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Coordination of four-limb movements during quadrupedal locomotion is controlled by supraspinal monoaminergic descending pathways, among which serotoninergic ones play a crucial role. Here we investigated the locomotor pattern during recovery from blockade of 5-HT 7 or 5-HT 2A receptors after intrathecal application of SB269970 or cyproheptadine in adult rats with chronic intrathecal cannula implanted in the lumbar spinal cord. The interlimb coordination was investigated based on electromyographic activity recorded from selected fore- and hindlimb muscles during rat locomotion on a treadmill. In the time of recovery after hindlimb transient paralysis, we noticed a presence of an unusual pattern of quadrupedal locomotion characterized by a doubling of forelimb stepping in relation to unaffected hindlimb stepping (2FL-1HL) after blockade of 5-HT 7 receptors but not after blockade of 5-HT 2A receptors. The 2FL-1HL pattern, although transient, was observed as a stable form of fore-hindlimb coupling during quadrupedal locomotion. We suggest that modulation of the 5-HT 7 receptors on interneurons located in lamina VII with ascending projections to the forelimb spinal network can be responsible for the 2FL-1HL locomotor pattern. In support, our immunohistochemical analysis of the lumbar spinal cord demonstrated the presence of the 5-HT 7 immunoreactive cells in the lamina VII, which were rarely 5-HT 2A immunoreactive.

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.)

Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an "induced-fit" protocol to improve the homology models of 5-HT(2A) receptor, and we assessed the quality of these models in retrospective virtual screening. Subsequently, we computationally screened the FDA approved drug molecules against the best induced-fit 5-HT(2A) models and chose six top scoring hits for experimental assays. Surprisingly, one well-known kinase inhibitor, sorafenib, has shown unexpected promiscuous 5-HTRs binding affinities, K(i) = 1959, 56, and 417 nM against 5-HT(2A), 5-HT(2B), and 5-HT(2C), respectively. Our preliminary SAR exploration supports the predicted binding mode and further suggests sorafenib to be a novel lead compound for 5HTR ligand discovery. Although it has been well-known that sorafenib produces anticancer effects through targeting multiple kinases, carefully designed experimental studies are desirable to fully understand whether its "off-target" 5-HTR binding activities contribute to its therapeutic efficacy or otherwise undesirable side effects.

Rationale: Acute administration of 40 mg paroxetine (a selective serotonin reuptake inhibitor) reportedly increases plasma cortisol in human subjects. This suggests that paroxetine may be a useful tool to probe brain serotonin function., Objective: To investigate a dose-response relationship for paroxetine administration, and to determine whether a lower dose of paroxetine is sufficient to increase plasma ACTH and cortisol., Methods: Twenty subjects were tested on three occasions in a double-blind, cross-over design receiving: (a) placebo, (b) paroxetine 20 mg and (c) paroxetine 40 mg administered orally at 8.00 a.m. In addition, five of the 20 subjects received paroxetine 20 mg plus cyproheptadine (a 5-HT(2) receptor antagonist) 4 mg and four subjects were given paroxetine 40 mg plus cyproheptadine 4 mg in an open manner. Plasma ACTH and cortisol levels were measured prior to administration and every hour for 6 h thereafter., Results: Paroxetine, particularly 20 mg rather than 40 mg, significantly increased plasma ACTH and cortisol. Paroxetine 40 mg but not 20 mg caused significantly more nausea than the placebo. Cyproheptadine attenuated ACTH and cortisol responses to 20 mg but not to 40 mg paroxetine., Conclusions: Low-dose (20 mg) paroxetine has greater potential utility than larger doses as a neuroendocrine challenge test. The endocrine responses to paroxetine are probably mediated at least partially by 5-HT(2A/2C) receptors.

We attempted to identify compounds that are effective in blocking the serotonin (5-hydroxytryptamine, 5-HT) receptor(s) that activate adenylyl cyclase (AC) in Aplysia CNS. We call this class of receptor 5-HT(apAC). Eight of the 14 antagonists tested were effective against 5-HT(apAC) in CNS membranes with the following rank order of potency: methiothepin > metergoline approximately fluphenazine > clozapine > cyproheptadine approximately risperidone approximately ritanserin > NAN-190. GR-113808, olanzapine, Ro-04-6790, RS-102221, SB-204070, and spiperone were inactive. Methiothepin completely blocked 5-HT stimulation of AC with a K(b) of 18 nM. Comparison of the pharmacological profile of the 5-HT(apAC) receptor with those of mammalian 5-HT receptor subtypes suggested it most closely resembles the 5-HT(6) receptor. AC stimulation in Aplysia sensory neuron (SN) membranes was also blocked by methiothepin. Methiothepin substantially inhibited two effects of 5-HT on SN firing properties that are mediated by a cAMP-dependent reduction in S-K(+) current: spike broadening in tetraethylammonium/nifedipine and increased excitability. Consistent with cyproheptadine blocking 5-HT stimulation of AC, cyproheptadine also blocked the 5-HT-induced increase in SN excitability. Methiothepin was less effective in blocking AC-mediated modulatory effects of 5-HT in electrophysiological experiments on SNs than in blocking AC stimulation in CNS or SN membranes. This reduction in potency appears to be due to effects of the high ionic strength of physiological saline on the binding of this antagonist to the receptor. Methiothepin also antagonized AC-coupled dopamine receptors but not AC-coupled small cardioactive peptide receptors. In conjunction with other pharmacological probes, this antagonist should be useful in analyzing the role of 5-HT in various forms of neuromodulation in Aplysia.

