Histaminergic Mechanisms Research Articles

Modulation of synergism COX-1 with COX-2 in the tail flick of mice

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used in the treatment of pain. In this study was evaluated, by isobolographic analysis, in a radiant heat model of mice, the tail flick, the potential antinociceptive pharmacological interaction of the combination between ketorolac and meloxicam and the modulation by tropisetron, risperidone, prazosin, yohimbine, naltrindole or 7-Nitroindazole. In the assay, the combination of ketorolac with meloxicam induces an additive interaction with an interaction index of 12.20 ± 0.92. Neither tropisetron nor risperidone nor prazosin nor yohimbine modify the nature of interaction, however naltrindole and 7-Nitroindazol change the nature of interaction from additive a subadditive with an interaction index of 16.85 ± 2.52 and 18.00 ± 2.57, respectively. The current results suggests that the interaction antinociceptive of the combination between ketorolac with meloxicam does not seem to be influenced by adrenergic, dopaminergic, histaminergic or serotonegic mechanisms. Nonetheless, the pretreatment of the mice with naltrindole or con 7-Nitroindazole induced a significant decrease in the antinociceptive power of the combination with a significant reduction in DE. It is suggested that DOR and NO may be involved, in the tail flick model, regulating the antinociceptive bioactivity of these NSAIDs.

Advances in the mechanisms of Hibiscus sabdariffa L. on hypertension

As a traditional edible beverage and medicinal application for high-pressure blood treatment with no side effects, Hibiscus sabdariffa L. (HS) has high prospect to be nutraceuticals as diet additive for anti-hypertension. The anti-hypertension effect of HS has also been scientific validated recently especially in diabetic patient and post-partum mothers. In this paper, we reviewed up-to-date mechanisms found for the anti-hypertensive effect of HS extracts. Those included the inhibition of angiotensin-converting enzymes (ACE) activity, diuretic effect, endothelium-derived nitric oxide-cGMP-relaxant pathway and inhibition of calcium (Ca2+)-influx into vascular smooth muscle cells, cholinergic and/or histaminergic mechanisms, reduction in the diffusion distance between capillaries and myocytes as well as new vessel formation. Phenolic acids, anthocyanins (e.g. cyanidin-3-sambubioside and delphinidin-3-sambubioside) and anthocyanin metabolites probably contribute mostly to the hypotensive activity.

Moringa oleifera Lam extract attenuates gastric ulcerations in high salt loaded rats

Moringa oleifera Lam is a plant used extensively both in traditional and orthodox medicine to treat myriad ailments, including gastrointestinal disorders. This study was carried out to investigate the effect of leaf extract of M. oleifera some gastrointestinal function parameters in high salt loaded rats. Acute toxicity study was done using 70 male white mice (18-20 g) were used for the study. They were randomly selected and assigned to 7 cages of 10 animals per cage. Percentage mortalities were converted to probits and plotted against the log 10 of the dose of the extract from which the LD 50 value was calculated. Fresh leaf extract of M. oleifera was Soxhlet extracted. 24 albino Wistar rats were randomly assigned into 4 main groups of 6 rats each. Fed on normal rat chow, high salt (8% NaCl) diet + 1% NaCl drinking water and/or M. oleifera extract (600 mg/kg bw). The feeding regimens lasted for 42 days. Results obtained revealed that the extract had an LD 50 value of 1,872.22 mg/kg from which a test dose of 600 mg/kg was derived for the feeding regimen. The salt fed rats had significantly (p<005) raised basal gastric acid output (9.03 ± 0.17 mmol/L/hr) compared with control (7.27 ± 0.17 mmol/L/hr), but had blunted response to administered histamine and cimetidine, while treatment with the extract enhanced the sensitivity of histamine in high salt loaded rats. Gastric mucus concentration was significantly (p<0.05) higher in the salt untreated group (0.25 ± 0.004 g) compared with other groups. The salt fed untreated group also had significantly (p<0.05) raised gastric ulcers (10.83 ± 0.70) compared with other groups, these were reversed following Moringa treatment . In conclusion, Moringa oleifera extract reverses gastric ulcers and blunted histaminergic receptors in high salt fed rats. The mechanism by which high salt increases gastric secretion is independent of the histaminergic mechanism.

