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New antiretroviral agents with alternative mechanisms are needed to complement the combination therapies used to treat HIV-1 infections. Here we report the identification of bioavailable molecules that interfere with the gene expression processes of HIV-1. The compounds were detected by screening a small library of FDA-approved drugs with an assay based on measuring the displacement of Rev, and essential virus-encoded protein, from its high-affinity RNA binding site. The antiretroviral activity of two hits was based on interference with post-integration steps of the HIV-1 cycle. Both hits inhibited RRE-Rev complex formation in vitro, and blocked LTR-dependent gene expression and viral transcription in cellular assays. The best compound altered the splicing pattern of HIV-1 transcripts in a manner consistent with Rev inhibition. This mechanism of action is different from those used by current antiretroviral agents. The screening hits recognized the Rev binding site in the viral RNA, and the best compound did so with substantial selectivity, allowing the identification of a new RNA-binding scaffold. These results may be used for developing novel antiretroviral drugs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The southern cattle tick (Rhipicephalus (Boophilus) microplus) is a hematophagous external parasite that vectors the causative agents of bovine babesiosis or cattle tick fever, Babesia bovis and B. bigemina, and anaplasmosis, Anaplasma marginale. The southern cattle tick is a threat to the livestock industry in many locations throughout the world. Control methods include the use of chemical acaricides including amitraz, a formamidine insecticide, which is proposed to activate octopamine receptors. Previous studies have identified a putative octopamine receptor from the southern cattle tick in Australia and the Americas. Furthermore, this putative octopamine receptor could play a role in acaricide resistance to amitraz. Recently, sequence data indicated that this putative octopamine receptor is probably a type-1 tyramine receptor (TAR1). In this study, the putative TAR1 was heterologously expressed in Chinese hamster ovary (CHO-K1) cells, and the expressed receptor resulted in a 39-fold higher potency for tyramine compared to octopamine. Furthermore, the expressed receptor was strongly antagonized by yohimbine and cyproheptadine, and mildly antagonized by mianserin and phentolamine. Tolazoline and naphazoline had agonistic or modulatory activity against the expressed receptor, as did the amitraz metabolite, BTS-27271; however, this was only observed in the presence of tyramine. The southern cattle tick's tyramine receptor may serve as a target for the development of anti-parasitic compounds, in addition to being a likely target of formamidine insecticides., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In crustaceans, serotonin (5-HT) controls various physiological processes, such as hormonal secretion, color changes, reproduction, and metabolism. Since 5-HT injections cause hyperglycemia, this study was designed to further investigate this action of 5-HT in the crab Neohelice granulate, fed with a high-carbohydrate (HC) or a high-protein (HP) diet. The effects of pre-treatment with mammalian 5-HT receptor antagonists, cyproheptadine and methiothepin, were also investigated. A series of in vivo experiments with (3)H-5-HT was carried out in order to investigate the presence of putative receptors in peripheral tissues. Since gills were the tissue with the highest labeling in in vivo experiments, in vitro studies with isolated anterior and posterior gills were also conducted. Cyproheptadine blocked the hyperglycemic effect of 5-HT in HP-fed crabs. Methiothepin reduced glycogen levels in the anterior gills of HP crabs and partially blocked the 5-HT-like posture. The injection of (3)H-5-HT identified specific binding sites in all the tissues studied and revealed that the binding can be influenced by the type of diet administered to the crabs. Incubation of the anterior and posterior gills with (3)H-5-HT and 5-HT confirmed the specificity of the binding sites. Both antagonists inhibited (3)H-5-HT binding. In conclusion, this study highlights the importance of serotonin in the control of glucose homeostasis in crustaceans and provides evidences of at least two types of 5-HT binding sites in peripheral tissues. Further studies are necessary to identify the structure of these receptors and their signaling pathways., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Nobiletin isolated from citrus peels up-regulates synaptic transmission and improves memory impairment in rodents. This study investigated the antidepressant-like effect of nobiletin in the forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the monoaminergic mechanisms involved in the antidepressant-like effect of nobiletin in mice were also assessed. Nobiletin (25, 50 and 100mg/kg, p.o.) decreased the immobility time in both the FST and TST without locomotor alterations in the open-field test (OFT). The anti-immobility effect of nobiletin (50mg/kg, p.o.) was completely prevented by the pretreatment of mice with WAY 100635 (0.1mg/kg, s.c., a serotonin 5-HT(1A) receptor antagonist), cyproheptadine (3mg/kg, i.p., a serotonin 5-HT(2) receptor antagonist), prazosin (62.5μg/kg, i.p., an α(1)-adrenoceptor antagonist), SCH23390 (0.05mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist). On the other hand, the pretreatment of mice with yohimbine (1mg/kg, i.p., an α(2)-adrenoceptor antagonist) or propranolol (5mg/kg, i.p., a β-adrenoceptor antagonist) did not block the antidepressant-like effect of nobiletin in the TST. Taken together, the data demonstrated that nobiletin produced an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. Thus, the present study suggests the therapeutic potential of this dietary flavonoid for the treatment of depression., (2010 Elsevier Inc. All rights reserved.)

The biogenic amines are widespread regulators of physiological processes, and play an important role in regulating heart rate in diverse organisms. Here, we present the first pharmacological evidence for a role of the biogenic amines in the regulation of dorsal blood vessel pulse rate in an aquatic oligochaete, Lumbriculus variegatus (Müller, 1774). Bath application of octopamine to intact worms resulted in an acceleration of pulse rate, but not when co-applied with the adenylyl cyclase inhibitor MDL-12,330a. The phosphodiesterase inhibitor theophylline mimicked the effects of OA, but the polar adenosine receptor antagonist 8(p-sulphophenyl)theophylline was significantly less potent than theophylline. Pharmacologically blocking synaptic reuptake of the biogenic amines using the selective 5-HT reuptake blocker fluoxetine or various tricyclic antidepressants also accelerated heart rate. Depletion of the biogenic amines by treatment with the monoamine vesicular transporter blocker reserpine dramatically depressed pulse rate. Pulse rate was partially restored in amine-depleted worms after treatment with octopamine or dopamine, but fully restored following treatment with serotonin. This effect of 5-HT was weakly mimicked by 5-methoxytryptamine, but not by alpha-methylserotonin; it was completely blocked by clozapine and partially blocked by cyproheptadine. Because they are known to orchestrate a variety of adaptive behaviors in invertebrates, the biogenic amines may coordinate blood flow with behavioral state in L.variegatus., (Copyright 2010 Elsevier Inc. All rights reserved.)