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.

The role of 5-HT2A and 5-HT2C subtypes of serotonergic receptors in the control of sexual behavior and plasma testosterone regulation was studied in male CBA mice exposed to a sexually receptive female separated by a transparent partition. Introduction of the receptive female induced sexual motivation and arousal in males, as evidenced by a prolonged time spent at the partition, unsuccessful attempts to step across it and a significant increase in plasma testosterone levels. Administration of 5-HT2A receptor antagonists ketanserin (1.0 and 2.0 mg/kg i.p.) or cyproheptadine (1.0 and 2.0 mg/kg i.p.) diminished the behavioral components and prevented the hormonal components of male sexual arousal. Administration of the selective 5-HT2C antagonist RS 102221 (1.0 and 2.0 mg/kg) considerably increased the time spent by males at the partition (p < 0.001) and, at the dose of 2.0 mg/kg, increased plasma testosterone levels (p < 0.01). Administration of ritanserin - a nonselective 5-HT2A/2C antagonist and, to a smaller degree, 5-HT2B antagonist - at doses of 0.1 and 0.5 mg/kg did not significantly influence male behavior and the activating effect of the presence of a female on the hypothalamo-pituitary-testicular system, although it increased resting testosterone levels (p < 0.05). The present findings suggest that 5-HT2A/5-HT2C receptors may be involved in the neural control of male sexual motivation and arousal, presumably by exerting reciprocal facilitative (5-HT2A) or suppressive (5-HT2C) influences., (Copyright 2002 S. Karger AG, Basel)

Interactions of serotonin (5-HT) with different specific 5-HT receptors that can coexist in the same blood vessel sometimes generate opposite effects. The aim of this study was to characterize the functional role of previously described mRNAs for 5-HT receptors in the rat aorta (5-HT(2A), 5-HT(2B), 5-HT(1B), 5-HT(7)) as well as to study the known 5-HT(2A) receptor-mediated constrictor response and investigate the influences of endothelium and preconstriction on the tissue in that response. A slight endothelium- and concentration-dependent relaxant effect was observed for 5-HT in aorta precontracted with either 5 microM phenylephrine (PE) or 1 microM prostaglandin F2alpha (PGF2alpha) in the presence of 0.3 microM ketanserin. EC50 values for 5-HT and alpha-methyl-5-HT relaxant responses after PE were 43.10 +/- 4.00 and 57.11 +/- 8.01 nM, respectively. pK(B) values for antagonists cyproheptadine and rauwolscine were 8.92 +/- 0.22 and 7.15 +/- 0.12, respectively. In nonprecontracted tissues, the contractile potency of 5-HT was higher in the absence of endothelium (EC50, degreesM): 2.60 +/- 0.28 and 4.12 +/- 0.21 in the absence and in the presence of endothelium, respectively. The differences were statistically significant (p<0.05). In precontracted tissues, the differences in EC50 values (2.22 +/- 0.40 and 4.65 +/- 0.60 microM without and with endothelium, respectively) were also statistically significant (p<0.05). pK(B) values for the 5-HT(2A) antagonist ketanserin were similar under all conditions tested. In conclusion, under our experimental conditions there are two functional 5-HT receptors in rat aorta: 5-HT(2A) contractile receptor in smooth muscle and a high-affinity relaxant receptor that mediates a very slight response and the pharmacology of which could be compatible with an endothelial 5-HT(2B) receptor.

Studies by the method of splenic exocolonies with serotonin receptor blockers methysergide and cyproheptadine showed that S2 receptors are involved in the stimulatory effect of serotonin on hemopoietic bone marrow stem cells.

Rationale: Intravenous administration of the selective serotonin re-uptake inhibitor, citalopram (20 mg), is known to increase plasma prolactin (PRL) and cortisol in human subjects. This suggests that citalopram may be a useful tool to probe brain serotonin function., Objective: To find out whether lower doses of intravenous citalopram would be sufficient to increase plasma prolactin and cortisol., Methods: Eleven subjects were tested on three occasions in a double-blind, cross-over design receiving: (a) placebo, (b) citalopram 5 mg and (c) citalopram 10 mg infused intravenously over a 30-min period. A further six subjects received intravenous citalopram (10 mg) on two occasions receiving in addition the 5-HT2A2C receptor antagonist, cyproheptadine (4 mg orally) or placebo, 6 h before each infusion in a double-blind, randomised, cross-over design. Plasma PRL and cortisol levels were measured before and for 150 min after the infusion., Results: Citalopram increased plasma PRL and cortisol in a dose-related manner. Cyproheptadine lowered baseline PRL and cortisol but did not attenuate the endocrine responses to citalopram. Citalopram infusions were well-tolerated., Conclusions: Low-dose citalopram has potential utility as a neuroendocrine challenge test. The endocrine responses to citalopram are probably not mediated predominantly by 5-HT2A/2C receptors.