Effect of Agonist and Antagonist on the In Vitro Contractility of Inflamed Vermiform Appendix.

Appendicitis poses a great health problem worldwide. Previous studies demonstrated structural damage to neuronal network and interstitial cell of Cajal in appendicitis. Above observations suggest for the alterations in appendicular motility/contractility in appendicitis. But the mechanisms involved in mediating the contractility in inflamed vermiform appendix is not known till date. The present in vitro study was performed to find out the mechanisms responsible for contractility in the inflamed human vermiform appendix. Contractions of the longitudinal muscle strips of inflamed appendix were recorded in vitro at 37±0.5°C. Control contractions were recorded for 30 min after an initial tension of 0.5 gram. Initially dose-response experiments of agonists (acetylcholine, serotonin and histamine) were performed separately and the dose that produced maximum contraction was determined with each agonist. This maximal dose of agonist was used to elicit contractions in next series of experiments before and after pre-treatment with appropriate antagonists like atropine, ondansetron (5-HT3 antagonist) and chlorpheniramine maleate respectively. Acetylcholine (ACh) and serotonin (5-HT) elicited maximum amplitude of contraction at 10 µM and 1 µM concentration respectively. These contractions were significantly blocked by prior exposure of muscle strips with atropine (100 µM) and ondansetron (10 µM). Histamine produced very low amplitude of contractions in comparison to ACh or 5-HT and did not exhibit dose-response relations. The histamine induced contractions were blocked by H1 antagonist chlorpheniramine maleate (100 µM). The observations suggested that the contractility of longitudinal muscle strips of inflamed vermiform appendix in human beings was predominantly mediated by muscarinic and serotonergic (5-HT3) mechanisms, whereas, histaminergic mechanisms played a minor role in mediating the contractility.

Histamine H3 Receptor Regulates Sensorimotor Gating and Dopaminergic Signaling in the Striatum.

The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling.

Forced Swimming Stress-Related Hypoalgesia:Nondependence on the Histaminergic Mechanisms

In experiments on mice, we examined the effects of 3-min-long forced swimming sessions on indices characterizing the state of the nociceptive system. Thirty minutes after the forced swimming episode, significantly shorter (P 0.05) the intensity of forced swimming-induced hypoalgesia in the tail flick and acetic acid-induced (writhing) tests. Thus, the histaminergic system is not significantly involved in the mechanisms of forced swimming-induced hypoalgesia.

Mirtazapine Provokes Periodic Leg Movements during Sleep in Young Healthy Men

Recent evidence suggests that certain antidepressants are associated with an increase of periodic leg movements (PLMS) that may disturb sleep. So far, this has been shown in patients clinically treated for depression and in cross-sectional studies for various substances, but not mirtazapine. It is unclear whether antidepressants induce the new onset of PLMS or only increase preexisting PLMS, and whether this is a general property of the antidepressant or only seen in depressed patients. We report here the effect of mirtazapine on PLMS in young healthy men. Open-labeled clinical trial (NCT00878540) including a 3-week preparatory phase with standardized food, physical activity, and sleep-wake behavior, and a 10-day experimental inpatient phase with an adaptation day, 2 baseline days, and 7 days with mirtazapine. Research institute. Twelve healthy young (20-25 years) men. Seven days of nightly intake (22:00) of 30 mg mirtazapine. Sleep was recorded on 2 drug-free baseline nights, the first 2 drug nights, and the last 2 drug nights. Eight of the 12 subjects showed increased PLMS after the first dose of mirtazapine. Frequency of PLMS was highest on the first drug night and attenuated over the course of the next 6 days. Three subjects reported transient restless legs symptoms. Mirtazapine provoked PLMS in 67% of young healthy males. The effect was most pronounced in the first days. The possible role of serotonergic, noradrenergic and histaminergic mechanisms in mirtazapine-induced PLMS is discussed.

