Qualitative evaluation of the Rey-Osterrieth Complex Figure Test in patients with progressive supranuclear palsy.

Objective: In early stages of disease, the differential diagnosis between Parkinson's Disease (PD) and atypical parkinsonism, such as Progressive Supranuclear Palsy (PSP), could be challenging. Growing attention has recently been dedicated to investigating neuropsychological markers of degenerative parkinsonism. The Rey-Osterrieth Complex Figure Test (ROCFT) copy score was hypothesized able to differentiate PSP from PD. However, ROCFT is a drawing test requiring multiple cognitive abilities and it is still unknown which of them assumes an important role in PSP performance. Using a qualitative scoring system, we investigated which cognitive abilities underpin the PSP performance at the ROCFT copy trial. Moreover, we evaluated usefulness of the BQSS scores in discriminating PSP from PD. Methods: Thirty PSP-Richardson's Syndrome (PSP-RS) patients, 30 PD patients, and 30 healthy control (HC) comparable for age, education, and gender were enrolled. All subjects underwent a neuropsychological evaluation; ROCFT copy were evaluated with the 36-Point Score and with the Boston Qualitative Scoring System (BQSS). Results: PSP-RS patients performed worse in ROCFT 36-Point Score and in several BQSS scores compared to other groups. Most suitable scores discriminating PSP-RS from PD were "Perseveration" and "Vertical Expansion" of BQSS. A logistic regression model considering "Perseveration" and "Vertical Expansion" showed a diagnostic accuracy of 83,3% for PSP-RS condition. Conclusion: our findings showed that "Perseveration" and "Vertical Expansion" BQSS scores were useful in discriminating PSP-RS from PD. "Perseveration" and "Vertical Expansion" BQSS scores might be included in the cognitive evaluation along with quantitative scores when PSP diagnosis is considered.

Inhibition of glucose oxidation by alpha-cyano-4-hydroxycinnamic acid stimulates feeding in rats.

Alpha-cyano-4-hydroxycinnamic acid (4-CIN, 100-200 mg/kg b.wt.), which impairs glucose oxidation by inhibiting pyruvate transport across the mitochondrial membrane, stimulated feeding in rats following intraperitoneal injection without affecting blood glucose level. Like 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis, 4-CIN probably acts mainly on the CNS through activation of alpha(2)-adrenergic receptors, because the feeding response to 4-CIN was eliminated by phentolamine or yohimbine. Unlike feeding elicited by 2-DG, 4-CIN-induced feeding was eliminated by total abdominal (but not hepatic branch) vagotomy. Since peripheral atropinization also blocked 4-CIN-induced feeding, activation of central parasympathetic neurons seems to be involved in 4-CIN-induced feeding. The feeding response to 4-CIN was diminished in rats fed a high-fat diet, probably because metabolic sensors sensing fatty acid oxidation counteract the feeding response to 4-CIN. The results suggest that inhibition of glucose oxidation by blocking pyruvate entry into mitochondria stimulates feeding in rats in particular when fed a high-carbohydrate diet.

Effects of amylin and salmon calcitonin on feeding and drinking behavior in pygmy goats.

In the present study, the effects of peripherally administered amylin and of the amylin-related peptide salmon calcitonin (sCT) on food and water intake was tested for the first time in pygmy goats. In the first series of experiments, the effect of amylin on food (0.5, 1.0 and 2.0 microg/kg b.wt.) and water (2.0 microg/kg) intake was tested. In the second series of experiments, the effect of sCT on food intake (1.0 microg/kg) was tested under ad libitum feeding conditions or after 14 h food deprivation. The relationship of dose on the effect of sCT (0.1, 0.5 and 1.0 microg/kg) on food and water intake was also tested. Finally, the effect of a low dose (0.1 sCT microg/kg) on water intake was also investigated during food withdrawal. We showed for the first time an anorexigenic effect of the satiety peptide amylin (2.0 microg/kg) in ruminants, which was characterized by a reduction in meal size. In pygmy goats, the administration of the three doses of sCT induced an anorexigenic effect, which was larger and of longer duration when compared with amylin, although the anorexigenic effect of the lowest dose never reached significance. This effect was not dose dependent and was partly due to a reduction in meal size and partly to a prolongation of the interval between meals. The anorexigenic effect of sCT was accompanied by a reduced water intake, probably due to reduced prandial drinking. Furthermore, the low dose of sCT (0.1 microg/kg) was dipsogenic during food withdrawal.

