Disruptive effects of lateral hypothalamic stimulation on the lick-interrupt cycle in rats

Consummatory licking at a water spout was compared with licking at a dry spout maintained by electrical hypothalamic stimulation in the same rats. Both forms of licking, recorded photoelectrically, were maintained on a fixed ratio 8 schedule. Duration of reinforcement delivery was equated [300 ms]. A computer analysis of the temporal distribution of licks in each 1024 ms period from onset of reinforcement revealed that lateral hypothalamic stimulation decreased the occurrence of licking and disrupted the normally synchronous pattern of this behaviour. An analysis of the effects of delivering lateral hypothalamic stimulation contingent on water-maintained licking revealed that this effect of stimulation was clearly current-dependent. It is proposed that differences in licking rates maintained by water and by electrical hypothalamic stimulation, respectively, are due to response interference in the latter case. This interference effect is also proposed to be a major factor underlying higher reward thresholds for self-stimulation when licking is the operant response.     

Effects of ventromedial and lateral hypothalamic stimulation on chemically-induced liver injury in rats

The effects of hypothalamic stimulation on experimental liver injury induced by carbon tetrachloride (CCl4) or dimethylnitrosamine (DMN) were studied in rats, by measuring plasma alanine aminotransferase (ALT) activity as an index of acute liver injury. Electrical stimulation of the ventromedial hypothalamus (VMH) in CCl4-treated rats caused a marked increase in plasma ALT activity, accompanied by a significant decrease in ALT activity in the liver, although CCl4 treatment alone had no significant effect on plasma ALT activity. A similar effect of VMH stimulation on plasma ALT activity was observed in rats treated with DMN, another hepatotoxic chemical. No such exaggerated effect of VMH stimulation on plasma ALT activity was observed after stimulation of the lateral hypothalamic area (LH). Surgical sympathetic denervation of the liver greatly suppressed the increase in plasma ALT activity after CCl4 injection and VMH stimulation. Measurement of regional blood flow indicated that VMH stimulation did not produce a significant change in blood flow to the liver. These results suggest that the VMH is involved in the progress of chemically-induced liver injury through activation of the sympathetic nerve (hepatic nerves), possibly by affecting liver metabolism more than the blood flow change to the liver.     

Effect of electrical field stimulation on insulin and glucagon secretion from the pancreas of normal and diabetic rats.

The effect of electrical field stimulation (EFS) on insulin (INS) and glucagon (GLU) secretion from normal and diabetic rat pancreas is poorly understood. In our study, EFS (5-20Hz, 50 V amplitude and 1.0 ms pulse width), when applied alone, resulted in a significant (p<0.05) increase in INS secretion from the pancreas of both normal and diabetic rats. Atropine (10(-5) M) did not inhibit the EFS (5 Hz)-evoked INS secretion in normal pancreas and failed to alter the effect of EFS (10-20 Hz) on INS secretion from the pancreas of both normal and diabetic rats. Propranolol (Prop) inhibited INS secretion to below basal level in the presence of EFS (5 Hz) but not at EFS (10- 20 Hz). Tetrodotoxin (TTX) also significantly (p = 0.002) inhibited INS secretion from normal pancreas in the presence of EFS (5-20 Hz). The decrease in insulin secretion observed when pancreatic tissue fragments were incubated in Prop and TTX in the presence of EFS was reversed by yohimbine (10(-5) M). In contrast, TTX did not significantly modify INS secretion from diabetic pancreas in the presence of EFS. EFS (5-20 Hz) significantly (p<0.05) increased GLU release from normal and diabetic rat pancreas when applied alone. Neither atropine, Prop nor TTX significantly modified GLU release from the pancreas of either normal or diabetic rats. This suggests that GLU secretion may be controlled through a different pathway. The EFS-evoked INS and GLU secretion is probably executed via different mechanisms. These mechanisms include 1) activation of cholinergic nerves by EFS; 2) EFS of alpha- and beta-adrenergic nerves; 3) activation of non-adrenergic non-cholinergic pathway by EFS; 4) EFS-induced depolarization and subsequent action potential in pancreatic endocrine cells and 5) electroporosity caused by EFS-induced membrane permeability. All of these effects may be summative. In conclusion, EFS (5-20 Hz), when applied alone, can evoke significant increases in INS and GLU secretion from the pancreas of both normal and diabetic rats. Insulin secretion is controlled via alpha-2 adrenergic (inhibition) and beta-adrenergic (stimulation) receptors. Glucagon secretion is enhanced by alpha2 adrenergic stimulation.     