Histaminergic regulation of seasonal metabolic rhythms in Siberian hamsters

We investigated whether histaminergic tone contributes to the seasonal catabolic state in Siberian hamsters by determining the effect of ablation of histaminergic neurons on food intake, metabolic rate and body weight. A ribosomal toxin (saporin) conjugated to orexin-B was infused into the ventral tuberomammillary region of the hypothalamus, since most histaminergic neurons express orexin receptors. This caused not only 75–80% loss of histaminergic neurons in the posterior hypothalamus, but also some loss of other orexin-receptor expressing cells e.g. MCH neurons. In the long-day anabolic state, lesions produced a transient post-surgical decrease in body weight, but the hamsters recovered and maintained constant body weight, whereas weight gradually increased in sham-lesioned hamsters. VO2 in the dark phase was significantly higher in the lesioned hamsters compared to shams, and locomotor activity also tended to be higher. In a second study in short days, sham-treated hamsters showed the expected seasonal decrease in body weight, but weight remained constant in the lesioned hamsters, as in the long-day study. Lesioned hamsters consumed more during the early dark phase and less during the light phase due to an increase in the frequency of meals during the dark and decreased meal size during the light, and their cumulative food intake in their home cages was greater than in the control hamsters. In summary, ablation of orexin-responsive cells in the posterior hypothalamus blocks the short-day induced decline in body weight by preventing seasonal hypophagia, evidence consistent with the hypothesis that central histaminergic mechanisms contribute to long-term regulation of body weight.

Histaminergic Mechanisms for Modulation of Memory Systems

Encoding for several memory types requires neural changes and the activity of distinct regions across the brain. These areas receive broad projections originating in nuclei located in the brainstem which are capable of modulating the activity of a particular area. The histaminergic system is one of the major modulatory systems, and it regulates basic homeostatic and higher functions including arousal, circadian, and feeding rhythms, and cognition. There is now evidence that histamine can modulate learning in different types of behavioral tasks, but the exact course of modulation and its mechanisms are controversial. In the present paper we review the involvement of the histaminergic system and the effects histaminergic receptor agonists/antagonists have on the performance of tasks associated with the main memory types as well as evidence provided by studies with knockout models. Thus, we aim to summarize the possible effects histamine has on modulation of circuits involved in memory formation.

Beneficial interaction between clobenpropit and pyridoxine in prevention of electroshock-induced seizures in mice: Lack of histaminergic mechanisms

Clobenpropit, an H( 3) receptor antagonist, has been reported to modulate both the release of neurotransmitters and also the activity of histidine decarboxylase (HDC). Therefore, a decarboxylase-positive modulator, namely pyridoxine, was taken for interaction studies with clobenpropit in the electroshock (ES) model of seizures in mice and subsequent changes in brain histamine levels were estimated. A significant inhibition of ES-induced seizures was seen after the simultaneous use of clobenpropit and pyridoxine. No significant effects were evident on the brain histamine levels following this combination. The combination of clobenpropit with pyridoxine appears to exhibit beneficial pharmacodynamic interaction for the prevention of ES-induced seizures, which might not be mediated by the histaminergic mechanisms.

Histamine H3 receptor activation decreases kainate‐induced hippocampal gamma oscillations in vitro by action potential desynchronization in pyramidal neurons

The study of rhythmic electrical activity in slice preparations has generated important insights into neural network function. While the synaptic mechanisms involved in the generation of in vitro network oscillations have been studied widely, little is known about the modulatory influence exerted on rhythmic activity in neuronal networks by neuropeptides and biogenic amines. Gamma oscillations play an important role in cognitive processes and are altered or disrupted in disorders such as Alzheimer's disease (AD) and schizophrenia. Given the importance of gamma oscillations for learning, memory and cognition processes as well as the recent interest in histamine H(3) receptors in the development of pro-cognitive drugs to treat disorders such as AD and schizophrenia, it is relevant to study the impact of histaminergic mechanisms on network gamma oscillations. Here we show for the first time a modulation of gamma oscillation by histaminergic mechanisms. Selective activation of the H(3) receptor by R-alpha-methylhistamine significantly reduces the power of kainate-induced gamma oscillations, but not carbachol-induced gamma oscillations, in the rat hippocampal slice preparation without affecting oscillation frequency. This effect is neither caused by a decrease in excitatory or inhibitory postsynaptic currents, nor a decrease in cellular excitability. Instead, we find that the decrease in oscillation power following H(3) receptor activation results from a desynchronization of pyramidal neuron action potential firing with regard to the local field potential oscillation cycle. Our data provide a possible mechanism of action for histamine in regulating gamma oscillations in the hippocampal network.