Suppression of feed intake after parenteral administration of D-beta-hydroxybutyrate in pygmy goats.

The effect of intraperitoneal injection of D,L- or D-beta-hydroxybutyrate on feed intake and plasma metabolites was investigated in pygmy goats. The combined intraperitoneal injection of D,L-beta-hydroxybutyrate or D-beta-hydroxybutyrate (15 mmol/kg0.75) and 1,3-butanediol (6.6 mmol/kg0.75), a ketogenic substrate, decreased cumulative food intake while the same dose of 1,3-butanediol or DL-beta-hydroxybutyrate alone had no effect. The decrease in food intake after combined injection of D-beta-hydroxybutyrate and 1,3-butanediol was characterized by a significant decrease in meal frequency and a prolongation of the latency to eat. The hypophagic effect of the combined injection of D-beta-hydroxybutyrate and 1,3-butanediol was significant for 8 h, while the hypophagia after D,L-beta-hydroxybutyrate and 1,3-butanediol was significant for only 2 h after injection. Injection of D,L-beta-hydroxybutyrate increased plasma D-beta-hydroxybutyrate levels to 0.55 mmol/l and decreased plasma free fatty acids. Addition of 1,3-butanediol (6.6 mmol/kg0.75) to the injection increased plasma D-beta-hydroxybutyrate level up to 0.75 mmol/l. The results show that parenteral administration of D-hydroxybutyrate reduces feed intake in pygmy goats and that the hypophagia appears to be related to the amount of D-beta-hydroxybutyrate injected. The hypophagia seems to be related to elevated plasma D-beta-hydroxybutyrate concentration, and the threshold concentration appeared to be about 0.7 mmol/l under the experimental conditions of this study.

Transient hypophagia in rats switched from high-fat diets with different fatty-acid pattern to a high-carbohydrate diet.

The present study investigates the mechanisms underlying the transient hypophagia occurring when rats adapted to high-fat, carbohydrate-free diets are switched to high-carbohydrate, low-fat diets. The hypophagia after the high-fat, carbohydrate-free to high-carbohydrate, low-fat diet shift seems to depend on the amount of carbohydrate in the diet, since an attenuation of hypophagia was observed when high-fat, carbohydrate-free-adapted rats were switched to a medium-carbohydrate, medium-fat diet. A role of glucose intolerance in the hypophagia is supported by the attenuation of carbohydrate anorexia in rats adapted to a high-fat diet containing n -3 polyunsaturated fatty acids from fish oil (60% of fat as fish oil), which has been shown to improve glucose tolerance in rats. Furthermore, the increased plasma glucose concentration in the high-fat, carbohydrate-free diet to high-carbohydrate, low-fat shifted rats despite the suppression in food intake also suggests an involvement of glucose intolerance in the hypophagia. The failure of the inhibitor of hepatic-fatty-acid oxidation mercaptoacetate (400 micromol/kg, i.p.) to counteract carbohydrate anorexia in the HF-adapted rats argues against an involvement of fatty-acids oxidation in the inhibition of eating after high-fat, carbohydrate-free to high-carbohydrate, low-fat diet shift. This is also supported by the failure to demonstrate a relationship between plasma beta-hydroxybutyrate and the severity of the hypophagia. A role of leptin in the hypophagia seems unlikely, since plasma leptin after diet shift was unchanged. Ingestion of the high-carbohydrate, low-fat diet also produced an aversion towards this diet in high-fat, carbohydrate-free-adapted rats. It is concluded that the transient hypophagia induced by switching rats from a high-fat to a high-carbohydrate diet is not related to fatty acid oxidation but to transiently impaired carbohydrate utilization.

Acute increase in food intake after intraperitoneal injection of metformin in rats.