Serotonin (5-hydroxytryptamine; 5-HT)-toxicity syndrome, an iatrogenic brain disorder induced by excessive efflux of 5-HT, has received much attention because of increasing incidents of serotonergic antidepressants. However, the neural mechanism by which extracellular 5-HT is elevated to a toxic level for the syndrome remains to be determined. The goal of the present study was to test the hypothesis that extracellular 5-HT is composed of two component effluxes responsible for distinct aspects of the syndrome. The first set of experiments was to characterize the syndrome by measuring changes in neuromuscular signs, body-core temperature and mortality rate. Our results indicate that the syndrome severity can be categorized into mild, moderate and severe levels. The second set of experiments was to determine a threshold of extracellular 5-HT for induction of each level of the syndrome. Our results demonstrate that there were an 11-fold increase in the mild syndrome and an over 55-fold increase in the severe syndrome. In the last series of experiments, the excessive increases in 5-HT were pharmacologically separated into primary and secondary component effluxes with the 5-HT2A receptor antagonists cyproheptadine and ketanserin and NMDA receptor antagonist (+)-MK-801. Our results suggest that the primary component efflux was caused by direct drug effects on 5-HT biosynthetic and metabolic pathways and secondary efflux ascribed to indirect drug effect on a positive-feedback circuit involving 5-HT2A and NMDA receptors. In summary, the primary efflux could be an initial cause for the induction of the syndrome while the secondary efflux might involve deterioration of the syndrome.

Patients are at high risk of developing serotonin-toxicity syndrome (toxidrome) when they take multiple serotonergic drugs, particularly co-administered with monoamine oxidase inhibitors or 5-hydroxytryptamine (5-HT) reuptake blockers. The toxidrome can vary from mild to severe. The primary goal of the present study was to understand the relationship between behavioral signs and degrees of toxidrome induced by 5-hydroxy-l-tryptophan (5-HTP) in clorgylinized rats. The severity was obtained by scoring behavioral signs including head shakes, penile erection, forepaw treading, hind limb abduction, Straub tail and tremor. It was found that 5-HTP produced a dose-dependent increase in degrees of the toxidrome. Furthermore, correlation between the toxidrome and changes in body-core temperature (delta Tcor) was determined. There was hypothermia in the mild toxidrome (delta Tcor<-1 degrees C), high hyperthermia in the severe toxidrome (delta Tcor>+2 degrees C) and a small change in T(cor) in the moderate toxidrome (-1 degrees C

Female NC/Jic mice were sensitized and challenged repeatedly at 48 h intervals for 10 and 30 days by painting 1% 2,4,6-trinitrochlorobenzene (TNCB) on both ears. Mice challenged with TNCB for 30 days developed an inflammatory dermatitis with high immunoglobulin E (IgE) titer. Histological analysis with acidic Toluidine Blue staining revealed that dermal mast cells markedly differentiated and intensely degranulated, consistent with a dramatic increase in scratching behavior. A significant increase in total scratching events could be observed in mice treated with TNCB for a short period of 10 days. Extending the term of TNCB application to 30 days, the IgE titer and number of mast cells elevated significantly, and thus various drugs were evaluated pharmacologically by using the mice treated with TNCB for 30 days. Terfenadine and cyproheptadine attenuated the chronic scratching behavior. Tacrolimus and dexamethasone were less effective and cromolyn showed no effect. In addition, terfenadine and tacrolimus suppressed the degranulation of mast cells. The present chronic scratching model could be suitable to evaluate drugs effective for suppression of mast cell differentiation and degranulation by irritation, and may represent a promising tool to develop new drugs for inflammatory pruritus associated with, for example, atopic dermatitis.

This study was undertaken to investigate the interactive effect of histamine and prostaglandin D(2) in nasal allergic symptoms in rats. The intranasal application of histamine at doses lower than 10 mumol/site caused no sneezing or nasal rubbing. In addition, prostaglandin D(2) also showed no significant increase in these responses, even at a dose of 10 nmol/site. On the other hand, the simultaneous instillation of histamine and prostaglandin D(2) resulted in a 1000 times more potent effect in inducing nasal symptoms than the administration of histamine alone. Thus, prostaglandin D(2) enhanced the actions of histamine in inducing sneezing and nasal rubbing in a dose-dependent manner, and significant effects were observed at doses higher than 1 nmol/site. The responses induced by the simultaneous application of histamine and prostaglandin D(2) were inhibited by chlorpheniramine, cyproheptadine, BW A868C and ramatroban. Chlorpheniramine and cyproheptadine showed the dose-related inhibition of nasal symptoms induced by the combined administration of histamine (10 nmol) and prostaglandin D(2) (10 nmol), but the effect of cyproheptadine was relatively weak compared with chlorpheniramine. Moreover, BW A868C and ramatroban also showed the inhibition of nasal symptoms induced by the simultaneous administration of histamine and prostaglandin D(2) in a dose-dependent manner. BW A868C was more potent in inhibiting the nasal symptoms than ramatroban. These results clearly indicate that prostaglandin D(2) showed a synergistic effect on sneezing and nasal rubbing induced by histamine in rats, and its effect occurred through both prostaglandin D(2) and CRTH2 (chemoattractant receptor-homologous molecule expressed on TH2 cells) receptors.

Spontaneous calcium release from the sarcoplasmic reticulum in cardiac myocytes plays a central role in cardiac arrhythmogenesis. Compounds intended for therapeutical use that interfere with intracellular calcium handling may therefore have an undesired proarrhythmic potential. Here we have used isolated human atrial myocytes to compare the effect of the proarrhythmic antihistaminic drug terfenadine with the non-proarrhythmic antihistaminic drugs fexofenadine and rupatadine on intracellular calcium homeostasis. Perforated patch-clamp technique was used to measure ionic currents and to detect spontaneous calcium release from the sarcoplasmic reticulum. Our results show that the compound terfenadine, with known arrhythmogenic effects, inhibits L-type calcium current (I(Ca)) with an IC(50) of 185 nM when cells are stimulated at 1.0 Hz. The inhibitory effect of 0.3 muM terfenadine increased from 19+/-4% at stimulation frequency of 0.2 Hz to 63+/-6% at 2.0 Hz. Moreover, terfenadine also increased spontaneous calcium release from the sarcoplasmic reticulum. At a concentration of 1 muM, terfenadine significantly increased the spontaneous Na-Ca exchange current (I(NCX)) frequency from 0.48+/-0.25 to 1.93+/-0.67 s(-1). In contrast, fexofenadine and rupatadine did not change I(Ca) or the frequency of spontaneous I(NCX). We conclude that the proarrhythmic antihistaminic drug terfenadine alters intracellular calcium handling in isolated human atrial myocytes. This experimental model may be suitable to screen for potential arrhythmogenic side-effects of compounds intended for therapeutical use.