The serotonin (5-HT) syndrome is the most serious side effect of antidepressants, and it often necessitates pharmacotherapy. In the present study, the efficacy of several drugs was evaluated in an animal model of the 5-HT syndrome. When 2 mg/kg of clorgyline, a type-A monoamine oxidase inhibiting antidepressant, and 100 mg/kg of 5-hydroxy-L-tryptophan, a precursor of 5-HT, were administered intraperitoneally to rats to induce the 5-HT syndrome, the rectal temperature of the rats increased to more than 40 degrees C, and all of the animals died by 90 min after the drug administration. The noradrenaline (NA) levels in the anterior hypothalamus, measured by microdialysis, increased to 15.9 times the preadministration level. Pretreatment with propranolol (10 mg/kg), a 5-HT(1A) receptor antagonist as well as a beta-blocker, and dantrolene (20 mg/kg), a peripheral muscle relaxant, did not prevent the death of the animals, even though these two drugs suppressed the increase in rectal temperature to some extent. Chlorpromazine and cyproheptadine prevented the lethality associated with the 5-HT syndrome only at high doses. By contrast, pretreatment with ritanserin (3 mg/kg) and pipamperone (20 mg/kg), both potent 5-HT(2A) receptor antagonists, completely prevented the increase in rectal temperature and death of the animals, and the hypothalamic NA levels in these two groups increased less than that in the other groups. These results suggest that potent 5-HT(2A) receptor antagonists are the most effective drugs for treatment of the 5-HT syndrome, and that NA hyperactivity occurs in the 5-HT syndrome.

We investigated the effects of various serotoninergic drugs and serotonin (5-HT) depletion on physostigmine-induced visible tremor in rats. Physostigmine (0.25-1.5 mg/kg) caused dose-dependent tremor, initiated at 3-5 min (latency decreases as dose increases) and lasted for 30-35 min. Serotonin agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (2.5 mg/kg) and buspirone (5 mg/kg) augmented the tremor response caused by physostigmine. The 5-HT(1)/5-HT(2) receptor antagonist, metergoline (1 mg/kg), and 5-HT(2) blocker, cyproheptadine (10 mg/kg) significantly decreased the duration (40%) as well as intensity (45-50%) of physostigmine-tremor. The 5-HT(2a)/5-HT(2c) antagonist ritanserin (5 mg/kg) significantly reduced the duration (60%) without affecting the intensity of the tremor. In 5-HT depleted rats (p-chlorophenylalanine; 300 mg/kg, for 3 days), physostigmine failed to produce tremor. Interestingly, in these animals, administration of a non-specific 5-HT agonist, 5-methoxy-N,N-dimethyl tryptamine, caused high intensity tremor. These results suggest that presence of 5-HT at the pre-synaptic terminals is needed for the tremor response by physostigmine and the response is greatly mediated via post-synaptic 5-HT receptors. The overall data indicated a direct involvement of central 5-HT system in the cholinergic tremor induced by physostigmine.

Mice-losers in social conflicts had an increased number of haemorrhages and erosions in gastric mucosa as compared with the control and winners-mice. Administration of ciproheptadine and/or ketanserin enhanced the neurogenic gastric damage both in the winners and in control mice. The CBA strain mice were more sensitive to the damaging effects of the drugs than the C57-strain winners. The experience of social confrontations seems to change the gastric mucosa condition and to modify the mucosa response to the brain serotonine receptor blockade, depending on the social confrontations outcome and the animals' genotype.

Effects of 5-HT2 receptor blockade on the amplitude of startle reflex, induced by an unexpected sound, and on its prepulse inhibition (PPI) were studied on mice of CBA strain and rats of Wistar and the genetically predisposed to catalepsy (GC) strains. The effect was dependent on type and dose of 5-HT2 antagonist used: 5-HT2A antagonist ketanserin increased startle amplitude at the dose of 0.5 mg/kg and decreased it at the dose of 2 mg/kg. Mixed 5-HT2A/2C antagonist ritanserin (0.1 and 0.2 mg/kg) markedly increased startle in mice. Ketanserin and cyproheptadine produced opposite effects on startle reflex in rats with inherited neuropathology and in rats with normal genotype: marked decrease in GC rats and increase in Wistar rats was shown. Ketanserin and cyproheptadine produced a pronounced potentiation of PPI in mice and rats of both strains, ritanserin was ineffective. Results suggest 5-HT2 receptors implication in both startle and PPI regulation with 5-HT2C receptors in startle response and 5-HT2A in PPI predominant involvement.

Serotonin [5-hydroxytryptamine (5-HT)] modulates feeding activity, egg-laying, and mating behavior in the free-living nematode, Caenorhabditis elegans. We have cloned a novel receptor cDNA from C. elegans (5-HT2Ce) that has high sequence homology with 5-HT2 receptors from other species. When transiently expressed in COS-7 cells, 5-HT2Ce exhibited 5-HT binding activity and activated Ca2+-mediated signaling in a manner analogous to other 5-HT2 receptors. However, 5-HT2Ce displayed unusual pharmacological properties, which resembled both 5-HT2 and 5-HT1-like receptors but did not correlate well with any of the known 5-HT2 subtypes. Two splice variants of 5-HT2Ce that differ by 48 N-terminal amino acids were identified. The two isoforms were found to have virtually identical binding and signaling properties but differed in their levels of mRNA expression, with the longer variant being four times more abundant than the shorter species in all developmental stages tested. Taken together, the results describe two variants of a novel C. elegans 5-HT receptor, which has some of the properties of the 5-HT2 family but whose pharmacological profile does not conform to any known class of receptor.