We studied the effect of intraperitoneal injection of different doses of the antihyperglycemic agent metformin on food intake and plasma metabolites (glucose, free fatty acids, beta-hydroxybutyrate) in rats fed a high-fat (HF) or a high-carbohydrate (HC) diet. Unexpectedly, metformin, at a dose of 120 mg/kg b.wt. stimulated food intake in both HF- and HC-fed rats, without affecting blood glucose level. This result is in contrast with the hitherto performed studies that found an anorectic effect of metformin in rodents. It is postulated that the hyperphagic effect of metformin might be related to reduced energy availability to hepatic metabolic sensors controlling food intake, because metformin's known inhibitory effect on oxidative phosphorylation mainly affects the hepatoportal area, and blockade of oxidative phosphorylation in this area has been shown to stimulate feeding.

Effect of the H1-histamine receptor agonist betahistine on drinking and eating behavior in pygmy goats.

The effect of different doses of the H1-receptor agonist betahistine (0.9 and 2, 4 and 8 mg/kg b.wt.(0.75)) on water and food intake was investigated in 12 pygmy goats. Intraperitoneal (i.p.) injection of betahistine (2, 4, and 8 mg/kg b.wt.(0.75)) stimulated drinking in a dose-dependent manner. Food intake was decreased after the injection of 4 or 8 mg/kg b.wt.(0.75) betahistine, respectively. The increase in water intake was characterized by an increased draft size and decreased latency to drink. The decrease in food intake at the highest dose tested was characterized by an increased latency to eat and by a decreased meal frequency, and food intake associated to drinking was decreased. In line with previous studies, these results support the hypothesis that food-associated drinking is mediated by stimulation of H1-receptors of histamine in pygmy goats.

Amylin reduces food intake more potently than calcitonin gene-related peptide (CGRP) when injected into the lateral brain ventricle in rats.

Amylin and the structurally and functionally related peptide calcitonin gene-related peptide (CGRP) have been shown to reduce food intake in rats. The aim of the present study was to compare the anorectic potency of both peptides over a wide dose range when administered into the lateral brain ventricle (ICV). Furthermore, we also tested the influence of a lesion in the area postrema/nucleus of the solitary tract (AP/NTS) region on the anorectic effects of amylin and CGRP after ICV administration because AP/NTS lesion has been shown to reduce the anorectic effects of both peptides when injected intraperitoneally (IP). Amylin [1-510 pmol/rat (0.004-2 microg/rat) ICV] and CGRP [1-131 pmol/rat (0.004-0.5 microg/rat) ICV] dose-dependently reduced food intake in food-deprived rats. At a dose of 26 pmol/rat (0.1 microg/rat), amylin almost completely suppressed food intake for 1 h after injection. Amylin [EC50 = 2 pmol/rat (0.007 microg/rat)] was markedly more potent than CGRP [57 pmol/rat (0.215 microg/rat)] with regard to its anorectic effect. A lesion in the AP/NTS region did not influence the anorectic effects of amylin and CGRP after administration into the lateral ventricle. It is concluded that amylin is more potent than CGRP in reducing food intake after administration into the lateral brain ventricle. Receptors in the forebrain may mediate the anorectic effects of both peptides when administered via this route.

Effects of histamine H1 receptors on the feeding and drinking patterns in pygmy goats.

The goal of these experiments was to determine which histamine receptors are involved in the relationship between drinking and feeding in ruminants. To this end, the effects of the histamine receptor antagonists dexbrompheniramine (H1 receptor antagonist), cimetidine (H2 receptor antagonist), and terfenadine (H1 receptor antagonist) on feeding and drinking patterns of pygmy goats were investigated. Two experiments using dexbrompheniramine [1 and 2 mg/kg of body weight (BW)0.75], two experiments using cimetidine (16 and 32 mg/kg of BW0.75), and two experiments using terfenadine (5 and 11.5 mg/kg of BW0.75) were performed to assess the type and location (periphery or central nervous system) of the histamine receptors involved in the mediation of prandial drinking by pygmy goats. The H1 receptor antagonists dexbrompheniramine (2 mg/kg of BW0.75) and terfenadine (11.5 mg/kg of BW0.75) significantly reduced water intake, but cumulative feed intake did not change. Consequently, the ratio of water intake to feed intake decreased. In contrast, the H2 receptor antagonist did not affect either water or feed intake. Dexbrompheniramine at 2 mg/kg of BW0.75 and terfenadine at 11.5 mg/kg of BW0.75 also decreased draft frequency and decreased the water intake associated with meals. Results showed that blockage of peripheral H1 histamine receptors attenuates the association between water and feed intake in pygmy goats. Therefore, the stimulating effect of feed intake on water intake appears to depend on activation of peripheral H1 histamine receptors.