Antiallergic drug cyproheptadine (Cyp) is known to have inhibitory activities for L-type calcium channels in addition to histamine and serotonin receptors. Since we found that Cyp had an inhibitory activity against N-type calcium channel, Cyp was optimized to obtain more selective N-type calcium channel blocker with analgesic action. As a consequence of the optimization, we found 13 with potent N-type calcium channel inhibitory activity which had lower inhibitory activities against L-type calcium channel, histamine (H1), and serotonin (5-HT2A) receptors than those of Cyp. 13 showed an oral analgesic activity in rat formalin-induced pain model.

The present study was undertaken to investigate the pathological role of substance P in allergic nasal symptoms in rats. The topical application of substance P caused an increase in the incidence of sneezing and nasal rubbing in a dose-dependent fashion, and at a dose of 30 nM/site it showed a significant effect. L-732,138, a tachykinin NK(1) receptor antagonist, at doses of 3 and 10 mg/kg showed a significant inhibition of the nasal signs induced by exogenous substance P in rats. In addition, L-732,138 also showed a significant inhibition of nasal behavior induced by antigen in actively sensitized rats at the same dose. On the other hand, histamine H(1) receptor antagonists, such as cyproheptadine, epinastine and olopatadine had no effect on the nasal behaviors induced by exogenous substance P, even at higher doses, indicating that exogenous substance P does not cause the degranulation of mucosal mast cells in the rat. Moreover, all the histamine H(1) receptor antagonists showed the dose-dependent inhibition of the nasal signs induced by antigen in actively sensitized rats, which revealed that the inhibition of these drugs was exhibited through the antagonistic effect on histamine H(1) receptors. Therefore, from these results, it is reasonable to conclude that substance P released from the nasal mucosa through the activation of tachykinin NK(1) receptors during the antigen antibody reaction plays an important role in allergic nasal symptoms.

We investigated the effects of several agents on the established itching model in NC/Nga mice, model of atopic dermatitis-like disease, to elucidate related characteristics. The number of spontaneous scratching behaviors (the duration time is over 1.5 s) by NC/Nga mice with severe skin lesions was measured before and after administration of agents for 24 h. The scratching behavior by NC/Nga mice was significantly suppressed by administration of dexamethasone or tacrolimus, but not by chlorpheniramine maleate or cyproheptadine hydrochloride. These results suggest that this method shows a good correlation with the effectiveness of drugs prescribed for itching in humans with atopic dermatitis, and histamine and serotonin do not play an important role in causing the scratching behavior seen by NC/Nga mice. The scratching behavior was also significantly suppressed by naloxone hydrochloride, dibucaine or capsaicin. These results suggest that the scratching behavior seen in this model is caused by itching signal transmission through neural system. Furthermore, we found that theophylline, pinacidil or limaprost had scratching suppression effects in this model.

The ability of allergens to induce hyperalgesia in immunoglobulin E (IgE)-sensitized rats was investigated. The left hind paws of Wistar rats were sensitized with intraplantar injections of IgE anti-dinitrophenylated bovine serum albumin monoclonal antibody, and challenged with dinitrophenylated bovine serum albumin 24 h later. Allergen challenge yielded rapid thermal hyperalgesia and oedema formation in the ipsilateral paws, both reaching a plateau from 15 min to 3 h, and both diminishing thereafter. Allergen-evoked hyperalgesia was inhibited by intraperitoneal treatment with meclizine or methysergide, histamine and 5-hydroxytryptamine receptor antagonists. There was also sensitivity to local treatment with either bradykinin B(1) or B(2) receptor antagonists, des-Arg(9)-[Leu(8)]-bradykinin or D-arginyl-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin (Hoe 140). Anaphylactic hyperalgesia was mimicked by the combined administration of histamine, 5-hydroxytryptamine and bradykinin at doses which were ineffective when injected alone. This synergistic effect was abolished by treatment with either meclizine, methysergide, Hoe 140 or des-Arg(9)-[Leu(8)]-bradykinin. Our findings show that local thermal hyperalgesia is a feature of allergen-evoked inflammation, and that a synergistic interaction among bradykinin, 5-hydroxytryptamine and histamine plays a critical role in this phenomenon.

The centrally acting muscle relaxant cyclobenzaprine decreases the amplitude of monosynaptic reflex potentials by inhibiting the facilitatory descending serotonergic influences in the spinal cord. Interestingly, the structure of cyclobenzaprine is much similar to those of amitriptyline and cyproheptadine. In the present study, we attempted to elucidate the relationship between 5-HT(2) receptor antagonistic and inhibitory effects of cyclobenzaprine, amitriptyline, cyproheptadine and ketanserin on the spinal reflexes. Cyclobenzaprine, amitriptyline, cyproheptadine, and ketanserin significantly inhibited facilitatory effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on flexor reflexes and mono- and polysynaptic spinal reflex potentials in spinalized rats. In intact rats, these drugs significantly reduced the mono- and polysynaptic reflex potentials. 5-HT depletion significantly prevented the depression of the spinal reflex potentials induced by these drugs. These results suggest that the inhibitory effects of cyclobenzaprine, amitriptyline, and cyproheptadine on mono- and polysynaptic reflex potentials are due to the inhibition of descending serotonergic systems through 5-HT(2) receptors in the spinal cord.

An antihistaminic drug, cyproheptadine (20-25mg/kg x 4 days), showed significant schizontocidal activity in the blood against a lethal multidrug-resistant (MDR) strain of Plasmodium yoelii nigeriensis (highly resistant to chloroquine, mefloquine, and quinine); the protection of mice ranged between 75 and 100%. A combination of cyproheptadine (15 mg/kg) and chloroquine improved antimalarial activity compared to treatment with either drug alone, whereas a combination of cyproheptadine with quinine or mefloquine did not improve its antimalarial activity. Chloroquine and cyproheptadine inhibited haem polymerization activity in cell-free extracts and in in vivo experiments with MDR P. yoelii, but the combination did not cause a more significant inhibition than found with either drug alone. Cyproheptadine has been shown to produce dose-dependent inhibition of haem polymerization activity both in vitro and in vivo. The mechanism of the antimalarial action of cyproheptadine and its enhanced antimalarial activity with chloroquine could be due, in part, to their inhibitory effect on haem polymerization.

