Effect of Vagotomy and Sympathectomy on the Feeding Responses Evoked by Intra-Aortic Cholecystokinin-8 in Adult Male Sprague Dawley Rats.

The vagus nerve and the celiaco-mesenteric ganglia (CMG) are required for reduction of meal size (MS) and prolongation of the intermeal interval (IMI) by intraperitoneal (ip) sulfated cholecystokinin-8 (CCK-8). However, recently we have shown that the gut regulates these responses. Therefore, reevaluating the role of the vagus and the CMG in the feeding responses evoked by CCK is necessary because the gut contains the highest concentration of enteric, vagal and splanchnic afferents and CCK-A receptors, which are required for reduction of food intake by this peptide, compared to other abdominal organs. To address this necessity, we injected sulfated CCK-8 (0, 0.1, 0.5, 1 and 3 nmol/kg) in the aorta, near the gastrointestinal sites of action of the peptide, in three groups of free-feeding rats (n = 10 rats per group), subdiaphragmatic vagotomy (VGX), celiaco-mesenteric ganglionectomy (CMGX) and sham-operated, and recorded seven feeding responses. In the sham group, CCK-8 reduced MS (normal chow), prolonged the intermeal interval (IMI, time between first and second meals), increased satiety ratio (SR, IMI/MS), shortened duration of first meal, reduced total (24 hrs) food intake and reduced number of meals relative to saline vehicle. Vagotomy attenuated all of the previous responses except IMI length and SR, and CMGX attenuated all of those responses. In conclusion, the feeding responses evoked by sulfated CCK-8 require, independently, the vagus nerve and the CMG.

Combined gastrin releasing peptide-29 and glucagon like peptide-1 reduce body weight more than each individual peptide in diet-induced obese male rats.

To test the hypothesis that gastrin releasing peptide-29 (GRP-29) combined with glucagon like peptide-1 (7-36) (GLP-1 (7-36)) reduce body weight (BW) more than each of the peptides given individually, we infused the two peptides (0.5nmol/kg each) in the aorta of free feeding, diet-induced obese (DIO) male Sprague Dawley rats once daily for 25days and measured BW. We found that GRP-29 and GLP-1 reduce BW, GRP-29 reduced it more than GLP-1 and GRP-29+GLP-1 reduce BW more than each peptide given alone. This reduction was accompanied by decrease 24-hour food intake (normal rat chow), meal size (MS), duration of first meal and number of meals, and increase latency to the first meal, intermeal interval (IMI) and satiety ratio (IMI/MS, amount of food consumed per a unit of time). Furthermore, the peptides and their combination decreased 24-hour glucose levels. In conclusion, GRP-29+GLP-1 reduce BW more than each of the peptides given individually.

Peptide Tyrosine Tyrosine 3-36 Reduces Meal Size and Activates the Enteric Neurons in Male Sprague-Dawley Rats.

BACKGROUND: Peptide tyrosine tyrosine 3-36 (peptide YY 3-36 or PYY 3-36) reduces food intake by unknown site(s). AIM: To test the hypothesis that the gastrointestinal tract contains sites of action regulating meal size (MS) and intermeal interval (IMI) length by PYY 3-36. METHODS: Peptide YY 3-36 (0, 1, 5, 10 and 20 nmol/kg) was injected in the aorta, the artery that supplies the gastrointestinal tract, prior to the onset of the dark cycle in free feeding male Sprague-Dawley rats and food intake was measured. Then, PYY 3-36 (25 nmol/kg) was injected intraperitoneally in these rats and Fos-like immunoreactivity (Fos-LI, a marker for neuronal activation) was quantified in the small intestinal enteric neurons, both myenteric and submucosal, and the dorsal vagal complex (DVC) of the hindbrain. RESULTS: PYY 3-36 reduced first MS, decreased IMI length, shortened duration of first meal and increased Fos-LI in enteric and DVC neurons. However, PYY 3-36 failed to change the size of the second meal, satiety ratio, latency to first meal, number of meals and 24 h intake relative to saline control. CONCLUSION: The gastrointestinal tract may contain sites of action regulating MS reduction by PYY 3-36.

Exogenous glucagon-like peptide-1 reduces body weight and cholecystokinin-8 enhances this reduction in diet-induced obese male rats.

The sites of action regulating meal size (MS) and intermeal interval (IMI) length by glucagon like peptide-1 (7-36) (GLP-1 (7-36)) and cholecystokinin-8 (CCK-8) reside in the areas supplied by the two major branches of the abdominal aorta, celiac and cranial mesenteric arteries. We hypothesized that infusing GLP-1 near those sites reduces body weight (BW) and adding CCK-8 to this infusion enhances the reduction. Here, we measured BW in diet-induced obese (DIO) male rats maintained and tested on normal rat chow and infused with saline, GLP-1 (0.5nmol/kg) and GLP-1+CCK-8 (0.5nmol/kg each) in the aorta once daily for 21days. We found that GLP-1 and GLP-1+CCK-8 decrease BW relative to saline vehicle and GLP-1+CCK-8 reduced it more than GLP-1 alone. Reduction of BW by GLP-1 alone was accompanied by decreased 24-h food intake, first MS, duration of first meal and number of meals, and an increase in latency to first meal. Reduction of BW by the combination of the peptides was accompanied by decrease 24-h food intake, first MS, duration of first meal and number of meals, and increase in the IMI length, satiety ratio and latency to first meal. In conclusion, GLP-1 reduces BW and CCK-8 enhances this reduction if the peptides are given near their sites of action.