Inhibitors of fatty acid oxidation (mercaptoacetate, R-3-amino-4-trimethylaminobutyric acid) stimulate feeding in mice.

Several lines of evidence indicate that fatty acid oxidation contributes to control of eating. We examined the effect of inhibitors of fatty acid oxidation (mercaptoacetate, R-3-amino-4-trimethylaminobutyric acid = emeriamine) on food intake in mice because fatty acid oxidation has been shown recently to increase the hepatic membrane potential in mouse liver, and this potential has been proposed to represent a signal for control of food intake. The effect of intraperitoneal injection of mercaptoacetate (200, 400, or 600 micromol/kg body weight) and emeriamine dihydrochloride (8.7, 17.4, 34.8, or 69.6 micromol/kg body weight) was investigated in mice fed a fat-enriched diet (18% fat). Both mercaptoacetate (400 or 600 micromol/kg) and emeriamine (34.8 or 69.6 micromol/kg) significantly increased food intake. These results suggest that fatty acid oxidation is also involved in feeding control in mice. Therefore, the pertinent mechanisms can be studied in mice.

Effects of a high NaCl diet on eating and drinking patterns in pygmy goats.

Eating and drinking patterns of eight pygmy goats were recorded under two diets with different NaCl content. A 3% NaCl diet in comparison to a 0.5% NaCl diet caused a long lasting depression of food intake, whereas water intake did not change. Therefore, the ratio between cumulative water and food intake increased significantly. Feeding the 3% NaCl diet mainly decreased food intake through a decrease in the size (31%) and frequency (16%) of meals which were not associated with drinking. Size and frequency of meals associated with drinking were not substantially affected by the 3% NaCl diet. Size and frequency of drafts were not altered. Size of meals associated with drinking was generally bigger than that of meals not associated with drinking. These findings can best be explained by control of feeding through osmolality of rumen fluid. Ruminal osmolality seems to be less important for control of drinking.

Lesion of the area postrema/nucleus of the solitary tract (AP/NTS) attenuates the anorectic effects of amylin and calcitonin gene-related peptide (CGRP) in rats.

The area postrema/nucleus of the solitary tract (AP/NTS) region plays an important role in the control of food intake since it receives peripheral satiety signals via splanchnic and vagal afferents. Due to the lack of the blood brain barrier in this region, blood borne signals can directly be monitored in the AP/NTS. Furthermore, receptors for anorectic peptides such as amylin or calcitonin gene-related peptide (CGRP) have been found in the AP/NTS. It was therefore the aim of the present study to investigate the role of the AP/NTS region in mediating the anorectic effects of these peptides. Thermal ablation of the AP/NTS resulted in a significant reduction of the anorectic effects of IP injected amylin (5 microg/kg) and CGRP (5 microg/kg) in food deprived rats. The anorectic actions of CCK and BBS were also reduced by the AP/NTS lesion which agrees with previous studies. We conclude that the AP/NTS region is an important brain site for mediating the anorectic effects of amylin and CGRP. It remains to be clarified whether this effect is due to amylin and CGRP action on receptors within the AP/NTS region or peripheral receptors on afferent nerves projecting to the AP/NTS.

Evidence for a physiological role of central calcitonin gene-related peptide (CGRP) receptors in the control of food intake in rats.