Four male and three female normal-weight research volunteers, participating in an 18-day residential study, received oral cyproheptadine (4 mg) or placebo at 0930, 1245, and 1730 hours daily. Food intake, performance, and subjective ratings were measured throughout the day. The interaction between cyproheptadine and carbohydrate consumption was examined by providing subjects diets that engendered varied levels of carbohydrate intake. Three diet conditions were tested for 6 days each: a regular diet, a low-carbohydrate (high-fat) diet, and a high-carbohydrate diet. Placebo was given on days 1, 2, 3, and 6, while cyproheptadine was given on days 4 and 5 of each diet condition. When subjects received placebo and had access to a regular diet, they consumed 2500 kcal/day (59% carbohydrate 28% fat, 13% protein). Total caloric intake decreased (p < 0.007) when subjects received placebo and had access to the low-carbohydrate diet (40% carbohydrate, 43% fat, 17% protein) and increased (p < 0.056) when subjects received placebo and had access to a high-carbohydrate diet (70% carbohydrate, 19% fat, 11% protein). Cyproheptadine significantly increased total daily caloric intake by 20%, to 3000 kcal, only under the regular diet condition. The increase in caloric intake was due to an increase in the number of eating occasions without a change in eating occasion size. Although subjects consumed more food under the regular diet and cyproheptadine condition, cyproheptadine had no effect on the relative contribution of macronutrients to total daily caloric intake. There was no evidence for a modulation of the food-intake increasing effects of cyproheptadine by the macronutrient mix of the available diet. Cyproheptadine also significantly altered self-reported mood: compared to placebo, cyproheptadine produced significant increases in ratings of "Tired", "Sleepy", "Headache", "Can't Concentrate", and "Bad Drug Effect" and decreases in "Alert". Furthermore, cyproheptadine produced small decrements in psychomotor task performance.

The methanol extract (mol. wt lower than 3,000 Da) of the sea squirt Phallusia nigra has stimulatory activity on guinea-pig ileum preparations. This effect was inhibited by cyproheptadine and mepyramine, but not be atropine. Mepyramine antagonized competitively the extract activity with a pA2 of 10.09 +/- 1.12, suggesting a direct activity on H1 histamine receptors. The extract was also assayed on guinea-pig right atria, however, only a mild increase in spontaneous contractions was observed compared to histamine, showing that the extract was a rather poor activator of cardiac H2 receptors. Histamine was not detected upon TLC analysis of the extract by comparison with an authentic standard.

1. The percentage of conditioned avoidance response was higher during proestrus compared to diestrus. 2. Cyproheptadine (CPH) significantly enhanced avoidance behavior during diestrus. 3. On the other hand, CPH treatment did not alter avoidance behavior during proestrus. 4. Serum progesterone and testosterone levels were determined at the end of 60 trials for acquisition of conditioned avoidance response after prolonged (12-15 days) CPH treatment (0.5 mg/kg for 24 h per os (p.o.). 5. Prolonged CPH treatment lowered adrenal testosterone levels, and rats with impaired avoidance had higher testosterone and progesterone levels. 6. The results of this study indicate a positive role for CPH in the acquisition of avoidance response during diestrus, and a negative effect of progesterone and adrenal testosterone on the avoidance response.

The possibility that elevation of serotonin in the circulation, which is found in various pathological states, influences the spontaneous cerebral cortical activity was examined in a rat model. The electroencephalogram was recorded using bipolar epidural electrodes placed over the frontal and parietal cerebral cortex. Intravenous infusion of serotonin (10 micrograms/kg per min for 10 min) decreased the electroencephalogram amplitude in both frontal and parietal recordings within 4 min of infusion. This decrease in amplitude was reversible, Pretreatment with cyproheptadine (a potent serotonin2 receptor antagonist) prevented the serotonin-induced decrease of the electroencephalogram amplitude. The blood-brain barrier permeability to Evans Blue and [131I]sodium was increased in frontal and parietal cortex. This increase in blood-brain barrier permeability was absent in animals pretreated with cyproheptadine. These results provide direct evidence that an elevated level of serotonin in blood has the capacity to influence spontaneous cortical electrical activity. This effect of serotonin on electroencephalogram appears to be due to its ability to enter into the brain parenchyma by inducing a short-term breakdown of the blood-brain barrier, probably via serotonin2 receptors.

Intake of an initial substance (e.g., 0.15% saccharin) is suppressed when the presentation of this substance precedes the availability of a preferred solution (e.g., 32% sucrose) in brief daily pairings. The present experiments show that degree of this anticipatory contrast effect is related to the relative hedonic value of the substances paired each day. When the initial substance has low hedonic value relative to the second substance (e.g., water or empty tube paired with 32% sucrose), then a facilitation effect rather than contrast occurs. As the hedonic value of the initial substance increases (0.0015% saccharin, 0.5% sucrose, 0.015% saccharin, 1% sucrose, 2% sucrose, 0.15% saccharin), facilitation is replaced by contrast, which develops sooner and becomes larger the greater the hedonic value of the initial substance. The serotonin antagonist cyproheptadine increased absolute lick frequencies, but did not alter contrast. The serotonin1A agonist buspirone tended to decrease absolute lick frequencies, but did not alter contrast. The occurrence of contrast is discussed in terms of response competition, inhibition, and devaluation of the initial substance.

In anesthetized rats, electrical stimulation of pineal gland elicited proportional hypertension and tachycardia, which could be mimicked by microinjection of an excitatory amino acid, kainic acid (0.3 micrograms), into the pineal gland. The hypertension induced by pineal stimulation was antagonized by either spinal transection or postsynaptic blockade of serotonin receptors, while the tachycardia induced by pineal stimulation was antagonized by either serotonin receptor antagonism, bilateral vagotomy or spinal transection. In addition, postsynaptic blockade of serotonin receptors with cyproheptadine (2-5 mg/Kg, IV) produced both hypotension and bradycardia, while stimulation of 5-HT receptors with DOI (10-250 micrograms/Kg, IV) produced both hypertension and tachycardia in rats. The results indicate that pineal stimulation activates brain 5-HT receptors and results in sympathetic stimulation or parasympathetic inhibition which leads to hypertension and tachycardia in rats.

1. The effects of the volatile oil (V.O.) of the black seed (Nigella sativa) on the arterial blood pressure and heart of urethane-anaesthetized rats were investigated and the effects were compared with those of its constituent thymoquinone (T.Q.). 2. Intravenous administration of V.O. in the dose range (4-32 microliters kg.-1) or T.Q. (0.2-1.6 mg kg-1) to rats decreased the arterial blood pressure and the heart rate in a dose-dependent manner. 3. The effects of V.O. were significantly antagonized by treatment of the animals with cyproheptadine, hexamethonium atropine and by spinal pithing. 4. Treatment of the animals with reserpine (5 mg kg- 1 day-1 for 2 days) significantly antagonized the cardiovascular depressant effects induced by 4 and 8 microliters of V.O. kg-1 but not those induced by the larger doses. 5. T.Q.-induced cardiovascular depressant effects were significantly antagonized by atropine and cyproheptadine but not by reserpine. 6. The results suggested that V.O.-induced cardiovascular depressant effects were mediated mainly centrally via indirect and direct mechanisms that involved both 5-hydroxytryptaminergic and muscarinic mechanisms. The direct mechanisms may be due to the presence of T.Q. in the V.O. The V.O. seemed to possess the potential of being a potent centrally acting antihypertensive agent.