Acute pancreatitis was induced in mice by feeding with a choline-deficient ethionine-supplemented diet. All the mice developed acute pancreatitis, and approximately 80% of them died within 4 days. Stereomicroscopic and light microscopic examinations revealed that pancreatic necrosis and circulatory disturbance that were not apparent on day 1 were increased markedly on days 2 and 3. Serum levels of pancreatic enzymes were normal or reduced on day 1 but then increased to peak on day 3. Plasma 5-hydroxyindoleacetic acid levels, which may indicate serotonin release, were significantly increased on days 1 through 3. Pretreatment with D, L-p-chlorophenylalanine methylester hydrochloride (200-400 mg/kg) significantly attenuated the mortality of the mice with pancreatitis. Dose-dependent attenuation was also obtained with ketaserin (0. 01-10 mg/kg), cyproheptadine (0.01-10 mg/kg), pindolol (0.1-100 mg/kg) and NAN-190 (0.1-100 mg/kg), but not with 0.01 to 10 mg/kg of ICS205-930 or M-840, and the activities were significantly correlated with the binding affinities for serotonin2 receptor on the rat cerebral cortex. In addition, ketanserin or cyproheptadine attenuated the morphologic changes in the choline-deficient ethionine-supplemented diet mice at a dose (3.2 mg/kg) that hardly affected the serum enzyme levels. We propose that serotonin2 receptor activation plays an important role in the aggravation of diet-induced acute pancreatitis.

Cyproheptadine is a drug that shows high affinity for type 2 (5-HT2) receptors. We studied a series of compounds obtained by modification of the tricyclic system of Cyp (dibenzocycloheptadiene): 2f (thioxanthene), 2g (xanthene), 2h (dihydrodibenzocycloheptadiene), 2j (diphenyl), 2i (fluorene), and 3b (phenylmethyl). Their activities at the rat cerebral cortex 5-HT2A receptor were (pKi +/- S.E.M.): 8.80 +/- 0.11 (Cyp), 8.60 +/- 0.07 (2f), 8.40 +/- 0.02 (2g), 8.05 +/- 0.03 (2h), 7.87 +/- 0.12 (2j), 6.70 +/- 0.02 (2i) and 6.45 +/- 0.02 (3b); those at the rat stomach fundus 5-HT2B receptor (pA2 +/- S.E.M.) were: 9.14 +/- 0.25 (Cyp), 8.49 +/- 0.07 (2f), 7.58 +/- 0.58 (2g), 7.02 +/- 0.14 (2h), 6.07 +/- 0.20 (2j), and undetectable (2i, 3b): and those at the pig choroidal plexus 5-HT2C receptor (pKi +/- S.E.M.) were: 8.71 +/- 0.08 (Cyp), 8.68 +/- 0.01 (2f), 8.58 +/- 0.20 (2g), 7.95 +/- 0.05 (2h), 7.57 +/- 0.04 (2j), 6.98 +/- 0.04 (2i) and 6.63 +/- 0.20 (3b). The slopes did not differ significantly from unity. The compounds exhibited the same order of activities at every type of receptor, and the most active molecules presented certain steric (butterfly conformation of the tricyclic system) and electrostatic (proton affinity on the top of the central rings) patterns. It is concluded that the activity of cyproheptadine derivatives at 5-HT2 receptors is related to these molecular features, which make feasible a common disposition to interact with all three 5-HT2 subtypes.

1. In order to determine whether 5HT2 receptor antagonists can modify Ca2+ uptake via voltage-operated Ca2+ channel (VOC) in arterial smooth muscle, a comparative study of the effects of selected Ca2+ uptake blockers and 5HT2 receptor antagonists on K(+)-induced contractions of rat aortic strip was undertaken. 2. The antagonist drugs studied included the Ca2+ uptake blockers verapamil, nifedipine, felodipine, diltiazem and cinnarizine, the 5HT2 receptor antagonists cyproheptadine, ritanserin, mianserin, and ketanserin and the alpha 1-adrenoceptor antagonist prazosin. 3. With the notable exception of prazosin, each of these compounds diminished K(+)-induced aortic responses. 4. The following order of potencies (mean IC50 values in mol/L) was established: felodipine (7.0 x 10(-11)) > nifedipine (4.8 x 10(-9) > verapamil (5.5 x 10(-8)) > cyproheptadine (6.2 x 10(-8)) > diltiazem (4.1 x 10(-7)) > cinnarizine (1.3 x 10(-6)) > ritanserin (1.8 x 10(-6)) > ketanserin (9.0 x 10(-6)) > mianserin (2.0 x 10(-5)). 5. The results suggest that antagonists of 5HT2 receptors can modulate Ca2+ uptake via VOC in rat aorta.

