Evidence of conditioned drinking following cholinergic stimulation of the hypothalamus.
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Animals↗
Biomedical subjects
W T Chance
Publications and source records attributed to W T Chance.
The discriminative stimulus properties of nicotine, d-amphetamine and morphine in dopamine depleted rats.
Rats permanetly depleted of central dopamine (DA) via 6-OHDA neonatally were studied in relation to their ability to discriminate various psychoactive drugs from saline using a two-bar operant procedure. DA rats learned to discriminate both morphine (4 mg/kh) and d-amphetamine (0.9 mg/kg) as rapidly as controls and exhibited similar sensitivity when dose-generalization studies were conducted. However, DA rats appeared to tolerate higher doses of the same drug better than controls indicating that they were more tolerant to behavioral disruption. It was suggested that the behavioral disruption. It was suggested that the behavioral disruption usurons. DA rats had more difficulty learning to discriminate nicotine than controls. In fact the peripherally injected nicotine stimulus generalized to hippocampal (Hp) injections in controls but was not observed in DA rats. These data suggest that part of nicotine's discriminative stimulus properties may be contingent upon the integrity of a Hp-DA connection.
Animals↗
Cholecystokinin-induced hypophagia is not potentiated by cancer anorexia.
The interaction of cholecystokinin-induced hypophagia with cancer anorexia was investigated within both acute (Walker 256 carcinosarcoma) and chronic (methylcholanthrene-induced sarcoma) animal models of cancer anorexia. Cholecystokinin octapeptide (CCK8) effectively reduced feeding for at least one hour in both groups of rats. However, this peptide was no more effective in inducing hypophagia in tumor-bearing rats than in nontumor-bearing control rats when tested at a variety of doses (0.5, 5.0 and 50.0 microgram/kg; IP) both prior to and after the development of anorexia. Therefore, these data do not support a role of cholecystokinin in the mediation of experimental cancer anorexia, since no synergism of CCK8-induced hypophagia with the anorexia was observed.
Animals↗
Pertussis toxin inhibits neuropeptide Y-induced feeding in rats.
Neuropeptide Y (NPY) is the most powerful peptide drug stimulating feeding in rats. Rats with paraventricular hypothalamic (PVH) cannulae were used to investigate the mechanisms involved in NPY-induced feeding. Consistent with previous reports, injection of 2 micrograms of NPY into the PVH significantly increased the cumulative food intake over 1-, 2- and 4-hr periods. Ad lib feeding decreased significantly two days after pertussis toxin (PT) administration, but recovered to nearly normal levels on the fourth day. PT had no immediate effect on NPY-induced feeding; however, four days after PT was injected NPY (2 micrograms) did not increase the food intake compared to control. In vitro investigations showed that isoproterenol-stimulated adenylate cyclase activity in the hypothalamus of control rats was inhibited by NPY. In PT-treated rats, however, no inhibition of cAMP production was observed. These results suggest that cAMP may mediate NPY-induced feeding and that a PT-sensitive G protein may be involved in this signal transduction.
Adenylate Cyclase Toxin↗
Salmon pancreatic polypeptide exhibits neuropeptide Y-like activities in rats.
Salmon pancreatic polypeptide (sPP) is a 36 residue peptide amide isolated from salmon pancreas. It has 83% sequence identity with porcine neuropeptide Y (NPY). To confirm the sequence and obtain sufficient quantity of peptide for biological investigations, sPP was synthesized by automated t-Boc solid phase synthesis. The purified product had the expected amino acid composition, primary structure and mass, and was chemically and biologically indistinguishable from natural sPP. Investigation of its biological properties revealed that, like NPY, sPP increased blood pressure and decreased heart rate in anesthetized rats in a dose-dependent manner. There was no significant difference in the responses of NPY and sPP. Furthermore, administration of sPP directly into the hypothalamus of rats induced a feeding response comparable to that induced by NPY. Based on these investigations it may be suggested that synthetic and natural sPP are identical, and that sPP can express NPY-like activities in mammals presumably by interacting with the receptors of NPY.