Infusion of exogenous cholecystokinin-8, gastrin releasing peptide-29 and their combination reduce body weight in diet-induced obese male rats.

We hypothesized that exogenous gastrin releasing peptide-29 (GRP-29), cholecystokinin-8 (CCK-8) and their combination reduce body weight (BW). To test this hypothesis, BW was measured in four groups of diet-induced obese (DIO) male rats infused in the aorta (close to the junctions of the celiac and cranial mesenteric arteries) with saline, CCK-8 (0.5 nmol/kg), GRP-29 (0.5 nmol/kg) and CCK-8+GRP-29 (0.5 nmol/kg each) once daily for a total of 23 days. We found that CCK-8, GRP-29 and CCK-8+GRP-29 reduce BW relative to saline control. In conclusion, CCK-8, GRP-29 and their combination reduce BW in the DIO rat model. If infused near their gastrointestinal sites of action CCK-8, GRP-29 and their combination may have a role in regulating BW.

Response inhibition is impaired by developmental methylmercury exposure: acquisition of low-rate lever-pressing.

Developmental methylmercury (MeHg) exposure produces response perseveration on discrimination reversal procedures, disrupts sensitivity to reinforcement, and enhances sensitivity to dopamine agonists - a profile suggesting a deficit in behavioral inhibition. To examine inhibition, we examined MeHg's effects on the acquisition and persistence of low-rate lever-pressing following a history of high-rate responding. Additionally, we examined whether chronic exposure to selenium protects against MeHg's developmental neurotoxicity. Female rats were exposed in utero via maternal exposure to drinking water containing 0ppm, 0.5ppm or 5ppm of Hg as MeHg, producing approximately 0µg/kg/day, 40µg/kg/day, or 400µg/kg/day of Hg. The mothers (during gestation) and the offspring (throughout life) consumed a purified diet containing 0.06ppm or 0.6ppm of Se (as sodium selenite), forming a 2 (lifespan diet)×3 (developmental MeHg) factorial design. Adult offspring lever-pressed under two schedules of reinforcement. A differential reinforcement of high-rate (DRH) schedule imposed rigid response requirements that remained constant through the study. A high-rate percentile schedule (PCNT-H) incorporated a flexible criterion that reinforced short interresponse times using an adjusting criterion that was sensitive to recent performance. After high-rate responding stabilized, the PCNT-H schedule was abruptly inverted by reinforcing long interresponse times. Acquisition of low-rate responding was impaired in the MeHg-exposed rats because of intrusions of high-rate response bursts. DRH response rates did not change. Dietary selenium did not influence MeHg's effects. High-rate operant behavior perseverated, suggesting that gestational MeHg exposure impairs response inhibition - an effect that extends results previously reported using choice procedures or spatial and visual discrimination reversals.

The effects of chronic ingestion of mercuric chloride on fertility and testosterone levels in male Sprague Dawley rats.

Although male infertility is well researched, the effects of inorganic mercury on male reproduction and fertility are less well known. Studies pertaining to mercury and male fertility identified reduced concentration of testosterone in the serum of male workers, a toxic influence on fertility of organic mercury compounds within concentrations at the workplace, and increased days to pregnancy. We evaluated the effect of chronic mercuric chloride (HgCl(2)) exposure in male rats on reproductive endpoints. Thirty-day old male Sprague Dawley rats (n = 31) were exposed to 0.0, 1.0, or 2.0 mg/kg/day of HgCl(2) via gavage. After 60 days exposure, they were housed with nonexposed females for 21 days. A survivor analysis revealed the exposed animals took longer to impregnate the females and had a lower rate of impregnation. Further statistical analysis revealed a lower correlation between testicular testosterone levels and days to impregnate, and also lower sperm counts in the epididymis head and body of the exposed males. The results indicate that HgCl(2) exposure had significant adverse effects on male rat reproduction endpoints including fertility at a dose that was not clinically toxic.

Dietary selenium protects against selected signs of aging and methylmercury exposure.

Acute or short-term exposure to high doses of methylmercury (MeHg) causes a well-characterized syndrome that includes sensory and motor deficits. The environmental threat from MeHg, however, comes from chronic, low-level exposure, the consequences of which are poorly understood. Selenium (Se), an essential nutrient, both increases deposition of mercury (Hg) in neurons and mitigates some of MeHg's neurotoxicity in the short term, but it is unclear whether this deposition produces long-term adverse consequences. To investigate these issues, adult Long-Evans rats were fed a diet containing 0.06 or 0.6 ppm of Se as sodium selenite. After 100 days on these diets, the subjects began consuming 0.0, 0.5, 5.0, or 15 ppm of Hg as methylmercuric chloride in their drinking water for 16 months. Somatosensory sensitivity, grip strength, hindlimb cross (clasping reflex), flexion, and voluntary wheel-running in overnight sessions were among the measures examined. MeHg caused a dose- and time-dependent impairment in all measures. No effects appeared in rats consuming 0 or 0.5 ppm of Hg. Somatosensory function, grip strength, and flexion were among the earliest signs of exposure. Selenium significantly delayed or blunted MeHg's effects. Selenium also increased running in unexposed animals as they aged, a novel finding that may have important clinical implications. Nerve pathology studies revealed axonal atrophy or mild degeneration in peripheral nerve fibers, which is consistent with abnormal sensorimotor function in chronic MeHg neurotoxicity. Lidocaine challenge reproduced the somatosensory deficits but not hindlimb cross or flexion. Together, these results quantify the neurotoxicity of long-term MeHg exposure, support the safety and efficacy of Se in ameliorating MeHg's neurotoxicity, and demonstrate the potential benefits of Se during aging.