电刺激下丘脑外侧区对大鼠胃缺血-再灌注损伤的影响

采用夹闭大鼠腹腔动脉30min,松开动脉夹血流复灌60min的胃缺血－再灌注损伤(gastric ischemia reperfusion injury,GI-RI)模型,用电和化学刺激,电损毁的方法观察了下丘脑外侧区（lateral hypothalamic area,LHA)对GI－RI的影响,并对其机制进行了初步分析,结果表明：（1）以0．2,0．4,0．6mA的电流强度刺激LHA,GI－RI均显著加重,且有强度－效应依赖关系,LHA内注射L－谷氨酸（L－Glu)后,对LI－RI的效应与电刺激相似,电损毁双侧LHA,GI－RI面积较电刺激组明显减小;（2）损毁双侧背侧迷走复合体（dorsal vagal complex,DVC)或切损毁是LHA,GI－RI面积较电刺激组明显减小;（2）损 侧背侧迷走复合体（dorsal vagal complex,DVC)或切断膈下迷走神经均能取消电刺激LHA加重GI－RI的作用。（3）电刺激LHA使缺血－再灌注（ischemia-reperfusion,I-R)的胃粘膜丙二醛（MDA）含量升高,超氧化物歧化酶（SOD）活性降低;（4）电刺激LHA使I－R的胃液量和总酸排出量增多,而酸度,胃蛋白酶活性和胃壁结合粘液量等无明显改变,结果提示;LHA是对GI－RI具有加重作用的中枢部位,其作用是通过DVC及迷走神经下传的,电刺激LHA加重GI－RI的作用与胃粘膜MDA含量增加,SOD活性降低,胃液量和总酸排出量增加等因素有关,而似与酸度,胃蛋白酶活性,胃壁结合粘液量等因素无关。     

Effect of leptin on the acute feeding-induced hypothalamic serotonergic stimulation in normal rats

Both hypothalamic serotonin and leptin reduce energy intake and stimulate expenditure. There are evidence that increased serotonin metabolism may be involved in leptin actions. Using microdialysis, we directly assessed the effect of an intracerebroventricular leptin injection on 5-HT release in the lateral hypothalamus of normal rats. When LH microdialysates were collected in the absence of food intake, neither artificial cerebrospinal fluid (CSF) nor 10 microg leptin i.c.v. caused significant variations in 5-HT release, measured for 2 h post-injection, at 20-min periods. When food was ingested after CSF, 5-HT release increased significantly, with a maximal elevation of 51+/-16% above baseline occurring at the 100-120 min post-injection interval. Leptin inhibited food intake (-75% at 0-20 min and -73% at 20-40 min) while it accentuated the food-induced serotonergic activation. At the 0-20 min interval, serotonin release was significantly higher after leptin (42+/-12% above baseline) than after CSF (6+/-5%) and the maximal increase after leptin was of 126+/-53% above baseline (100-120 min, p>0.05 vs. CSF). These observations indicate that leptin probably interacts with the serotonergic-stimulating mechanisms elicited by food intake, intensifying them. The additional serotonergic activation induced by leptin may be significant for the hormone effects on energy balance.     

Inhibitory effect of obestatin on glucose-induced insulin secretion in rats

Obestatin is a bioactive peptide encoded by the same gene that encodes ghrelin. Our aim was to investigate the effect of obestatin on insulin secretion. We evaluated the effects of obestatin on insulin secretion from rat islet cells which had been incubated overnight in the presence of 8.3, 11.1, and 22.2 mmol/l of glucose. In vivo, the serum levels of glucose and insulin were measured 0, 1, 5, 10, 20, 40, and 60 min after the intravenous administration of saline or glucose (1 g/kg), with or without obestatin, and the area under the 60 min curve of insulin concentration (AUC_insulin) was calculated. Obestatin (0.01-100 nmol/l) inhibited insulin secretion from rat islets in a dose-dependent fashion. In vivo, when administered intravenously to rats together with glucose, obestatin (10, 50, and 250 nmol/kg) inhibited both the rapid 1-min insulin response and the AUC_insulin in a dose-dependent fashion. Our data demonstrate that under glucose-stimulated conditions, exogenous obestatin acts as a potent inhibitor of insulin secretion in anaesthetized rats in vivo as well as in cultured islets in vitro.     

Direct effect of corticosterone upon insulin secretion studied by three different techniques.

The immediate effect of corticosterone upon insulin secretion rates estimated by three different techniques (perfusior of isolated rat pancreas and perifusion or incubation of isolated islets of Langerhans) was studied for one hour. Three corticosterone concentrations were used: 0.02, 0.2 or 20 mg/l. With 4.2 mmol/l glucose, corticosterone did not affect insulin secretion, whereas, with a stimulating glucose concentration (16.7 mmol/l), insulin secretion was inhibited by the three corticosterone concentrations tested during incubation experiments, and by only the two physiological ones (0.02 and 0.2 mg/l) during islets perifusion and pancreas perfusion experiments. Moreover the inhibitory effect appeared more rapid with perifused islets than perfused pancreas, where only the second insulin secretory phase was disturbed.     