In the present study, we investigated the role of central calcitonin gene-related peptide (CGRP) and amylin receptors in mediating the anorectic effects of CGRP and amylin in rats chronically cannulated in the lateral brain ventricle. Intracerebroventricular (ICV) injection of the CGRP and amylin receptor antagonist CGRP(8-37) failed to influence the anorectic effects of peripherally injected CGRP and amylin. CGRP(8-37) alone, however, increased food intake in food deprived rats when administered 2 h before food presentation. Under the same experimental conditions, the more specific amylin receptor antagonists amylin(8-37) or AC 187 did not affect food intake. We therefore conclude, that CGRP is a physiological regulator of food intake within the central nervous system, acting at central CGRP receptors. Peripheral receptors, however, are likely to mediate the anorectic effects of peripherally administered amylin and CGRP.

Food-associated drinking in pygmy goats: importance of histamine receptors.

The combined effect of the histamine receptor antagonists Dexbrompheniramine (DXB: H1-receptor antagonist) and Cimetidine (C: H2-receptor antagonist) on food and water intake was investigated in pygmy goats. DXB (1 mg/kg BW0.75) and C (16 mg/kg BW0.75) were injected together intraperitoneally (i.p.). Cumulative food and water intake, as well as meal and draft pattern, were recorded. DXB and C significantly reduced cumulative water intake, whereas cumulative food intake did not change. Water to food ratio was also significantly diminished. Draft frequency and the percentage of drafts associated with meals were significantly reduced during the 6 h post injection, while meal frequency and meal size did not change during this period. The results show that blockade of the H1- and H2-histamine receptors attenuates the association between water and food intake in pygmy goats. Therefore, mechanisms responsible for meal-associated drinking seem to depend upon activation of histamine receptors.

Different influence of CGRP (8-37), an amylin and CGRP antagonist, on the anorectic effects of cholecystokinin and bombesin in diabetic and normal rats.

Because previous studies had suggested that the anorectic effects of cholecystokinin (CCK) and bombesin (BBS) depend partly on the release of amylin or calcitonin gene-related peptide (CGRP), we investigated the influence of the amylin and CGRP receptor antagonist CGRP (8-37) on the anorectic effects of CCK and BBS in streptozotocin (STZ)-diabetic and nondiabetic rats. STZ-diabetic rats had significantly lower plasma amylin and insulin concentrations than nondiabetic control rats. Amylin (5 micrograms/kg or 2.5 micrograms/rat) injected IP at dark onset after 24-h food deprivation elicited an anorectic effect of similar extent in STZ-diabetic and control rats. Under similar conditions, CCK (0.25 and 2 micrograms/kg) and BBS (5 micrograms/kg) reduced food intake in both STZ-diabetic and nondiabetic rats. These effects were markedly attenuated by CGRP (8-37) (10 micrograms/kg) in non-diabetics but not in STZ-diabetic rats. It is concluded that part of the anorectic effects of CCK and BBS depend on the release of amylin from pancreatic B-cells.

Inhibition of food intake in rats by the K+ channel opener cromakalim.

We studied the effect of the K+ channel opener cromakalim, which exhibits antihypertensive properties, on food intake in rats. Intraperitoneally injected cromakalim induced a dose-dependent (0.1, 0.5, and 1.0 mg/kg body wt.) reduction in food intake, which was associated with an inhibition of gastric emptying. The anorectic effect was not influenced by subdiaphragmatic vagotomy. Cromakalim's anorectic effect did not appear to be due to a learned taste aversion. Therefore, an intact abdominal vagus is not a prerequisite for cromakalim's anorectic effect.

The histaminergic, but not the serotoninergic, system mediates amylin's anorectic effect.

In the present study, we investigated the influence of blockade of the serotoninergic and histaminergic neurotransmitter system on the anorectic effect of IP-injected amylin in rats. In 12- or 24-h food-deprived rats, blockade of central and peripheral serotonin (5-HT) receptors with the 5-HT1 and 5-HT2 receptor antagonist metergoline (0.5 or 0.05 mg/kg, IP, respectively) did not seem to influence the anorectic effect of IP injected amylin (1 microgram/kg). Similarly, inhibition of 5-HT synthesis and release with the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (200 micrograms/kg, IP) did not diminish amylin's (5 micrograms/kg, IP) anorectic effect in 24-h food-deprived rats whereas that of CCK (3 micrograms/kg, IP) was blocked under comparable conditions. Pretreatment of rats with the histamine H3 receptor agonists R-alpha-methylhistamine (MH: 3 mg/kg, IP) and Imerit (3 mg/kg, IP), which block transmission in the histaminergic system by inhibiting release of endogenous histamine, attenuated amylin's (1 microgram/kg) anorectic effect in 24-h food-deprived rats. These results suggest that the histaminergic system in involved in transduction of IP amylin's inhibitory effect on feeding in rats. In contrast, the serotoninergic system does not seem to be involved in mediating amylin's anorectic effect.