Histaminergic and cholinergic neuron systems in the impairment of human thermoregulation during motion sickness

Motion sickness (MS) exaggerates body cooling during cold-water immersion. The aim of the present study was to investigate whether such MS-induced predisposition to hypothermia is influenced by two anti-MS drugs: the histamine-receptor blocker dimenhydrinate (DMH) and the muscarine-receptor blocker scopolamine (Scop). Nine healthy male subjects were immersed in 15 °C water for a maximum of 90 min in five conditions: (1) control (CN): no medication, no MS provocation; (2) MS-control (MS-CN): no medication, MS provocation; (3) MS-placebo (MS-P): placebo DMH and placebo Scop, MS provocation; (4) MS-DMH: DMH and placebo Scop, MS provocation; (5) MS-Scop: Scop and placebo DMH, MS provocation. MS was induced by use of a rotating chair. Throughout the experiments rectal temperature ( T re ), the difference in temperature between the non-immersed right forearm and third finger ( T ff ) as an index of peripheral vasoconstriction, and oxygen uptake ( VO 2) as a measure of shivering thermogenesis, were recorded. DMH and Scop were similarly efficacious in ameliorating nausea. The fall in T re was greater in the MS-CN and MS-P conditions than in the CN condition. DMH, but not Scop, prevented the MS-induced increase in body-core cooling. MS attenuated the cold-induced vasoconstriction, an effect which was fully prevented by DMH but only partially by Scop. MS provocation did not affect VO 2 in any condition. The results suggest that the MS-induced predisposition to hypothermia is predominantly mediated by histaminergic mechanisms and that DMH might be useful in conjunction with maritime accidents or other scenarios where exposure to cold and MS are imminent features.

Carnosine inhibits pentylenetetrazol-induced seizures by histaminergic mechanisms in histidine decarboxylase knock-out mice

In the present study, we used both histidine decarboxylase-deficient (HDC-KO) mice and wild-type (WT) mice to elucidate the possible role of carnosine in pentylenetetrazol (PTZ)-induced seizures. In the acute PTZ challenge study, PTZ (75 mg/kg) was injected intraperitoneally (i.p.) to induce seizures. Carnosine (200, 500 or 1000 mg/kg, i.p.) significantly decreased seizure stage, and prolonged the latency for myoclonic jerks in WT mice in a dose-dependent manner. The effects of carnosine (500 mg/kg) were time-dependent and reached a peak at 1 h. However, it had no significant effect on HDC-KO mice. Carnosine (500 mg/kg) also significantly elevated the thresholds in WT mice but not HDC-KO mice following intravenous (tail vein) administration of PTZ. We also found that α-fluoromethylhistidine substantially reversed the protective effects of carnosine in WT mice. In addition, carnosine pretreatment reduced the cortical EEG activity induced by PTZ (75 mg/kg, i.p.). These results indicate that carnosine can protect against PTZ-induced seizures and its action is mainly through the carnosine–histidine–histamine metabolic pathway. This suggests that carnosine may be an endogenous anticonvulsant factor in the brain and may be used as a new antiepileptic drug in the future.

Histaminergic modulation of acoustically induced running behavior in rats

Explosive running is a reliable initial component of audiogenic seizures (AS) induced by acoustic stimulation in genetically prone rodents. This profound locomotor activation is usually considered as a convulsive manifestation of AS although some studies attribute running to a panic-like response. Increase in central histamine activity has been shown to suppress clonic and tonic seizures. The present study examined the involvement of histaminergic mechanisms in the expression of running component of AS. Metoprine, an inhibitor of histamine- N-methyltransferase, was used to increase brain histamine level. Running was induced 4 and 24 h after intraperitoneal injection of metoprine or vehicle in rats of different strains. A brief sound stimulation elicited running followed by clonic–tonic convulsions in Krushinsky–Molodkina (KM) rats or running alone in AS-prone Wistar and WAG/Rij rats. In KM rats, metoprine exerted opposite effects on the main phases of AS. It increased the duration of running and decreased the duration and severity of clonic–tonic convulsions. In Wistar rats, metoprine produced a remarkable aggravation of running leading to its 2- to 3-fold prolongation. In WAG/Rij rats with mixed seizures (absence and audiogenic), the drug caused either aggravation or suppression of running behavior. These results suggest specific role for histaminergic system in the expression of behavioral components of AS. Suppressive role of histamine in clonic–tonic seizures is associated with facilitation of running suggesting specific effects of histamine on brainstem neuronal networks underlying these phases of AS. Possible roles of histaminergic mechanisms in seizure, motor and aversive aspects of sound-induced running are discussed.