The glutamate receptor agonists, kainate and N-methyl-D-aspartate (NMDA) result in the elevation of intracellular calcium levels ([Ca2+]i) in primary cultures of cerebellar granule neurons. Several tricyclic antidepressants (TCAs), amitriptyline (0.5-1 microM), desipramine (1 microM) and doxepine (1 microM) partially prevent this elevation induced by both of these excitatory amino acids (EAAs), but not elevations of [Ca2+]i induced by another EAA, quisqualate. Evidence suggests that this EAA-tricyclic interaction may involve voltage-dependent Ca2+ channels since amitriptyline also partially blocks the elevation of [Ca2+]i induced by membrane depolarization with 40 mM KCl. However, the blockade is not reversed in high concentrations of extracellular Ca2+ ([Ca2+]o) as would be predicted by a direct interaction with Ca2+ channels. Cyproheptadine (0.5-1 microM), a serotonin antagonist that is structurally similar to amitriptyline, causes similar effects as reported above for the TCAs; however, ketanserine (10 microM), also a serotonin antagonist but without the tricyclic nucleus, is less effective in this regard. Carbamazepine, an anticonvulsant with a tricyclic nucleus, produces similar effects as the above three compounds only in higher, yet therapeutic, concentrations (50 microM). Neither 5-hydroxytryptamine nor norepinephrine (100 microM, each) had effects on the EAA-induced elevation of [Ca2+]i. This is the first report to show an interaction of tricyclic antidepressants with the function of glutamate receptors in concentrations which are consistent with therapeutic dosages.

The non-sedating anti-histamine, loratadine [ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin- 11-ylidene-1-piperidinecarboxylate], was administered orally in the diet to mature male rats at dosages of 4, 10 and 25 mg/kg/day for 2 weeks. The effects of these treatments on liver microsomal cytochrome P450 were evaluated by immunochemical and biochemical techniques, and were compared with the effects of treating rats with three different inducers of cytochrome P450, namely phenobarbital, 3-methylcholanthrene and dexamethasone. Treatment of rats with loratadine caused a dose-dependent increase in the levels of P450 2B1 and 2B2, the major phenobarbital-inducible P450 enzymes, as determined by Western immunoblotting. At the highest dosage tested, loratadine was less effective than phenobarbital as an inducer of 2B1 and 2B2, although the induction of these proteins could be detected immunochemically even at the lowest dosage of loratadine tested. Consistent with these observations, treatment of rats with loratadine caused a dose-dependent increase in the rate of two reactions that are catalyzed predominantly by 2B1/2, namely testosterone 16 beta-hydroxylation and 7-pentoxyresorufin O-dealkylation. At the highest dosage tested, loratadine caused a 7.3- and 8.5-fold increase in the rate of testosterone 16 beta-hydroxylation and 7-pentoxyresorufin O-dealkylation, respectively, compared with a 22- and 45-fold increase caused by phenobarbital treatment. Treatment of rats with loratadine caused a 1.4- to 2.0-fold increase in the 2 beta-, 6 beta- and 15 beta-hydroxylation of testosterone, which was associated with a similar increase in the levels of immunoreactive P450 3A1 and/or 3A2. As an inducer of P450 3A1/2, loratadine was slightly less effective than phenobarbital, and was considerably less effective than dexamethasone, which caused a 10- to 33-fold increase in testosterone 2 beta-, 6 beta- and 15 beta-hydroxylase activity. At the dosages tested, loratadine did not increase the levels of P450 1A1, the major 3-methylcholanthrene-inducible P450 enzyme, as determined by Western immunoblotting. The rate of 7-ethoxyresorufin O-dealkylation, which is catalyzed predominantly by P450 1A1, increased 1.9-fold after loratidine treatment, but this increase was less than that caused by phenobarbital treatment (2.2-fold), and was considerably less than that caused by 3-methylcholanthrene treatment (33-fold). The effects of treating mature male mice with loratadine on liver microsomal cytochrome P450 resembled the effects observed in rats. These results indicate that loratadine is a phenobarbital-type inducer of liver microsomal cytochrome P450 in rats and mice.

The affinity of pizotifen, ketotifen and other tricyclic antimuscarinic drugs for different muscarinic receptor subtypes was investigated in vitro in functional experiments with field-stimulated vas deferens of the rabbit (M1 and M2 receptors) and with ileum and trachea of the guinea-pig (M3 receptors). All compounds were competitive antagonists in the three tissues. Like the close analogue cyproheptadine (pA2 = 7.99-8.08), pizotifen (pA2 = 7.23-7.81) and ketotifen (pA2 = 6.34-6.99) were devoid of selectivity for the receptor subtypes studied. Thiazinamium, although exhibiting high affinity for muscarinic receptors (pA2 = 7.83-8.51), was found to be non-selective. In contrast, the novel pirenzepine analogue nuvenzepine was selective for M1 receptors (pA2 = 6.63-7.74). The lack of selectivity of cyproheptadine, pizotifen and ketotifen is reflected in the chemical structures of these drugs. All three antagonists are composed of a very similar tricyclic ring system linked to a 1-methyl-4-piperidylene ring. The finding that thiazinamium, pizotifen and cyproheptadine were potent muscarinic antagonists and possessed non-selective affinity characteristics may have therapeutic implications.

1. The present study investigated the presence of 5-HT3 receptor using 2-methylserotonin (2-Me-5-HT) in the smooth muscle of Mytilus ABRM. 2. 2-Me-5-HT relaxed the acetylcholine-induced contraction in a dose-dependent manner ranging from 10(-6) to 3 x 10(-4) M (pD2 = 5.55 +/- 0.32). 3. 2-Me-5-HT-induced relaxation was antagonized by 3 x 10(-5) M ketanserin in a competitive manner (pA2 = 5.14 +/- 0.1), but not by cypropheptadine, mianserin, MDL 72222 or ICS 205-930 at a concentration of 3 x 10(-5) M. 4. 2-Me-5-HT (3 x 10(-4) M) did not alter the content of cyclic AMP and cyclic GMP in the ABRM. 5. These findings suggested that the 2-Me-5-HT-induced relaxation was mediated through 5-HT2-like receptors and was not linked to cyclic AMP or GMP systems, and, further, that 5-HT3 receptor subtype was not present in the ABRM.

