptidic substances. Three peptides that neither improved nor impaired retention blocked the amnestic effects of beta-(12-28), a peptide homologous to amyloid beta protein, opening the way to development of substances that can antagonize the neurotoxic effects of amyloid beta protein on neural structures and thus attenuate symptoms and progression of Alzheimer disease.

Amino Acid Sequence↗

PubMed1994

Endothelin-C-terminal hexapeptide increases grooming in mice.

Grooming behavior has been considered a response to stress, and a number of stress-related peptides have been demonstrated to modulate grooming behavior. In the experiments reported here, endothelin-C-terminal hexapeptide containing amino acid residues 16-21, ET[16-21], increased grooming with a maximum effect at 0.75 microgram. ET[16-21] did not significantly alter eating or locomotor behavior. Both alpha-helical CRF (10 micrograms) and neuropeptide Y (1 microgram) inhibited the grooming produced by ET[16-21].

Animals↗

PubMed1994

Effects of localized injections of neuropeptide Y antibody on motor activity and other behaviors.

Neuropeptide Y (NPY) was shown to increase feeding when injected into the hypothalamus. Neuropeptide Y antibody (aNPY) decreased feeding in the ventromedial area of the hypothalamus as well as when it was injected into the ventromedial or ventrolateral areas of the thalamus, but not when injected into other hypothalamic areas. The decrease in feeding produced by aNPY in the hypothalamus was associated with a sterotypic increase in general activity in the hypothalamus, circling in the ventromedial thalamic area, and barrel rolling in the ventrolateral thalamic area. Neuropeptide Y antibody also reduced by 54-73% the time it required for mice to recover from anesthesia. The marked increase in stereotypic activity and enhanced recovery from anesthetic suggest that blocking endogenous NPY released the brain areas from inhibitory control. These studies further confirm a physiological role for NPY in the central nervous system.

Anesthetics↗

PubMed1994

Allele specific inactivation of insulin 1 and 2, in the mouse yolk sac, indicates imprinting.

Genomic imprinting, gene inactivation during gametogenesis, causes maternal and paternal alleles of some genes to function unequally. We examined the possibility of imprinting in insulin genes because the human insulin gene (ins) and its mouse homologue (ins2) are adjacent to the known imprinted genes, igf2 and H19, and because imprinting has been implicated in the transmission of an ins linked risk for Type I diabetes. We show, by single strand conformational polymorphism (SSCP) analysis of cDNAs from parents and progeny of interspecies mouse crosses, that insulin genes are imprinted. While both alleles of the two mouse insulin genes were active in embryonic pancreas, only paternal alleles for both genes were active in the yolk sac.

Alleles↗