In vitro and in vivo experiments were used to determine the relationship between 5-hydroxytryptaminergic and alpha 2-adrenergic receptors in regulation of growth hormone secretion in cattle. Activation of 5-hydroxytryptaminergic receptors (10(-8), 10(-6), 10(-4) M quipazine) or alpha 2-adrenergic receptors (10(-8), 10(-6), 10(-4) M clonidine) had no effect on secretion of growth hormone from perifused anterior pituitary cells. In vivo, quipazine (0.2 mg/kg body wt, i.v.) and clonidine (8 micrograms/kg body wt, i.v.), when injected separately, each maximized secretion of growth hormone in Holstein steers. However, concurrent administration of quipazine and clonidine at these doses additively increased secretion of growth hormone (mean areas under curves = 439, 914, 1425, and 2359 +/- a pooled SEM of 246 ng.ml-1.min for vehicle, clonidine, quipazine, and quipazine plus clonidine treatments, respectively). Blockade of 5-hydroxytryptaminergic receptors with cyproheptadine (0.2 or 1.0 mg/kg body wt, s.c., 0740 hr) decreased basal concentrations of growth hormone but had no effect on the ability of clonidine (8 micrograms/kg body wt, i.v., 0840 hr) to increase secretion of growth hormone (mean areas under curves = 591, 1218, 363, 1087, and 1002 +/- a pooled SEM of 177 ng.ml-1.min for vehicle-vehicle, vehicle-clonidine, 0.2 mg cyproheptadine-vehicle, 0.2 mg cyproheptadine-clonidine and 1.0 mg cyproheptadine-clonidine treatments, respectively). Blockade of alpha 2-adrenergic receptors with either yohimbine (5 mg/kg body wt, s.c., 0740 hr) or idazoxan (20 mg/kg body wt, s.c., 0740 hr) suppressed both basal and 5-hydroxytryptaminergic receptor-stimulated (0.2 mg quipazine/kg body wt, i.v., 0840 hr) secretion of growth hormone (mean areas under curves = 568, 1252, 410, and 558 +/- a pooled SEM of 108 ng.ml-1.min for vehicle-vehicle, vehicle-quipazine, yohimbine-vehicle, and yohimbine-quipazine treatments, respectively, and means of 553, 1468, 194, and 686 +/- a pooled SEM of 221 ng.ml-1.min for vehicle-vehicle, vehicle-quipazine, idazoxan-vehicle, and idazoxan-quipazine treatments, respectively). We conclude that two mechanisms in the central nervous system mediate 5-hydroxytryptaminergic receptor-stimulated secretion of growth hormone in cattle; one independent and another dependent on alpha 2-adrenergic receptors, possibly via regulation of basal growth hormone secretion. In contrast, alpha 2-adrenergic receptor-induced secretion of growth hormone occurs independently of 5-hydroxytryptaminergic receptors.

Effects of activation or blockade of 5-hydroxytryptaminergic receptors on concentrations of growth hormone and somatostatin in serum were studied in Holstein steers (mean +/- SEM: 159 +/- 8 days of age; 160 +/- 9 kg of body wt). A pelleted diet was available ad libitum between 1000 and 1200 hr each day. Blood was sampled from a cannula in a jugular vein. Peak concentration of growth hormone in serum within 1 hr before feeding (12.8 +/- 3.8 ng/ml) was greater than peak concentration within 1 hr after removal of feed (3.3 +/- 1.0 ng/ml). In contrast, concentration of somatostatin in plasma did not change from 1 hr before feeding through 1 hr after removal of feed (47.3 to 43.0 +/- 4.5 pg/ml). Relative to saline-injected controls, activation of 5-hydroxytryptaminergic receptors with quipazine (0.5, 0.1, and 0.2 mg/kg body wt, iv) increased the area under growth hormone response curves 5.5- to 25-fold before and after feeding. In another experiment, injection of 0.1 mg of quipazine/kg body wt at 1300 hr increased the concentration of growth hormone in serum 7.8-fold compared with controls, but had no effect on concentration of somatostatin in plasma. Relative to water-injected controls, blockade of 5-hydroxytryptaminergic receptors with cyproheptadine (0.2 mg/kg body wt, sc) decreased the area under growth hormone response curves for at least 110 min before feeding (71%) and after removal of feed (69%). The data support the hypothesis that 5-hydroxytryptaminergic receptors are involved in stimulation of pulsatile growth hormone secretion in meal-fed cattle. Lack of a change in concentration of somatostatin in plasma with respect to time of meal-feeding or after injection of the 5-hydroxytryptaminergic-receptor agonist quipazine suggests that 5-hydroxytryptaminergic receptor-stimulated growth hormone secretion is likely mediated within the central nervous system, rather than by meal-induced changes in peripheral secretion of somatostatin.

The two alpha-methylated tryptamine derivatives, 5- (5-FMT) and 6-fluoro-alpha-methyltryptamine (6-FMT), rapidly induced a head-twitch response (HTR) in mice. Two derivatives that lack the methyl group in their chemical structures, 5- (5-FT) and 6-fluorotryptamine (6-FT), did not induce the HTR. The induced HTR was depressed by pretreatment with cycloheptadine, p-chlorophenylalanine or fluoxetine, but was potentiated by 5,7-dihydroxytryptamine. Both 5- and 6-FMT increased brain 5-HT levels in hypothalamus, hippocampus, brainstem, striatum and cortex. 5-FMT decreased the levels of 5-hydroxyindoleacetic acid in those regions, but 6-FMT caused a significant decrease in only the hypothalamus and cortex. The two methylated derivatives inhibited mouse brain MAO-A activity more selectively than non-methylated derivatives. The results suggest that the HTR induced by 5- and 6-FMT may result from increased activity of central 5-HT neurons, probably due to increased 5-HT levels after MAO-A inhibition. This probably results in release of 5-HT with a concomitant increased interaction with postsynaptic 5-HT2 receptors. The present results also indicate the importance of the methyl group to selective MAO-A inhibition by the substrate-analogues tested, and the concomitantly induced animal behavior.

