Histamine is a ubiquitous molecule utilised for a variety of signals in biological systems. Histminegic receptors are expressed throughout the system as H1, H2, H3 and H4 subtypes, regulating gastric acid secretion, reproduction and several neuronal and behavioral functions. Hypothalamic neuronal histamine and its H1 receptor (H1-R), one of leptin signalling pathways in the brain, regulate body weight and adiposity by affecting food intake and energy expenditure. Histamine-containing neurons and histamine H1 receptors are distributed within the brain and peripheral tissues. The results of physiological and pharmacological studies have revealed that brain histamine and H1 receptors are involved in the regulation of feeding and obesity in rodents. The adipocytokine leptin regulates feeding and obesity, partially through brain histamine. Furthermore, recent studies have evinced that regulation of the diurnal rhythm of feeding through H1 receptors is a crucial factor in the development of obesity. Thus, the regulation of H1 receptors is important for the control of energy metabolism, feeding rhythms and obesity in rodents.

In brain, histamine is synthesised in specific neurons that are localised in the tuberomammillary nucleus of the posterior hypothalamus. These neurons project to all major brain areas and are involved in a variety of important physiological functions, including the regulation of the sleep-wake cycle, cardiovascular control, hypothalamic pituitary adrenal-axis (HPA-axis), learning and memory. Histamine exerts its action via at least four distinct receptor subtypes. Molecular biological approaches have shown that all histamine receptors belong to the large family of G protein-coupled receptors.
The gene encoding the H3 receptor has been recently cloned. In contrast to the H1 and H2 receptor gene, the H3 receptor gene contains intronic sequences. Using the H3 receptor sequence, a new histamine (H4) receptor was identified 'in silico'. This receptor shows the strongest homology to the H3 receptor and recognises histamine with high affinity. For the H4 receptor, no pharmacological significance is presently known.

In view of the important role of H1 and H2 receptors in allergic responses and gastric acid secretion respectively, many potent and selective antagonists have been developed as successful drugs. The H3 receptor was originally described as an auto receptor, inhibiting the release of histamine from Histminegic neurons in brain. Recently, it was shown that this inhibitory effect is due to constitutive activity of the H3 receptor. The H3 receptor regulates the release of several important neurotransmitters (e.g. acetylcholine, dopamine, GABA, nor epinephrine, serotonin), in both the peripheral and central nervous systems. Highly potent and selective agonists and antagonists have recently been developed for the H3 receptor. These ligands are useful pharmacological tools for drug development in the areas like allergy, inflammatory disorders, attention deficit hyperactivity disorder, Alzheimer's disease and obesity.

Regulation of feeding behaviour
Thioperamide is a specific and potent histamine H3 receptor antagonist. It prevents the action of histamine neurons activity in vivo by removing the 'normal feedback autoinhibitory control system' histamine synthesis. ?-Fluoromethylhistidine (FMH) is a specific suicide inhibitor of histamine decarboxylase (HDC). A suicide inhibitor is a substrate activated by its specific enzyme and the biochemical reaction, which in turn, irreversibly inhibits activity of the target enzyme, because the substrate bounds to the catalysed metabolites throughout the catalytic processes. FMH inactivates HDC more specifically and potently than any other HDC inhibitors and inhibits HDC in a time-concentration-dependent manner.
When examined in Wistar King A (WKA) rats, intracerebroventricular (ICV) infusion of 100-nmol thioperamide into the third cerebroventricle potently and significantly suppressed food intake in them. This suppressive effect of thioperamide was abolished by ip pretreatment with chlorpheniramine (CPM), an H1-antagonist. If the feeding suppression induced by thioperamide depends on an increase in concentration of hypothalamic neuronal histamine, histamine depletion should accelerate feeding behaviour. WKA rats with ICV infusion of FMH increased food intake in a dose-dependent manner. Water intake and ambulatory activity were also affected by the same manipulation of neuronal histamine. The VMH and the PVN, important areas in hypothalamic histamine and H1-receptor, responded to CPM by feeding elicitation, but application to the remaining regions had no effect. Bilateral micro infusion of H2-receptor antagonists into the same nuclei showed no effect on feeding behavior. Effects of CPM on neuronal activity in the VMH and the LHA were further examined iontophoretically. The results proved that H1-antagonist specifically and selectively suppressed the activity of feeding related neurons in the VMH significantly, but not neurons in the LHA.

