Kazuyoshi Ookuma

Blockade of the histamine H1-receptor in the rat ventromedial hypothalamus and feeding elicitation

All H1-, but no H2-antagonists infused into the rat third cerebroventricle, induced feeding during the early light, but not during the early dark, reflecting a concentration of hypothalamic histamine. Bilateral microinfusion identified the ventromedial hypothalamus (VMH), but not the lateral hypothalamus or the paraventricular nucleus, as a main locus for the induction of feeding by an H1-antagonist. The effect was completely abolished when brain histamine was decreased by pretreatment with alpha-fluoromethylhistidine. Hypothalamic neuronal histamine suppresses food intake, at least in part, through H1-receptors in the VMH.

Hypothalamic sites of neuronal histamine action on food intake by rats.

To identify sites of histaminergic modulation of food intake, histamine H1-receptor antagonist was microinfused into the rat hypothalamus, the ventromedial hypothalamus (VMH), the lateral hypothalamus (LHA), the paraventricular nucleus (PVN), the dorsomedial hypothalamus (DMH), or the preoptic anterior hypothalamus (POAH), during the early light period. Feeding, but not drinking, was elicited in 100% of the rats (P less than 0.01) that were bilaterally microinfused with 26 nmol chlorpheniramine into the VMH. Unilateral infusion into the VMH did not affect food intake at doses of 26 or 52 nmol. Feeding was also induced by bilateral microinfusion into the PVN, but only the 52 nmol dose was effective. Bilateral infusions into the LHA, the DMH or the POAH did not affect ingestive behavior. Feeding induced by an H1-antagonist was completely abolished in all 7 rats tested when endogenous neuronal histamine was decreased by pretreatment with alpha-fluoromethylhistidine (100 mg/kg). The findings suggest that H1-receptors in the VMH and the PVN, but not in the LHA, the DMH or the POAH, may be involved in histaminergic suppression of food intake.

Zucker obese rats: defect in brain histamine control of feeding

Manipulation of hypothalamic histamine produced different effects on feeding between the Zucker obese (fa/fa) and their lean littermate rats (Fa/-). Infusion of a histamine H1-receptor antagonist into the third cerebroventricle elicited feeding in the lean and Wistar King A rats, but it did not affect feeding in the obese rats. To enhance hypothalamic neuronal histamine, thioperamide, and H3-receptor antagonist, was similarly infused. The lean and Wistar rats decreased their food intake after the infusion, but thioperamide produced no significant effect on feeding in the obese rats. Infusion of histamine into the third cerebroventricle mimicked the effects of thioperamide on feeding: reduction of food intake in the lean and Wistar rats, but no significant change in the obese rats. Hypothalamic histamine of the obese rats (0.430 nmol/g) was significantly lower than the lean (1.209 nmol/g) and Wistar rats (4.838 nmol/g). The histamine concentration of the cerebral cortex in the obese rats was also lower than the non-obese animals. The results indicate that the feeding abnormality of Zucker obese rats may be at least due to disturbance of histamine suppressive signals both at presynaptic and postsynaptic levels.

Hypothalamic neuronal histamine modulates ad libitum feeding by rats

Manipulating histamine endogenously, its effects on brain functions were assessed in rats. alpha-Fluoromethylhistidine (FMH), an inhibitor of histamine synthesis, elicited feeding (P less than 0.01) after intra-third cerebroventricular infusion at the early light phase when hypothalamic histamine was normally highest. No periprandial drinking was observed. The effect of FMH was attenuated, and thioperamide, an antagonist of auto-inhibitory effects on both histamine synthesis and release at presynaptic H3-receptor, conversely suppressed food intake (P less than 0.05), when these probes were carried out during the minimum histamine level early in the dark period. Bilateral microinfusion of FMH into the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN) selectively induced feeding, but the infusion into the remaining sites of the hypothalamus had no effect. These data show that neuronal histamine plays a physiological role in feeding suppression through the VMH and the PVN in the rat.

Charting of Daily Weight Pattern Reinforces Maintenance of Weight Reduction in Moderately Obese Patients

To maintain reduced body weight by behavioral therapy in moderately obese patients, body weight was measured four times daily and charted in a weekly graph. Seventy-two female patients with simple obesity were divided into two groups: 55 patients with appliance of charting of weight pattern (group-I), and 17 patients without the charting (group-II). The percentage of patients followed for 2 years was different between group-I (87%) and group-II (65%) during 2 years after completion of weight reduction therapy interviews (p less than 0.05). Forty-eight of group-I patients succeeded in decreasing their weight by 15.2 +/- 1.5 (mean +/- SEM) kg during the 6.5 +/- 0.8 months of the therapy interviews. They were followed up for 3.8 years with no rebound weight gain. Eleven patients in group-II also succeeded in decreasing their weight by 16.8 +/- 1.9 kg during 7.8 +/- 1.3 months but their body weight rebounded by 9.0 kg during the 2-year followup period. Twelve of 15 male patients with weight charting maintained reduced weight during 4.3 years. It was easier and more effective for obese patients to maintain weight graphs for the longer period than to record no weight graphs. Obese patients could themselves monitor irregular weight patterns produced by overeating and correct the irregularities in food intake and daily lifestyles. This seems to explain why the illustration of daily fluctuations of weight measurements was useful for long-term maintenance of weight reduction.