Amino Acid Sequence↗
Syntheses, structures and anorectic effects of human and rat amylin.
Amylin, a 37-residue polypeptide with a single disulfide bond originally isolated from the pancreas of type-II diabetic patients, has been shown to cause peripheral insulin resistance and to attenuate the inhibition of hepatic glucose output by insulin. We have also shown that amylin is present in the rat hypothalamus and that it inhibits food intake by rats. In order to further investigate the anorectic properties we synthesized both human and rat amylin by the solid phase method and purified to homogeneity in an overall yield of 10-20%. Structural analyses indicated that human amylin exhibited predominantly a beta-sheet structure at both acidic and alkaline pH, whereas no ordered structure was evident in the case of rat amylin. Intrahypothalamic injection of rat amylin resulted in a potent dose-dependent inhibitory effect on the food intake by rats adapted to eat their daily ration of food in an eight-hour period. Human amylin was less effective as an anorectic agent. Furthermore, rat amylin completely blocked the potent orexigenic effect of neuropeptide Y (NPY). These investigations show that there is a fundamental difference in the secondary structures of human and rat amylin and that rat amylin is a potent inhibitor of both basal and NPY-induced feeding by rats.
Amino Acid Sequence↗
Tests of adipsia and conditioned taste aversion following the intrahypothalamic injection of amylin.
Intrahypothalamic injection of amylin (AMY) was shown to reduce the intake of rat chow and water for 8 and 4 h, respectively, in schedule-fed rats. Amylin also reduced water intake to a much lesser degree in 24-h water-deprived rats. A test of the ability of AMY to form a conditioned taste aversion yielded no change in saccharin preference, as compared to controls treated with vehicle. These results suggest that although AMY has adipsic effects, the reduction in water is not of sufficient magnitude to cause the anorexia. In addition, the failure of AMY to support a conditioned taste aversion suggests that AMY does not cause anorexia by inducing malaise. Therefore, in addition to other metabolic effects, AMY may be involved in the control of food and water intake.
Amyloid↗
Some basic observations concerning experimental cancer anorexia.
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Animals↗
Antagonism of NPY-induced feeding by pretreatment with cyclic AMP response element binding protein antisense oligonucleotide.
Although second messenger systems subserving neuropeptide Y (NPY)-mediated behaviors have been identified for a variety of receptors in several tissues, downstream signaling events are not well known. The nuclear binding protein, cyclic AMP response element binding protein (CREB) appears to be a transcription factor that is activated following injection of NPY into rat hypothalamus. To allow determination of the functional nature of CREB mediation of NPY-induced feeding, injection cannulae were implanted into the perifornical hypothalamus of 18 rats. Treatment of seven rats with CREB antisense oligonucleotide (15 ug) significantly antagonized NPY feeding for up to one week after treatment, while similar injections of CREB sense oligonucleotide (15 ug) had no significant effect on NPY-induced feeding. Two weeks after the antisense oligonucleotide treatment, feeding was once again elicited by the injection of NPY. Hypothalamic CREB protein was also reduced significantly two days after the CREB antisense oligonucleotide treatment. These results suggest that activation of CREB, probably through phosphorylation, may be a necessary event for the signal transduction of NPY stimulation into feeding behavior.
Animals↗
Glucagon-like peptide-2 stimulates gut mucosal growth and immune response in burned rats.