Significant interstrain differences in intensity and character of changes in gastric mucosa induced by affecting the serotoninergic system, were found. The main mechanism of stress-induced stomach ulceration was found to involve brain serotonin in central regulation of the stomach blood flow. Use of exogenic amine and its precursor corroborated the serotonin-dependent ulceration of the stomach in mice.

5HT modulates the rhythmic locomotor output of most vertebrates by enhancing the duration and intensity of motor bursts in each cycle, but there is little clear evidence on the pharmacological profile of the 5HT receptor subtype(s) involved. In this study we extend our previous work on the role of 5HT in the development and modulation of locomotor behaviour in newly hatched Xenopus tadpoles by examining the 5HT receptor type responsible for enhancing the swimming activity in immobilized preparations. By applying a range of agonists and antagonists against different 5HT receptor subtypes, we conclude that serotonergic modulation of swimming activity is accomplished via the activation of just one receptor type with a pharmacological profile similar to the mammalian 5HT1a receptor. The effects of 5HT on burst duration (an increase) and on episode length (a decrease) are mimicked by the 5HT1a receptor agonists, 5-carboxamidotryptamine (5CT) and R(+)-8-OH-DPAT, and reversed by the 5HT1a receptor antagonist NAN-190. Agents acting at other 5HT1, as well as 5HT2 and 5HT3, receptor subtypes were without noticeable effect on the 5HT-enhanced swimming rhythm.

Previous studies with high doses of cyproheptadine suggested that serotonergic (5HT) neural mechanisms participate in the photoperiodic inhibition of secretion of LH in ovariectomized estradiol-treated ewes. In the present study, we tested this hypothesis further with lower doses of more specific 5HT2 receptor antagonists, including the highly specific ketanserin. Eight ovariectomized estradiol-treated ewes were subjected to 90 long days (16L:8D) followed by 207 short days (8L:16D) in order to induce photorefractoriness. Plasma LH concentrations were measured in blood sampled twice weekly. Changes in LH pulse frequency were measured after intrajugular injections of cyproheptadine or ketanserin (0.1, 0.25, 0.6, and 1.5 mg/kg) before the increase in LH secretion induced by the short days (SD ewes). After the ewes became refractory to short days (RSD ewes), they were again treated with the three lowest doses of cyproheptadine and ketanserin and, in addition, methysergide at the same doses. In the period following the transition from long to short photoperiod, LH secretion increased above basal levels after 42.0 +/- 0.0 days (mean +/- SEM) and then decreased after 137.0 +/- 7.4 days. In SD ewes, cyproheptadine significantly increased the number of LH pulses at the lowest dose tested (0.13 vs. 1.13 pulses/3 h at 0.1 mg/kg). Similar responses were observed at 0.25 mg/kg (0.13 vs. 0.88 pulses/3 h), at 0.6 mg/kg (0.13 vs. 0.75 pulses/3 h) and at 1.5 mg/kg (0.13 vs. 0.88 pulses/3 h). Ketanserin induced a dose-dependent increase in the number of LH pulses at 0.6 mg/kg (0 vs. 0.63 pulses/3 h) and at 1.5 mg/kg (0 vs. 0.75 pulses/3 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous single-unit and intracortical activity were recorded from neocortical neurons in urethane-anaesthetized rats to investigate the role of serotonin (5-HT) in modifying cortical excitability. Units, at a depth of 775-1100 microns from the pial surface, discharged in a burst-pause pattern that was correlated with slow wave activity. Application of noxious somatic stimulation resulted in cortical desynchronization and altered the pattern of unit activity such that firing was continuous, i.e., the pauses were eliminated. Intravenous administration of the mixed 5-HT1C/5-HT2 antagonists (cinanserin, cyproheptadine, ketanserin, and ritanserin) prevented both desynchronization and the change in unit activity induced by noxious stimulation within 2.5-15 min of the injection. The basic pattern of burst-pause activity remained intact, but the number of spikes per burst was typically reduced, whereas interburst intervals were increased. Iontophoretic application of these antagonists onto cortical neurons resulted in actions similar to those observed following systemic administration. Intravenous and iontophoretic application of m-trifluomethylphenylpiperazine (5-HT1C agonist, 5-HT2 antagonist) resulted in actions indistinguishable from those observed with the above antagonists, from which we conclude 5-HT2 and not 5-HT1C receptors mediate the alteration in unit activity observed with noxious stimulation. The results are discussed with respect to an interaction between N-methyl-D-aspartate and 5-HT2 receptors leading to the enhanced unit activity observed with noxious stimulation.

Serotonin agonists (for the acute treatment of attacks) and antagonists (for prophylactic treatment) are the most widely used drugs to treat migraine. However, their effectiveness is not complete and their use is limited by side effects. The activity and presumptive mode of action of these drugs provide support for the role of serotonin in the pathophysiology of migraine and suggest that the trigeminal-vascular system is at the center of the attack; however, other factors and mechanisms may also be involved.