Modulation of neuronal histamine in control of food intake

Neuronal histamine affects physiological functions of the hypothalamus. To investigate involvement of histamine receptors in feeding, histamine antagonists were infused into the rat third cerebroventricle. All H1- but no H2-antagonists tested, induced transient feeding during the early light when concentration of hypothalamic histamine was highest. No periprandial drinking was observed. Ambulation concomitantly increased during feeding. The effect on feeding was attenuated when brain histamine was normally low during the early dark or was decreased by alpha-fluoromethylhistidine (alpha-FMH). Bilateral microinjection indicated that the ventromedial hypothalamus, but not the lateral hypothalamus or the paraventricular nucleus, was a main locus for the induction of feeding by an H1-antagonist. The effect was completely abolished when brain histamine was decreased by pretreatment with alpha-FMH. Hypothalamic neuronal histamine suppresses food intake, at least in part, through H1-receptors in the VMH, and diurnal fluctuations of food intake may mirror neuronal histamine level.

Hypothalamic histamine modulates adaptive behavior of rats at high environmental temperature

Histamine content in the rat hypothalamus was lower at 4°C and higher at 31°C compared to that at 21°C. Pretreatment with α-fluoromethylhistidine, a ‘suicide’ inhibitor of histidine decarboxylase, attenuated both the increased level of hypothalamic histamine and rat adaptive behavior at 31°C. Increase of histamine content in the hypothalamus appears to be an important factor contributing to rat adaptive behavior to high environmental temperature.

Histaminergic control of energy balance in rats

Manipulating neuronal histamine in the hypothalamus, its effects on brain functions were assessed in nonobese normal rats and Zucker rats. Alpha-fluoromethylhistidine (FMH), an inhibitor of histamine synthesis, induced feeding dose-dependently after 2.24 mumol infusion at 1100 h, when hypothalamic histamine was normally high. This dose of FMH selectively decreased hypothalamic histamine, but not other neurotransmitters. Thioperamide, an antagonist of autoinhibitory H3-receptors, decreased food intake after infusion at 1940 h, when hypothalamic histamine was normally low. Bilateral microinfusion of 224 nmol FMH or 26 nmol chlorpheniramine, an H1-antagonist, into the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN), elicited feeding. However, Zucker obese rats showed no significant responses to chlorpheniramine, thioperamide or histamine. Concentration of their hypothalamic histamine was excessively lower than that of the nonobese. Contents of hypothalamic histamine were lowered at 4 degrees C and raised at 31 degrees C. FMH attenuated increase in histamine, and then disrupted adaptive behavior. These findings indicate that neuronal histamine may convey the suppressive signal of food intake through H1-receptors in the VMH and/or the PVN, and play critical roles in homeostatic control of adaptive behavior.

Attenuation of anorexia induced by heat or surgery during sustained administration of ginsenoside Rg1 into rat third ventricle

Effects of ginsenoside Rg1 (Rg1), a major component of panax ginseng, on modulation of ingestive behavior were investigated. No direct effect was observed on food intake after 10 μl infusion of 1.0, 2.0, 4.0 or 8.0 mM Rg1 into the rat third ventricle for 10 min. Continuous osmotic infusion of 4.0 mM Rg1 at a rate of 0.966 μl/h into the third ventricle prevented feeding suppression caused by surgical procedure to implant an osmotic minipump. Continuous infusion of Rg1 attenuated anorexia, increased water intake, and decreased ambulation, that were produced by elevation of environmental temperature from 21° C to 30° C. Consequently, rats maintained body weight and rectal temperature unchanged. The results indicate that sustained central administration of Rg1 may relieve anorexia caused by implantation surgery or by a heated environment.

Evidence for feeding elicited through antihistaminergic effects of tricyclic antidepressants in the rat hypothalamus.

We studied central mechanisms of antidepressants that affect feeding behavior in rats. The tricyclic compounds amitriptyline, doxepin and imipramine significantly induced feeding after their infusion into the third cerebral ventricle in the light phase, but the tricyclic, desipramine, and the dicyclic zimelidine, did not. Drinking was not affected by any compound tested. The relative order of potency in eliciting feeding was: amitriptyline and doxepin > imipramine > desipramine and zimelidine. To clarify the involvement of neuronal histamine in antidepressant-induced feeding, alpha-fluoromethylhistidine (FMH), a “suicide” inhibitor of histidine decarboxylase, was intraperitoneally administered before infusion of amitriptyline. FMH attenuated the amitriptylines effect. Bilateral microinfusion of amitriptyline into the ventromedial hypothalamus or the paraventricular nucleus verified that these are loci for the modulation of feeding by amitriptyline. In the lateral hypothalamus, amitriptyline was less effective. These findings indicate that tricyclic antidepressants directly facilitate feeding, which is, at least in part, mediated by histamine in the hypothalamus.