The affinities of cyproheptadine, pizotifen and (+/-)-quinuclidinyl xanthane-9-carboxylate hemioxylate (QNX) were determined at muscarinic autoreceptors and postsynaptic (IP1 formation) receptors in rat hippocampal slices. The affinity values for QNX were 8.2 and 8.5 respectively. Cyproheptadine and pizotifen were less potent than QNX. Pizotifen was slightly (2-fold) less active at antagonizing IP1 formation than blocking the autoreceptors whereas cyproheptadine was equally active at antagonizing the two hippocampal muscarinic receptors.

Quipazine (0.5 mg/kg i.v.) produced a sustained pressor response and an increase in splanchnic nerve activity in intact as well as in baroreceptor-denervated cats without causing a significant change in heart rate. These effects were prevented by the 5-HT2 receptor antagonists, ritanserin (0.5 mg/kg i.v.) or BW 501 C (0.5 mg/kg i.v.). Quipazine induced an hypertensive response and an increase in splanchnic discharge in cats pretreated with prazosin (0.1 mg/kg) or hexamethonium (10 mg/kg i.v.). Bilateral application of quipazine (25 micrograms/side) to the ventrolateral pressor area produced a rapid increase in mean blood pressure and in splanchnic discharge. Pretreatment with prazosin (0.1 mg/kg i.v.) abolished the hypertension but not the sympatho-excitatory effects of quipazine. Local application of the 5-HT2 receptor antagonists, LY53857 (10 micrograms/side) or cyproheptadine (10 micrograms/side), had no effects on blood pressure and splanchnic nerve activity but prevented or reversed the actions of locally applied quipazine. LY 53857 (10 micrograms/side) antagonized the sympatho-excitatory effects of systemically administered quipazine. These results indicate that the cardiovascular changes induced by quipazine in anaesthetized cats are mediated by central 5-HT2 receptors located in the ventrolateral pressor area and by peripheral vascular 5-HT2 receptors.

1. Platelets induced an endothelium-independent contraction in isolated cat middle cerebral artery under resting conditions. In precontracted segments they evoked an endothelium-dependent contraction followed by a relaxation. 2. The contraction induced by serotonin was unaffected by endothelium removal either in the absence or in the presence of a previous tone. 3. The contractile response to platelets and serotonin under resting tension was blocked in the same way by ketanserin, methysergide or cyproheptadine. 4. After adding the platelets, serotonin could be measured in the bath medium. 5. These results suggest that the endothelium plays a minor role in the contraction induced by platelets, which is partly due to serotonin release.

1. Econazole released histamine from rat mast cells in vitro. This response was not affected by the addition of calcium or by prior treatment of mast cells with EDTA or cromoglycate. 2. Rat mast cells treated with econazole were stained by the vital dye trypan blue. 3. The intradermal injection of econazole increased vascular permeability. This response was antagonized by chlorpheniramine and cyproheptadine. 4. Our results demonstrate that econazole releases histamine by the "nonselective" mechanism. It is suggested that econazole inflammatory effects may be due to histamine release from mast cells.

To determine the selectivity of the non-sedating antihistamines loratadine and terfenadine and the sedating antihistamine diphenhydramine for peripheral and central histamine H1-receptors, these compounds were examined against intravenous (i.v.) and intracerebroventricular (i.c.v.) histamine-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs. Animals were prepared with i.c.v. or i.v. cannulas and instrumented for the measurement of airway resistance (RAW) and dynamic lung compliance (CDyN). Loratadine, terfenadine or diphenhydramine were administered orally 2 h before either i.v. or i.c.v. injection of histamine. Each antihistamine blocked the i.v. histamine bronchospasm with the order of potency loratadine (ED40 = 0.08 mg/kg) greater than terfenadine (ED40 = 0.44 mg/kg) greater than diphenhydramine (ED40 = 5 mg/kg). These drugs also blocked i.c.v. histamine-induced bronchoconstrictions, but loratadine and terfenadine were approximately 10 times less potent against i.c.v. histamine bronchoconstriction than they were against i.v. histamine. In contrast, diphenhydramine was equipotent against i.c.v. and i.v. histamine bronchoconstriction. These results demonstrate that the non-sedating antihistamines loratadine and terfenadine, unlike diphenhydramine, are more effective against peripheral than central H1-receptors, probably because of poor penetration of the blood-brain barrier.

Cyproheptadine (CPH) inhibits glucose-stimulated insulin synthesis and secretion, and reversibly depletes pancreatic insulin content in the rat. To examine whether the inhibitory actions of CPH on insulin cell function are linked to the ability of glucose to stimulate insulin synthesis and secretion, studies were performed in two different insulin-producing cell lines. CPH effects were compared in HIT-T15 cells, which respond to glucose with increased insulin synthesis and secretion, and in glucose-unresponsive RINm5F cells. CPH produced similar alterations in both cells lines. After a 48-hr culture period in the presence of 0, 0.1, 1.0 or 10.0 microM CPH, cellular insulin stores and media insulin levels were decreased in a concentration-dependent manner. At 10.0 microM CPH, RIN and HIT cell insulin content declined to 34 and 33% of controls respectively. Cellular insulin returned to control levels 48 hr after removal of CPH. In experiments designed to test a direct inhibitory effect on stimulated insulin secretion, 1 and 10.0 microM concentrations of CPH were found to inhibit glucose-stimulated insulin release from HIT cells, and K+, alanine and glyceraldehyde-stimulated release from RIN cells. CPH was also shown to inhibit insulin biosynthesis in both cell lines at concentrations that did not alter the synthesis of total cellular proteins. All of these alterations in cellular function were shown to occur at CPH concentrations that did not affect cell growth or viability. The results show that the actions of CPH do not appear to be dependent upon the existence of operational glucose signalling mechanisms for insulin synthesis and secretion.

Acetylcholine (ACh) applied within the pulmonary artery elicited either a pressor or depressor response in the pulmonary vascular bed of rabbits, while ACh applied at the 4th ventricle induced a depressor response only. Both responses could be blocked by atropine and the pressor response could also be blocked partially by hexamethonium and phentolamine. Damage to the sympathoinhibition center in the median area of the medulla significantly reduced the centrogenic ACh-induced depressor response in both carotid and pulmonary arteries; the response could also be greatly diminished by the 5-HT blockers and naloxone applied centrally. It is thus suggested that ACh may exert a direct action on the M-receptors of the pulmonary vessels. It may also activate the N-receptors in the sympathetic ganglion which then induces a pulmonary vasoconstriction as a consequence. The centrogenic ACh-induced depressor responses involve the central M-receptors and are mediated by the medullary 5-HT and endorphin neuronal systems, resulting in suppression of the sympathetic tonus.