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.

Autoradiographic receptor binding studies using 125I-LSD (2-[125I]lysergic acid diethyamide) revealed intense labelling on the soma of a symmetrically located pair of cells in the abdominal ganglion of Aplysia californica. This binding was blocked by micromolar concentrations of serotonin and lower concentrations of the serotonergic antagonists, cyproheptadine and mianserin (Kadan and Hartig, 1988). Electrophysiological investigation of responses to serotonin of neurons in the left upper quadrant, where one of the labeled neurons is located, revealed a range of serotonin responses. Cells L3 and L6 have a K+ conductance increase in response to serotonin that is not blocked by cyproheptadine or mianserin. Cells L2 and L4 have a biphasic response to serotonin: a Na+ conductance increase, which can be blocked by cyproheptadine and mianserin, followed by a voltage dependent Ca2+ conductance which is blocked by Co2+ but not the serotonergic antagonists. Cell L1, and its symmetrical pair, R1, have in addition to the Na+ and Ca2+ responses observed in L2 and L4, a Cl- conductance increase blocked by LSD, cyproheptadine and mianserin. LSD had little effect on the other responses. We conclude that the symmetrically located cells L1 and R1 have a Cl- channel linked to a cyproheptadine- and mianserin-sensitive serotonin receptor that is selectively labelled by 125I-LSD. This receptor has many properties in common with the mammalian serotonin 1C receptor.

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.

Opioid induced locomotor excitation in mice was studied. Both morphine and fentanyl increased spontaneous locomotor activity (SLA). Pentazocine produced a significant inhibition of SLA and also blocked the effects of subsequent morphine and fentanyl, thereby underscoring the importance of mu receptors for the opioid induced enhancement of SLA. Serotonergic receptor blockade with cyproheptadine or depletion with fenfluramine blocked, while uptake blockade with clomipramine potentiated the excitatory effect of fentanyl. Thus a mu receptor-serotonin link for the expression of opioid induced locomotor excitation becomes evident.

1. Mice were isolated for 7-9 days. An isolated mouse and a mouse reared in group showed a difference in their behaviour when observed together under an inverted beaker. The isolated mouse makes one half escape attempts in regard to the grouped mouse. This is considered as a social behavioural deficit. 2. 1- 3-(trifluoromethyl)phenyl piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (m-CPP) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl) 1-H indole (RU-24969) activating preferentially the 5-HT1B receptors increased the number of escape attempts of the isolated mice up to the level of grouped mice. 3. Penbutolol, a beta-blocking drug acting also at 5-HT1 receptors, devoid of effect when given alone, antagonized significantly and dose-dependently the effects of TFMPP, m-CPP and RU-24969. 4. The interaction between TFMPP and five various serotonin antagonists was examined. Neither the 5-HT2 receptor antagonist ritanserine, the 5-HT3 receptor antagonist ICS 205-930, the 5-HT1C receptor antagonists mianserin and cyproheptadine antagonized the effect of TFMPP. The neuroleptic spiperone decreased by itself the number of escape attempts and opposed the TFMPP effect. 5. Taken together, these results suggest that the isolation-induced social behavioural deficit may be considered as a behavioural model responsive to 5-HT1B agonists.

The functional role of brain 5-HT and 5-HT receptor subtypes in periaqueductal gray (PAG) induced aversion has been investigated in rats. Antiaversive effects were found with the serotonin agonists TFMPP, mCPP and DOI but not with RU 24969 which was found to facilitate PAG aversion. The first three serotonin agonists share potent 5-HT1C activity while RU 24969 differs with a high 5-HT1A activity. Proaversive effects were found with the mixed 5-HT1C/5-HT2 antagonists cyproheptadine and ritanserin; this effect was already reported for the mixed 5-HT1C/5-HT2 antagonists metergoline and mianserin and is opposite to the effects of the selective 5-HT2 antagonists ketanserin, pirenperone, trazodone and spiperone. The antiaversive effects of mCPP (1 mg/kg) could be prevented by pretreatment of the animals with mianserin (1 and 10 mg/kg). These results suggest that 5-HT1C receptors play an important role in the serotonergic control of PAG aversion. 5-HT1C receptor activation seems to mediate antiaversive effects whereas acute 5-HT1C receptor blockade appears to facilitate PAG aversion. Functional interactions take place between several receptor types in the in vivo control of PAG aversion, where 5-HT1C receptors appear to play a predominant function.

A study was made of the effect of systemic injection of lys8-vasopressin (LVP) and Arg8-vasotocin (AVT) on avoidance reaction in male rats. Both the compounds had no appreciable effect on the rate of the formation. However, in the presence of learning disorders induced by cyproheptadine. LVP completely and AVT partially recovered the normal time course of learning.