Major burn trauma often leads to reduced gut barrier function, immunosuppression, and increased bacterial translocation. We hypothesized that treatments that maintain normal gut after burn trauma will also reduce immunosuppression and bacterial translocation. Recent studies suggest that treatment with glucagon-like peptide-2 (GLP-2), which is synthesized in the intestine and released after food intake, elicits mucosal hyperplasia in the small intestine of rodents and prevents parenteral nutrition-induced gut hypoplasia. Therefore, we determined whether GLP-2 would prevent loss of gut integrity after major burn trauma. Osmotic minipumps were implanted into the peritoneum of 22 adult, male, Sprague-Dawley rats to infuse saline (10 microl/hr; n = 14) or GLP-2 (1 microg/hr; n = 8). On the next day 8 saline-infused and 8 GLP-2-infused rats were subjected to a 25 sec duration 30% BSA open flame burn, with the remaining rats serving as sham-burn controls. Five days after burn, all rats were killed. Gut protein was assessed, and immunosuppression was estimated by the mitogenic response of cultured splenocytes to phytohemagglutinin, pokeweed, and concanavalin A. Bacterial translocation was determined by culturing the mesenteric lymph nodes. Although protein content was significantly decreased in the ileum of burned rats treated with saline, the burned rats treated with GLP-2 exhibited significant increases in protein levels in duodenum, jejunum. and ileum. Colon protein was not affected by GLP-2 infusion. Saline-treated burned rats also exhibited immunosuppression, as suggested by significantly decreased responses to each of the mitogens. Infusion of GLP-2 normalized the response by the burned rats to each of the mitogens. Lymph nodes taken from sham rats exhibited no colony forming units, whereas in both of the burn groups, 50% of the cultures were positive. However, more aggressive colonization may have occurred in the saline-infused burned rats as compared with the GLP-2-infused burned rats (81 +/- 63 vs 3 +/- 2 colony forming units). These results suggest that GLP-2 may stimulate gut mucosa and reduce immunosuppression in burned rats. However, there does not seem to be a statistically significant positive effect of GLP-2 on bacterial translocation. Thus, improving small intestine mucosa may increase immunity while being ineffective against bacterial translocation.
Analysis of Variance↗
Amino acid requirements of a rat sarcoma as determined by a stem cell assay.
Knowledge of the amino acid requirements of a neoplasm is valuable in determining optimal nutritional support and antineoplastic therapy for the tumor-bearing host. The standard human tumor stem cell assay (HTSCA) was modified by reducing an individual amino acid below the normal plasma concentration of the Fischer 344 rat. All other amino acids were maintained at levels sufficient for normal HTSCA tumor colony growth. Twenty-two amino acids were tested at a mean concentration of 12% (range 3% to 35%) of their normal plasma level. Results indicated that all amino acids except L-glutamine and L-asparagine were present in sufficient quantity for normal tumor growth. Dose-response curves have shown more than 70% inhibition of tumor growth with a glutamine concentration of 50% and an asparagine concentration of 25%. Glutamine and asparagine levels of 4% and 1%, respectively, resulted in 100% inhibition. The data indicate that rat sarcoma stem cells are sensitive to decreased glutamine and asparagine concentrations.
Amino Acids↗
Response of tumor and host to hyperalimentation and antiglutamine treatments.
In two experiments, treatment of tumor-bearing (TB) rats with the glutamine antimetabolite, acivicin, reduced tumor growth during 14 days of total parenteral nutrition (TPN) that supplied 120% and 130% of the nutritional intake of non-TB control rats. The acivicin treatment or combination of acivicin with TPN produced increased carcass weights and decreased tumor/carcass ratios. Significant muscle saving was observed in TB rats receiving TPN or TPN and acivicin as compared to acivicin-treated TB rats maintained on rat chow. Tumor growth was not stimulated by TPN at 130% of ad libitum. intake with a calorie/nitrogen ratio of 102:1. However, when the calorie/nitrogen ratio was increased to 143:1, tumor growth was increased by TPN at 120% of ad libitum. intake. These results suggest that acivicin may prove useful in the stabilization of tumors in situations where tumor growth may be stimulated, such as during TPN.
Animals↗
Total parenteral nutrition, glutamine, and tumor growth.