Intracisternal injection of the TRH analogs, MK 771 (0.01-1 micrograms) or A 3475 [pGlu-His-(1,3'-dicarboxymethyl)-Pro-NH2] (0.1-1 micrograms), dose-dependently stimulated gastric acid secretion in pylorus-ligated rats although A 43475 was devoid of TSH-releasing activity by cultured anterior pituitary cells. Depletion of brain catecholamine by combined administration of the neurotoxic agent, 6-hydroxydopamine, and the catecholamine synthesis inhibitor, alpha-methyl-ptyrosine, completely abolished intracisternal TRH-induced stimulation of gastric secretion. Blockade of dopamine receptors by intracisternal haloperidol, peripheral depletion of catecholamine by chronic treatment with guanethidine combined with acute adrenalectomy or cervical cord transection at C5 level, did not modify gastric response to TRH. These results suggested that the stimulation of gastric secretion by intracisternal TRH is unrelated to its hypophysiotropic activity and required the integrity of central but not peripheral catecholaminergic system.

Previous studies have shown that brain serotonin is increased and noradrenaline decreased in acupuncture and transcutaneous nerve stimulation (TNS). Increases in available brain serotonin and decreases in noradrenaline enhance pain suppression. The present study tests the possibility that the widespread and prolonged cutaneous vasodilation which can be produced by low-frequency TNS in patients with peripheral circulatory insufficiency is similarly dependent on a central serotonergic pathway leading to sympatho-inhibition. The serotonin receptor antagonist cyproheptadine was given to 4 patients with either Raynaud's phenomenon or diabetic polyneuropathy, who all prior to drug administration responded to TNS with marked and prolonged cutaneous vasodilation in the ischaemic limbs. Cyproheptadine almost completely blocked the vascular response. Contrary to endorphin-serotonin mediated pain inhibition, vasoconstrictor inhibition is not antagonized by conventional, low doses of naloxone (Kaada, 1982a). However, the involvement of more naloxone-resistant opioid receptors in the vascular response cannot be excluded.

Pharmacological agents were used to manipulate the surge of luteinizing hormone (LH) induced by progesterone in ovariectomized rats primed with estradiol benzoate. The LH surge was abolished with p-chlorophenylalanine (PCPA), an inhibitor of tryptophan hydroxylase, and restored by 5-hydroxytryptophan, a serotonin precursor. Serotonin receptor agonists, quipazine and N-N-dimethyl-5-methoxytryptamine, were also capable of inducing an LH surge in rats pretreated with PCPA. The serotonin reuptake blocker chlorimipramine was ineffective in stimulating LH release in PCPA blocked animals. Another reuptake blocker, zimelidine was only partially effective in this regard. These two reuptake blockers, as well as amitriptyline, when injected to non-PCPA treated rats led to the reduction or inhibition of the expected LH surge. Four serotonin receptor antagonists, cyproheptadine, methysergide, cinanserin and SQ-10,631, were each able to reduce or abolish the progesterone induced surge of LH. These results suggest that some of the reuptake blockers of serotonin are also capable of inhibiting receptor binding for this neurotransmitter and strongly indicate that serotonin has a stimulatory role in the steroid induced release of LH in castrated rats.

The effects of serotonin (5-hydroxytryptamine; 5-HT) antagonists and 5-HT uptake inhibitors on the behavioral response to amphetamine and haloperidol in monkeys (cercopithecus aethiops) were investigated. Amphetamine increased locomotor activity and reactivity and induced repetitive movements of head, limbs and trunk, but no oral hyperkinesia. Haloperidol induced dystonia and parkinsonism. Pretreatment with the 5-HT antagonists cyproheptadine and mianserin increased amphetamine-induced locomotor activity, reactivity and repetitive movements and decreased haloperidol-induced dystonia and parkinsonism. Conversely the 5-HT uptake inhibitors paroxetine and CGP 6085 A decreased amphetamine-induced repetitive movements and aggravated haloperidol-induced dystonia and parkinsonism. The 5-HT uptake inhibitors produced oral hyperkinesia resembling human tardive dyskinesia, which was intensified by amphetamine and blocked by haloperidol. These findings support the suggestion that 5-HT inhibits dopamine functions and may imply that 5-HT antagonists could have a beneficial effect against acute extrapyramidal side-effects of neuroleptic treatment. 5-HT uptake inhibitors in the monkey may serve as a model for tardive dyskinesia.

The effects of 'peripheral' serotonin (5-HT) antagonists on the facilitation of facial motoneuron excitation by 5-HT were investigated in the present study. Microiontophoretic application (5--10 aA) or intravenous administration of methysergide (0.5--1.0 mg/kg), cyproheptadine (0.5--1.0 mg/kg), cinanserin (0.5--1.0 mg/kg), or metergoline (50--100 micrograms/kg) antagonized the facilitating effect of 5-HT but not that of norepinephrine (NE) on facial motoneurons. Blockade developed within 1--2 min of the intravenous administration of methysergide, cyproheptadine and cinanserin and continued up to 30 min. The antagonism produced by intravenous metergoline took 8--15 min to develop and lasted for at least 6 h. Chronic administration of metergoline resulted in supersensitivity to 5-HT and NE in the facial nucleus. The putative 5-HT antagonists chlorpromazine, propranolol, and methiothepin failed to block the facilitating effect of 5-HT; however, methiothepin did block NE. The results are discussed in relation to a two-component model of the 5-HT mediated motor syndrome consisting of : (1) patterned excitatory inputs to motor nuclei; (2) 5-HT facilitation of these excitatory inputs. The 'peripheral' 5-HT antagonists appear to directly block the latter component.

The local anesthetic effect of cyproheptadine on nerve fibres in the rabbit's cervical vagus and sciatic nerve was studied by the single sucrose-gap technique. Local anesthetics such as procaine and tetracaine, and an antihistaminic with local anesthetic activity, diphenhydramine, were studied for comparison. Increasing concentrations of cypropheptadine, starting from 5 x 10(-5) M, produced a dose-related fall in the amplitude of the compound action potential of the vagus nerve without significant change in the resting membrane potential. A complete reversibility of the local anesthetic effect was difficult or impossible to obtain when doses greater than 1 x 10(-4) M were used. Cyproheptadine was more potent than procaine and diphenhydramine, and less potent than tetracaine in producing nerve conduction block. Frequency-dependent block was observed with cyproheptadine and the other agents at frequencies that can be considered low (1--5 Hz). Myelinated fibres of the sciatic nerves were also blocked by cyproheptadine within the same range of concentrations (1 x 10(-4) to 1 x 10(-3) M). Our results provide an additional explanation for the mechanism underlying the actions of cyproheptadine as an antiarrhythmic and an antipruritic agent.