The brain H 3-receptor as a novel therapeutic target for vigilance and sleep–wake disorders

Brain histaminergic neurons play a prominent role in arousal and maintenance of wakefulness (W). H 3-receptors control the activity of histaminergic neurons through presynaptic autoinhibition. The role of H 3-receptor antagonists/inverse agonists (H 3R-antagonists) in the potential therapy of vigilance deficiency and sleep–wake disorders were studied by assessing their effects on the mouse cortical EEG and sleep–wake cycle in comparison to modafinil and classical psychostimulants. The H 3R-antagonists, thioperamide and ciproxifan increased W and cortical EEG fast rhythms and, like modafinil, but unlike amphetamine and caffeine, their waking effects were not accompanied by sleep rebound. Conversely, imetit (H 3R-agonist) enhanced slow wave sleep and dose-dependently attenuated ciproxifan-induced W, indicating that the effects of both ligands involve H 3-receptor mechanisms. Additional studies using knockout (KO) mice confirmed the essential role of H 3-receptors and histamine-mediated transmission in the wake properties of H 3R-antagonists. Thus ciproxifan produced no increase in W in either histidine-decarboxylase (HDC, histamine-synthesizing enzyme) or H 1- or H 3-receptor KO-mice whereas its waking effects persisted in H 2-receptor KO-mice. These data validate the hypothesis that H 3R-antagonists, through disinhibition of H 3-autoreceptors, enhancing synaptic histamine that in turn activates postsynaptic H 1-receptors promoting W. Interestingly amphetamine and modafinil, despite their potent arousal effects, appear unlikely to depend on histaminergic mechanism as their effects still occurred in HDC KO-mice. The present study thus distinguishes two classes of wake-improving agents: the first acting through non-histaminergic mechanisms and the second acting via histamine and supports brain H 3-receptors as potentially novel therapeutic targets for vigilance and sleep–wake disorders.

Ginkgo biloba extract improves spatial memory in rats mainly but not exclusively via a histaminergic mechanism

In order to clarify the mechanism of Ginkgo biloba extract (GBE) on learning and memory, we studied the effect of GBE on spatial memory deficits induced by diphenhydramine, pyrilamine and scopolamine using the eight-arm radial maze performance of rats, in comparison with donepezil. Total error (TE), reference memory error (RME) and working memory error (WME) were used as indices of spatial memory deficits. Both GBE and donepezil caused a potent antagonistic effect on the increase in TE, RME and WME induced by diphenhydramine. GBE and donepezil also antagonized scopolamine-induced spatial memory deficits. Although the antagonistic effect of GBE on pyrilamine-induced spatial memory deficits was weak, a significant difference was observed with TE and WME. However, donepezil caused no antagonistic effect on pyrilamine-induced memory deficits. From these findings, we concluded that the effects of GBE are mainly contributable to cholinergic activity and perhaps partly due to a histaminergic mechanism.

H1and H2receptors mediate postexercise hyperemia in sedentary and endurance exercise-trained men and women

In sedentary individuals, H(1) receptors mediate the early portion of postexercise skeletal muscle hyperemia, whereas H(2) receptors mediate the later portion. It is not known whether postexercise hyperemia also presents in endurance-trained individuals. We hypothesized that the postexercise skeletal muscle hyperemia would also exist in endurance-trained individuals and that combined blockade of H(1) and H(2) receptors would abolish the long-lasting postexercise hyperemia in trained and sedentary individuals. We studied 28 sedentary and endurance trained men and women before and through 90 min after a 60-min bout of cycling at 60% peak O(2) uptake on control and combined H(1)- and H(2)-receptor antagonist days (fexofenadine and ranitidine). We measured arterial pressure (brachial auscultation) and femoral blood flow (Doppler ultrasound). On the control day, femoral vascular conductance (calculated as flow/pressure) was elevated in all groups 60 min after exercise (sedentary men: Delta86 +/- 35%, trained men, Delta65 +/- 18%; sedentary women, Delta61 +/- 19%, trained women: Delta59 +/- 23%, where Delta is change; all P < 0.05 vs. preexercise). In contrast, on the histamine antagonist day, femoral vascular conductance was not elevated in any of the groups after exercise (sedentary men: Delta21 +/- 17%, trained men: Delta9 +/- 5%, sedentary women: Delta19 +/- 4%, trained women: Delta11 +/- 11%; all P > 0.16 vs. preexercise; all P < 0.05 vs. control day). These data suggest postexercise skeletal muscle hyperemia exists in endurance trained men and women. Furthermore, histaminergic mechanisms produce the long-lasting hyperemia in sedentary and endurance-trained individuals.