It is indicated that neuronal histamine transmits signals to suppress food intake through H1-receptor in the VMH and the PVN. This histminegic neuronal transudation is conveyed through the histminegic pathway that originates from cell bodies localised in the tuberomammillary nuclei of the posterior hypothalamus.

Impact of mastication
Mastication is regulated through the mesencephalic trigeminal motor nucleus (MOM), which forms a reflex with the mesencephalic trigeminal sensory nucleus (Me5). Primary sensory afferents of the trigeminal nerve convey proprioceptive sensation from the oral cavity into the Me5. Proprioceptive sensation during mastication originates mainly from the periodontal ligaments and the muscle spindles in the masseters, a thick muscle in the cheek that closes the jaws during chewing. Unique to the central nervous system, the soma of the Me5 was shown to possess synaptic formation of histminegic fibres. Thus, mastication enhances satiation independently of caloric intake through activation of neuronal histamine in the VMH, while Me5 with the Mo5 through the reflex modulates eating speed.

Energy deficiency activates satiation
When WKA rats were fasted for at least 24-hour, concentration of hypothalamic histamine increased to almost double than that of the non-fasted controls. This activation of hypothalamic histminegic neurons induced by fasting may adequately explain the phenomenon of 'post-starvation anorexia.' Glycogen is the largest energy reservoir in the brain and is exclusively localised in astrocytes. Glycogenolysis in the rat brain is enhanced under conditions of food deprivation. These findings suggest that activation of hypothalamic histamine in response to an energy deficit may play an essential role in glucose utilisation, maintaining homeostatic control of energy supply in the brain.

Modulation of feeding circadian rhythm
Circadian rhythm of histamine concentration and HDC activity in the rat hypothalamus is well known. Thioperamide suppressed feeding by elevating activity of histminegic neurons during the early dark period, when the neuronal activity would otherwise have been low, and the rats would have normally eaten. ICV infusion of FMH in the early light, on the other hand, increased food intake by decreasing the concentration of neuronal histamine at a time when the histamine content would otherwise have been high, and the rats would rarely eat. It thus seems reasonable to estimate that the relation between feeding and histamine concentration may reflect the diurnal fluctuations of both.

Obese zucker rats
Genetically obese zucker rats are known to have various abnormalities in behaviour levels, metabolism, and neurohumoral factors, as with or aside from the abnormalities of VMH-lesioned rats. The mechanisms of these abnormalities of obese zucker rats remain unclear. To examine involvement of histamine in the abnormalities, manipulation of hypothalamic histamine was carried out in obese zucker rats. Activation of histamine neuron systems by ICV treatment with thioperamide decreased food intake in zucker lean littermates and WKA normal control rats. However, thioperamide failed to induce the suppressive effect in obese zucker rats. This deficient reaction to thioperamide indicates the possibility of histamine receptor insensitivity in obese zucker rats. The eating parameters of meal size, meal duration and eating speed were also evaluated in zucker rats. The obese zucker rat ate heavy meals with longer duration than its lean littermates. Eating speed of obese zucker rats was slower than that of the lean. Consequently, these abnormal eating patterns of the obese rats resulted in an increase of daily 24-hour food intake. These findings indicate that obese zucker rats may possess Histminegic dysfunction of both the VMH and the Me5.

These findings from obese zucker rats led us to measure histamine concentration and HDC activities in the hypothalamus in these rats. Concentration of hypothalamic histamine in obese zucker rats was less than one-tenth of that in the WKA controls. Residual histamine was mainly of mast-cell origin and there was only negligible histamine of neuronal origin. HDC in the zucker hypothalamus was relatively inactive compared with that in the lean and the WKA control rats. The changes in the amine concentration and the HDC activity were restricted to hypothalamic histamine. Neither histamine in the cerebral cortex nor other neurotransmitters including catecholamines and serotonin had an affect in the obese zucker rats.

Conclusion
Effects of neuronal histamine on feeding regulation and energy metabolism have been assessed in normal and zucker lean and obese rats. Histminegic neurons in the brain are involved in coordinating regulation of ingestive behaviour, circadian rhythm, mastication, homeostatic glucose supply into the brain against energy deficiency, and thermoregulation. Behavioral and metabolic abnormalities of obese zucker rats are estimated as a model caused by dysfunction of histamine neuron systems in the brain, because the inactivity and deficit in the functions of neuronal histamine induces similar abnormalities, whereas transplantation of lean fetal hypothalamus attenuates the abnormalities.

(The authors are with Pharmacy Practice, MCOPS, Manipal; Pharmacy Group, BITS-Pilani; JSS College of Pharmacy, Mysore)