The effects of d,1-alpha-methyltyrosine (alphaMT), haloperidol, phenoxybenazmine, propranolol, methysergide and cyproheptadine on the anorexigenic activities of DITA and d-amphetamine were studied in male mice. The pretreatment of mice with methysergide (10 mg/kg, s.c.), cyproheptadine (5 mg/kg, i.p.), phenoxybenzamine (10 mg/kg, i.p.), and propranolol (5 mg/kg, i.p.) failed to alter the anorexigenic effect of DITA and d-amphetamine. On the other hand, alphaMT (32 mg/kg, i.p.) and haloperidol (0.5 mg/kg, i.p.) significantly antagonized the anorexigenic effect of DITA and d-amphetamine. Our data indicate that the anorexigenic activities of DITA and d-amphetamine are mediated mainly through the dopaminergic system.

A study was undertaken to determine the effect of 5-Hydroxytryptamine (5-HT) on sympathetic neurotransmission to the myocardium. Intravenous infusion of 5-HT (20 microgram/kg/min) produced a decrease in mean blood pressure and caused significantly impairment of cardioacceleration observed during the stimulation of right post-ganglionic cardiac sympathetic nerve. The pressor and tachycardic responses to norepinephrine as well as tyramine were potentiated during 5-HT infusion. The inhibitory effect of 5-HT on responses to cardiac nerve stimulation was not prevented by desipramine. Prior treatment with cyproheptadine prevented the depressor effect of 5-HT and significantly antagonized the inhibitory action of 5-HT on the positive chronotropic effect of cardiac nerve stimulation. Methysergide administration to a different group of dogs antagonized the effect of 5-HT on blood pressure, but did not alter the impairment of cardioacceleration caused by 5-ht during cardiac nerve stimulation. Neither cyproheptadine nor methysergide had any effect on the responses to cardiac nerve stimulation. These results suggest that 5-HT inhibits sympathetic neurotransmission of the myocardium via an action on 'trypaminergic' receptors which may be located on sympathetic nerve terminal and that these receptors can be selectively blocked by cyproheptadine but not by methysergide.

Some of the presynaptic and postsynaptic excitatory and inhibitory actions of 5-hydroxytryptamine (5-HT) in the rat mesenteric arteries were reexamined with particular reference to the genetic hypertensive rat model. Mesenteric arteries were perfused and the perfusion pressure monitored in the presence or absence of 5-HT, norepinephrine or periarterial sympathetic nerve stimulation. The vasoconstrictor response to 5-HT was resistant to prazosin but effectively inhibited by cyproheptadine and ketanserin. The vasoconstrictor responses to norepinephrine and nerve stimulation were markedly potentiated by 5-HT, and this potentiation was blocked by ketanserin at concentrations which inhibited the 5-HT-induced vasoconstriction, while much higher concentrations were required for cyproheptadine. No significant difference was found in these regards between mesenteric arteries from the spontaneously hypertensive rats (SHR) and those from the normotensive Kyoto Wistar rats (WKY). 5-HT significantly increased the nerve stimulation-evoked 3H overflow in [3H]norepinephrine-treated mesenteric arteries of SHR, but reduced the 3H overflow in the WKY preparations. These results suggest that ketanserin-sensitive 5-HT2 receptors are involved in the potentiating effect of 5-HT in the rat mesenteric arteries, and that an increase in transmitter release by 5-HT may contribute to its potentiation of nerve stimulation-induced vasoconstriction in SHR.

The influence of some serotoninergic agents on nitrazepam-induced sleep was studied in 5-8-day-old chicks. Nitrazepam (0.4-51.2 mg/kg) induced behavioural sleep in chicks dose-dependently. 5-Hydroxytryptamine (5-HT; 10-20 mg/kg) hypnotised young chicks. Similarly, 5-HT (5-20 mg/kg) shortened the onset and significantly prolonged the duration of nitrazepam-induced sleep in chicks and increased the proportion of chicks that were hypnotized by nitrazepam; these effects were dose-dependent. 5-Hydroxytryptophan (5-HTP; 2-8 mg/kg) did not induce sleep but dose-dependently shortened the onset and profoundly prolonged the duration of nitrazepam (1.6 mg/kg)-induced sleep. Cyproheptadine (0.5-2 mg/kg) delayed the onset of nitrazepam sleep and reduced the proportion of chicks that were hypnotized by nitrazepam. Parachlorophenylalanine (PCPA, 200 mg/kg) completely blocked nitrazepam-induced sleep. Nitrazepam sleep was associated with synchronization of the electroencephalogram (EEG) of the hyperstriatum, optic tectum and pontine reticular formation. 5-HT synchronized the EEG of the hyperstriatum and the pontine reticular formation while the electromyograph (EMG) activity was profoundly reduced. These behavioural and electrocortical data suggest that 5-HT may be involved in nitrazepam-induced sleep in young chicks.

The ability of 5-hydroxytryptamine (5-HT) as compared to norepinephrine (NE) to mobilize different Ca2+ pools was investigated in rabbit ear artery (REA). 5-HT appears to both mobilize intracellular Ca2+ and trigger transmembrane Ca2+ influx in this preparation. Although stimulation of alpha-adrenoceptors by 5-HT appears to be involved, the duration of 5-HT-induced cellular and extracellular Ca2+-dependent contractions outlasts the duration of those produced by equipotent concentrations of NE. Both cellular and extracellular Ca2+-dependent contractile responses produced by low but not high concentrations of 5-HT were significantly higher in arterial segments pretreated with 6-OH dopamine and in presence of desoxycorticosterone and propranolol while those produced by NE were unaffected. The duration of extracellular Ca2+-dependent 5-HT and NE-induced contractions was enhanced over the whole concentration range and in a similar manner. These findings as well as the results obtained with the receptor antagonists cyproheptadine and phentolamine could be interpreted as an indication that: (a) stimulation of alpha-adrenoceptors by 5-HT is only in part responsible for the contractile effects of 5-HT in REA; (b) additional mechanism(s) activated by 5-HT appear to modulate the duration of both cellular and extracellular Ca2+-dependent contractions and, (c) difference(s) in tissular handling of these amines do not appear to play a role in their different contractile effects.