2. Histaminergic mechanisms in the CNS

2. Histaminergic mechanisms in the CNS

Possible mechanisms of hypotension produced 70% alcoholic extract of Terminalia arjuna (L.) in anaesthetized dogs.

BackgroundThe bark of Terminalia arjuna L. (Combretaceae) is used in Ayurveda since ancient times for the treatment of cardiac disorders. Previous laboratory investigations have demonstrated the use of the bark in cardiovascular complications. The present study was aimed to find the effect of 70% alcoholic extract of Terminalia arjuna on anaesthetized dog blood pressure and probable site of action.MethodsSix dogs were anaesthetized with intraperitoneal injection of thiopental sodium and the blood pressure of each dog (n = 6) was measured from the left common carotid artery connected to a mercury manometer on kymograph. The femoral vein was cannulated for administration of drug solutions. The extract of T. arjuna (dissolved in propylene glycol) in the dose range of 5 to 15 mg/kg were administered intravenously in a pilot study and the dose (6 mg/kg) which produced appreciable hypotension was selected for further studies.ResultsIntravenous administration of T. arjuna produced dose-dependent hypotension in anaesthetized dogs. The hypotension produced by 6 mg/kg dose of the extract was blocked by propranolol but not by atropine or mepyramine maleate. This indicates that muscarinic or histaminergic mechanisms are not likely to be involved in the hypotension produced by the extract. The blockade by propranolol of the hypotension produced by T. arjuna indicates that the extract might contain active compound(s) possessing adrenergic ß2-receptor agonist action and/or that act directly on the heart muscle.ConclusionThe results indicated the likely involvement of peripheral mechanism for hypotension produced by the 70% alcoholic extract of Terminalia arjuna and lends support for the claims of its traditional usage in cardiovascular disorders.

Serotonergic and histaminergic mechanisms involved in intralipid drinking?

Some newer antipsychotic agents are associated with weight gain in humans and a hyperphagic response to intralipid solutions in rodents. To examine the possible contribution of serotonin (5-HT) and histamine (H) receptor blockade in antipsychotic-associated hyperphagia, rats were trained to drink a palatable, high-calorie fat emulsion (10% intralipid) during 30-min sessions and were tested following pretreatment with mepyramine (H 1 receptor antagonist), metergoline (5-HT 1/2 receptor antagonist), cyproheptadine (H 1 and 5-HT 2A/2B/2C and muscarinic receptor antagonist), SB 242084 (5-HT 2C receptor antagonist) and an SB 242084–mepyramine combination. Total intake and ingestive behaviour microstructure were measured. Mepyramine (10 mg/kg) reduced intake, as did metergoline (3.0 mg/kg). Cyproheptadine (0.1–1.0 mg/kg) increased intake and microstructural analysis suggests that this was due to increased numbers of clusters of licking. SB 242084 (3 mg/kg) reduced intake, either when administered alone, or in combination with mepyramine (1 mg/kg). In conclusion, simple antagonism of either H 1 (mepyramine) or 5-HT 1/2 receptors (metergoline) alone was not sufficient to increase intake. Furthermore, combined blockade of H 1 and 5-HT 2C receptors (SB 242084 and mepyramine) was also insufficient to produce hyperphagia. Conversely, simultaneous blockade of H 1, 5-HT 2A/2C and muscarinic receptors (cyproheptadine) led to a substantial hyperphagia and pattern of ingestive behaviour that was similar to that previously observed with some newer antipsychotic agents.