Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration.

Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase.

Administration of metformin is known to reduce both body weight and food intake. Although the hypothalamus is recognized as a critical regulator of energy balance and body weight, there is currently no evidence for an effect of metformin in the hypothalamus. Therefore, we sought to determine the central action of metformin on energy balance and body weight, as well as its potential involvement with key hypothalamic energy sensors, including adenosine monophosphate-activated protein kinase (AMPK) and S6 kinase (S6K). We used meal pattern analysis and a conditioned taste aversion (CTA) test and measured energy expenditure in C56BL/6 mice administered metformin (0, 7.5, 15, or 30 µg) into the third ventricle (I3V). Furthermore, we I3V-administered either control or metformin (30 µg) and compared the phosphorylation of AMPK and S6K in the mouse mediobasal hypothalamus. Compared with the control, I3V administration of metformin decreased body weight and food intake in a dose-dependent manner and did not result in CTA. Furthermore, the reduction in food intake induced by I3V administration of metformin was accomplished by decreases in both nocturnal meal size and number. Compared with the control, I3V administration of metformin significantly increased phosphorylation of S6K at Thr(389) and AMPK at Ser(485/491) in the mediobasal hypothalamus, while AMPK phosphorylation at Thr(172) was not significantly altered. Moreover, I3V rapamycin pretreatment restored the metformin-induced anorexia and weight loss. These results suggest that the reduction in food intake induced by the central administration of metformin in the mice may be mediated by activation of S6K pathway.

Electroconvulsive shock increases SIRT1 immunoreactivity in the mouse hippocampus and hypothalamus.

OBJECTIVES: Recent study shows that silent mating-type information regulation 2 homolog 1 (SIRT1) regulation may be involved with depression. Electroconvulsive shock (ECS) has been used for the treatment of depression, but little is known about the effect of ECS on the changes in SIRT1 levels in the brain. The present study was designed to observe whether ECS dynamically regulates SIRT1 levels in the hippocampus and hypothalamus; both of these regions have been implicated in the pathophysiology of depression. METHODS: Male imprinting control region mice were given a single ECS via ear clip electrodes, and then killed 0.5, 2, 8, 24, or 48 hours after ECS. Changes in SIRT1 were observed by Immunohistochemistry, and obtained results were compared with sham controls that did not receive ECS. RESULTS: Silent mating-type information regulation 2 homolog 1 immunoreactivity levels in the CA1 and CA3 subfields of the hippocampus peaked 2 hours after ECS and then returned to control levels by 24 hours after ECS. Silent mating-type information regulation 2 homolog 1 immunoreactivity levels in the dentate gyrus of hippocampus, hypothalamic paraventricular, dorsomedial, arcuate, and suprachiasmatic nuclei peaked 8 hours after ECS but had not completely returned to baseline levels 48 hours after ECS, except for the dentate gyrus. Electroconvulsive shock resulted in a gradual increase of SIRT1 immunoreactivity in the hypothalamic ventromedial nucleus and lateral hypothalamic area, which appeared to be still rising or peaking at the 48-hour post-ECS time point. CONCLUSIONS: The present results demonstrate that a single ECS increases SIRT1 in the mouse hippocampus and hypothalamus differentially in a region-specific time-dependent manner.

High fat diet altered the mechanism of energy homeostasis induced by nicotine and withdrawal in C57BL/6 mice.

Nicotine treatment has known to produce an inverse relationship between body weight and food intake in rodents. Present study determined the effect of repeated treatment with nicotine and withdrawal in control and obese mice, on: (1) body weight, caloric intake and energy expenditure; (2) hypothalamic neuropeptides mRNA expression; and (3) serum leptin. 21-week-old C57BL/6 mice (n = 65) received nicotine (3.0 mg/kg/day; 2 weeks) and saline (1 ml/kg/day; 2 weeks) subcutaneously. Animals were given either a normal-fat (10% kcal from fat, NF) or a high-fat diet (45% kcal from fat, HF) from the 12th week to 25th week. While, nicotine treatment for 14 days induced an increase in hypothalamic agouti-related protein, cocaine- and amphetamine- regulated transcript, pro-opiomelanocortin mRNA expressions, nicotine also produced a reducing effect in body weight gain and leptin concentration in NF mice. High-fat diet induced obese mice showed a blunted hypothalamic and leptin response to nicotine. Remarkable weight loss in obese mice was mediated not just by decreasing caloric intake, but also by increasing total energy expenditure (EE). During nicotine withdrawal period, weight gain occurred in NF and HF groups, which was ascribed to a decrease in EE rather than changes in caloric intake. Hypothalamic AgRP might play a role for maintaining energy balance under the nicotine-induced negative energy status.

A single administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin that produces reduced food and water intake induces long-lasting expression of corticotropin-releasing factor, arginine vasopressin, and proopiomelanocortin in rat brain.

The mechanism by which a single administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) reduces food and water intake is unclear. We examined whether such a food and water intake-reducing single administration of TCDD induced changes in corticotropin-releasing factor (CRF), arginine vasopressin (AVP), and proopiomelanocortin (POMC) expression in rat brain. To observe time-dependent changes in these neuropeptides, male Sprague-Dawley rats were given TCDD (50 microg/kg) and terminated 1, 2, 4, or 7 days later. In addition, to observe dose-dependent changes in feeding and neuropeptides, rats were also given a range of TCDD doses (12.5, 25, or 50 microg/kg) and terminated 14 days later. TCDD suppressed food and water intake over 14 days in a dose-dependent manner. TCDD treatment also increased CRF and POMC mRNA levels in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus, respectively, in a dose- and time-dependent manner. These increases were related to decreased food intake following TCDD administration. TCDD treatment increased AVP and CRF mRNA levels in the PVN, and these increases were related to decreased water intake. Interestingly, the increases in CRF, AVP and POMC expression were observed 7 to 14 days after TCDD administration. These results suggest that a single administration of TCDD induced long-lasting increases in CRF, AVP, and POMC mRNA levels in the hypothalamus and that these changes are related to reduced food and water intake 7 to 14 days after TCDD administration.