Gastric electrical stimulation parameter dependently alters ventral medial hypothalamic activity and feeding in obese rats

Gastric electrical stimulation (GES) has been used to treat obesity with unclear mechanisms and limited parameter ranges. This study explores effects of GES parameters on ventral medial hypothalamic (VMH) activity, feeding, and body weight in diet-induced obese (DIO) rats. For experiment 1, discharge rates were recorded in 39 gastric distension-responsive (GD-R) neurons in 12 DIO rats. Basal rates were compared with rates under GES using varied pulse amplitudes, widths, frequencies, and train-on times. For experiment 2, a crossover experiment in 16 DIO rats measured food intake and weight effects of GES pulse width, the parameter with the steepest neuronal response gradient in experiment 1. Treatments were sham and 0.5-, 2.0-, and 5.0-ms pulse GES. In experiment 1, 11 of 13 GES parameter sets tested produced significantly (P < 0.05) altered discharge rates of GD-R neurons. Increases in pulse amplitude (P < 0.05) and width (P < 0.0001) produced significant upward linear trends in response over the range tested, with the trend being strongest for pulse width. In experiment 2, over 4 days of 0.5-, 2.0-, and 5.0-ms GES treatment, food intake was 9.6% (P < 0.05), 21.0% (P < 0.0001), and 47.3% (P < 0.0001) lower than under sham-GES, whereas body weight changes were 0.7 (P = 0.48), 2.2 (P < 0.05), and 3.5 (P < 0.002) percentage points lower, respectively. We concluded that GES pulse width increases had the largest effect on VMH neuronal activity, and these effects were paralleled by pulse width-dependent reductions in food intake and body weight. Lengthening pulse width beyond the range used in prior clinical studies may be critical to making GES a viable obesity treatment.     

Separate hypoglycaemic thresholds for gastric acid and pepsin secretion following insulin or posterior hypothalamic stimulation.

The level of hypoglycaemia required to elicit gastric secretion of acid and pepsin was studied in urethane-anaesthetized rats. Hypoglycaemia was induced by intravenous injection of insulin or by electrical stimulation of the posterior hypothalamus. In each case the blood glucose values below which gastric secretion was stimulated were significantly higher for pepsin than for acid secretion. This consistently resulted in the onset of pepsin secretion in advance of the onset of acid secretion. These observations suggest that the production of the different components of the gastric juice was under the influence of either separate hypothalamic glucoreceptors, or a single set of glucoreceptors able to respond selectively to different blood glucose levels.     

L-arginine stimulates insulin secretion from the pancreas of normal and diabetic rats

Summary. Several reports have shown that nitric oxide (NO) stimulates glucose-induced insulin secretion in the pancreas of normal rat but the effect of L-arginine (a NO donor) on insulin secretion from the pancreas of diabetic pancreas is unknown. Fragments of pancreatic tissue from normal and diabetic rats were incubated for 45 min in Krebs solution containing 100 mM L-arginine. The supernatant was subsequently analyzed for the insulin content using radioimmunoassay technique. L-arginine evoked large increases in insulin secretion from the pancreas of diabetic rat. The insulin secreted from the pancreas of diabetic rat was numerically but not significantly lower compared to that of normal rat pancreas. In conclusion, L-arginine, a nitric oxide donor stimulates insulin secretion from the pancreas of diabetic rats. Received October 3, 2000 Accepted November 10, 2000     

Lack of effect of dynorphin on consummatory behaviors in obese and normal rats

The possible role of dynorphin, an endogenous opioid peptide, in the regulation of appetite was studied in male genetically-obese (Zucker) rats and their litter mates of normal weight. Eighteen pairs were divided into 3 treatment groups: control, acutely dynorphin-treated (5 mg/rat), and implanted with Alzet mini-osmotic pumps containing 2 mg dynorphin to be delivered at a rate of 10 micrograms/hr. Body weights and food and water consumption were determined daily for 7 days. Body weights were not significantly changed from initial values for any treatment group. Food and water consumption per 24 hours were generally the same for obese rats and their normal littermates, but in terms of consumption per 100 g body weight, the obese rats generally consumed less food and water. Neither acute nor continuous dynorphin administration affected consummatory levels.     

Cephalic phase of insulin secretion in obese women

The cephalic phase of reflex insulin secretion was studied in normoglycemic and normoinsulinemic female patients, obese (more than 30% over IBW) and normal subjects. After an overnight fasting, at the sight of breakfast food, the obese group did not present a cephalic response. Their glycemia and insulinemia levels remained at base levels. One minute after visual and olfactory stimulation, a statistically significant rise in immunoreactive insulin levels which was maintained throughout the test, was observed in the control group.