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Animals↗
Clenbuterol treatment increases muscle mass and protein content of tumor-bearing rats maintained on total parenteral nutrition.
Treatment of tumor-bearing (TB) and control rats with the anabolic beta-2 agonist drug clenbuterol (CLE) for 14 days reduced food intake for 4 days initially. Feeding was increased in anorectic TB rats, however, during the last 7 days of drug administration. Since minimal muscle savings were observed in chow-fed TB rats treated with CLE, the anabolic effects of this drug were investigated in a second experiment on TB rats maintained on total parenteral nutrition (TPN). Sixteen days after the subcutaneous transplantation of methylcholanthrene-induced sarcomas rats was begun on a 2-week schedule of TPN. One group of these rats was treated daily for 14 days with CLE, while the remaining rats received injections of saline. Additional groups of TB and nonTB rats were maintained on rat chow for this period and treated with saline. Although TB rats maintained on rat chow or TPN and treated with saline exhibited significantly decreased gastrocnemius muscle weight and protein content, treatment of TB-TPN rats with clenbuterol normalized muscle mass and increased muscle protein content significantly and increased plasma concentrations of branched-chain amino acids. These results indicate that although nutritional support of TB organisms does not result in protein repletion, the addition of an anabolic drug renders the nutritional support highly efficacious.
Animals↗
Parenteral vs enteral nutrition in tumor-bearing rats.
The development of cachexia may complicate cancer therapy, yet controversy exists concerning its nutritional management. For example, use of total parenteral nutrition (TPN) may not be appropriate because of gut atrophy, possible stimulation of tumor growth, and lack of total host protein repletion. In the present experiment, host and tumor responses were compared after identical parenteral or enteral nutritional supplementation (EN). Eighteen days after subcutaneous inoculation of adult male Fischer-344 rats with fresh methylcholanthrene-induced sarcoma (tumor-bearing [TB] rats), catheters were placed into either the external jugular vein or the stomach. Four days later, rats were started on an 11-day course of either TPN or EN with a Freamine-III-based formula (amino acids = 6%, dextrose = 21.5%, lipid = 1.5%). When the rats were killed, there was no difference in tumor weight between the various TB groups. Carcass weight was increased significantly in both the TB-TPN and TB-EN groups, and there was an elevation in gastrocnemius protein content in both groups compared with the TB-rat food group. Small intestine protein was preserved in the TB-EN group to the level observed in the control-rat food animals. Total lipids in the liver were increased in both TB-TPN and TB-EN groups; however, the magnitude of the increase was less in the TB-EN animals. Neither treatment resulted in complete protein repletion of tumor-bearing rats. EN may be more appropriate than TPN in that gut mass is preserved. The maintenance of gut mucosa may prove to be beneficial in the treatment of the depleted, immunocompromised, and metabolically stressed host.
Animals↗
Central and peripheral effects of sculpin pancreatic polypeptide and anglerfish peptide Y in rats.
Sculpin pancreatic polypeptide (PP) and anglerfish peptide Y (aPY-amide) are 36-residue peptide amides isolated from the pancreas of the respective species of fish. They are 86% homologous, and exhibit about 65% homology to porcine neuropeptide Y (NPY) and peptide YY (PYY). This homology to mammalian peptides suggests that the fish peptides may constitute a good model system for structure-activity investigations. We therefore synthesized sculpin PP and aPY-amide by the solid phase method and investigated their central and peripheral effects on feeding and blood pressure, respectively. These investigations revealed that both peptides, like NPY, increased blood pressure and induced feeding in rats, presumably by interacting with receptors of NPY. Although there were comparable responses to both peptides on feeding, aPY-amide exhibited a more potent pressor effect than sculpin PP. These observations suggest that the central and peripheral effects of NPY may be mediated by different subclasses of NPY receptors.
Amino Acid Sequence↗
Neurotransmitters and food intake.
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Animals↗