Attenuation of the anorectic effects of glucagon, cholecystokinin, and bombesin by the amylin receptor antagonist CGRP(8-37).

The anorectic effect of IP injection of amylin (1 microgram/kg) was abolished by simultaneous IP injection of the amylin receptor antagonist calcitonin gene-related peptide-(8-37) [CGRP(8-37), 10 micrograms/kg]. The IP injection of pancreatic glucagon (400 micrograms/kg) at dark onset also reduced food intake in 24-h food-deprived rats, and this effect was also totally blocked by coadministration of CGRP(8-37) (10 micrograms/kg). In another feeding paradigm with glucagon (540 micrograms/kg IP 3 h into the light phase in 3 h-prefed rats), however, the anorectic effect of glucagon was not significantly antagonized by CGRP(8-37). The anorectic effect of cholecystokinin (CCK) (0.25 microgram/kg) and bombesin (BBS) (2 micrograms/kg) was partly neutralized by CGRP(8-37). In contrast, the anorectic effect of vasopressin (VP) (2.5 micrograms/kg) was not influenced by CGRP(8-37). As glucagon has been shown previously to increase the secretion of amylin, we conclude that the anorectic effect of peripherally administered glucagon is mediated by the release of amylin, at least under certain conditions. This may also be true for CCK and BBS, as these peptides are insulinotropic and may therefore be presumed to increase amylin release.

Hepatic branch vagotomy enhances feeding in response to centrally elicited glucose deprivation in rats.

Intracerebroventricular (I.C.V.) administration of 2-deoxy-D-glucose (2-DG) produces glucose deprivation-induced ('glucoprivic') feeding and sympathoadrenal activation. To find out whether peripheral mechanisms modulate centrally elicited glucoprivic feeding the effect of hepatic branch vagotomy (HBV) compared with sham vagotomy (SV) on the feeding response to I.C.V.-injected 2-DG (1.2 or 2.4 mg per rat) was tested in rats fed a fat-enriched diet (18% fat). 2-DG was injected into the lateral ventricle 1 h after after dark onset, at light onset or 6 h after light onset of the 12 h light-12 h dark cycle. Apart from one (1.2 mg 2-DG injected 1 h after dark onset) out of six experiments, HBV enhanced glucoprivic feeding. This finding is consistent with the assumption that centrally elicited glucoprivic feeding is antagonized by peripheral stimuli signalled to the brain through the hepatic vagus branch.

Amylin decreases meal size in rats.

Adult male rats were intraperitoneally (i.p.) injected with 1.0 microgram/kg amylin at the beginning of the dark phase in 24 h food deprived or undeprived rats, and a computerized system measured feeding behavior. In food deprived rats, amylin reduced the size of the first postdeprivation meal without affecting intrameal feeding rate or the size or timing of subsequent meals. The same pattern was observed in undeprived rats, but amylin also increased the latency to the first postinjection meal. In a conditioned taste aversion test, i.p. amylin (1 microgram/kg) injection just prior to rats' first access to a saccharine-flavored version of their maintenance diet, failed to affect their subsequent selection of that diet relative to the maintenance diet 2 d later. Finally, 2-min meal-contingent hepatic portal infusions of amylin (1-3.2 microgram/rat) during nocturnal spontaneous meals in undisturbed, ad lib fed rats reduced the meal size and meal duration, and increased the postprandial satiety ratio. Again, feeding rate and the size and duration of subsequent meals were not affected. These results suggest that amylin inhibits feeding by facilitating meal-ending satiety processes.