The possible involvement of chemical mediator(s) in the induction of the antitumor effects of recombinant human tumor necrosis factor-alpha (rTNF-alpha) on Meth A fibrosarcoma (Meth A) in mice was studied. On day 7 after intradermal implantation of Meth A in mice, rTNF-alpha caused tumor necrosis and inhibited the tumor growth. Ketanserin, cyproheptadine, and spiperone [serotonin (5-HT) receptor blockers] inhibited or attenuated the antitumor effects of rTNF-alpha, but the other types of receptor blockers tested (histamine H1 and H2, adrenaline alpha and beta, dopamine, and acetylcholine receptor blockers) did not. The large i.v. doses of 5-HT caused tumor necrosis and inhibited tumor growth in mice when given i.v. on day 7 but not when given on day 3 after Meth A implantation, which effects closely resemble those of rTNF-alpha. Its anti-tumor effects were completely inhibited by the 5-HT receptor blockers. 5-HT, like rTNF-alpha, showed no cytotoxicity against in vitro cultured Meth A cells. The results suggest that 5-HT is, at least in part, important for the induction of antitumor effects of rTNF-alpha on Meth A in mice.

Activation of a cardiac chemoreceptor with serotonin elicits a reflex which includes changes in heart rate, contractile force, regional blood flow and hypertension. In six anaesthetised dogs we simultaneously recorded parasympathetic and sympathetic efferent traffic elicited during this cardiogenic reflex. The parasympathetic fibres were confirmed by reciprocal frequency changes with changes in blood pressure. The sympathetic fibre activity (anterior ansa subclavia) was attenuated or eliminated by ganglionic blockade or by clonidine. Whereas the phasic sympathetic multifibre discharge was only followed by a quiet period, the parasympathetic multifibre discharge was both preceded and followed by a quiet period. The sympathetic discharge preceded the parasympathetic discharge by 683 +/- 170 ms. These autonomic efferent discharges were not elicited by administration of serotonin into the carotid artery, but were abolished by pretreatment with the serotonin antagonist, cyproheptadine. Cyproheptadine blockade could be overcome by increasing the serotonin concentration tenfold. This remarkable neural asynchrony has important implications concerning the electrical stability of the heart.

1. Either electrical stimulation of midbrain raphe nuclei or administration of 5-hydroxytryptamine (5-HT; serotonin) into the preoptic anterior hypothalamus caused hypothermia in conscious rats at ambient temperatures (Ta) of both 8 degrees C and 22 degrees C. The hypothermia was due to decreased metabolic heat production at Ta = 8 degrees C, while at Ta = 22 degrees C the hypothermia was due to both decreased metabolism and increased heat loss (cutaneous vasodilatation). However, at Ta = 30 degrees C, electrical stimulation of midbrain raphe or intrahypothalamic injection of 5-HT caused an insignificant change in the thermoregulatory responses. There was no changes in respiratory evaporative heat loss in response to these treatments at various Ta's. 2. Direct administration of the serotonergic receptor antagonists such as cyproheptadine and methysergide into the preoptic anterior hypothalamus caused hyperthermia in conscious rats at Ta's of 8 degrees C, 22 degrees C and 30 degrees C. The hyperthermia was due to increased metabolism and cutaneous vasoconstriction. 3. The hypothermia induced by intrahypothalamic administration of 5-HT was antagonized by pretreatment with an intrahypothalamic dose of either cyproheptadine or methysergide in rats at Ta = 22 degrees C. 4. Inhibition of 5-HT neuronal activity with administration of 5-HT into the midbrain raphe regions also caused hyperthermia, increased metabolism and cutaneous vasoconstriction in rats at Ta's of 8 degrees C, 22 degrees C and 30 degrees C. 5. These observations tend to suggest that the functional activity of serotonergic receptors in the preoptic anterior hypothalamus mediates thermoregulatory responses in the rat. Activation of serotonergic receptors in the hypothalamus decreases heat production and/or increases heat loss, while inhibition of serotonergic receptors in the hypothalamus increases heat production and/or decreases heat loss in the rat.

Using animals with large electrolytic lesions of the median eminence-mediobasal hypothalamus, we confirmed earlier findings that metergoline (ME) and methysergide (MS) inhibit PRL secretion through activation of the dopamine receptors of the pituitary lactotrophs and established, in a quantitative manner, that their dopaminergic potencies are comparable to the potency of the dopamine receptor agonist, piribedil, with ED50 in the order of 0.35 to 0.22 mg/kg. Cyproheptadine (CYP), acting by an unknown mechanism, had only a weak inhibiting effect (ED50 greater than 20.0 mg/kg) in these experimental conditions. In the second part of the study, the PRL-inhibiting actions of ME, MS, CYP, and piribedil, respectively, were tested against the PRL release-stimulating effect of activation of the central serotonergic system that was induced by administration of a large dose of L-5-hydroxytryptophan (5HTP; 100 mg/kg), a small dose of 5HTP (15 mg/kg) in rats pretreated with fluoxetine, or by the serotonin receptor agonist quipazine (10.0 mg/kg, ip). The inhibiting potencies of ME (ED50 0.019, 0.014, and 0.048 mg/kg, respectively) against these three stimuli were much larger than in the lesioned animals or than the corresponding potencies of piribedil (ED50 2.2, 0.24, and 0.41 mg/kg, respectively). It is assumed that in these experimental conditions ME inhibited PRL release by blockade of the central serotonin receptors in addition to its dopaminergic effect and that at low doses (0.1 mg/kg or less) the entire inhibiting effect of ME was probably due to its antiserotonergic activity. With MS, which is a weaker serotonin receptor blocker than ME (ED50 0.178, 0.075, and 0.55 mg/kg, respectively, for the three serotonergic stimuli of PRL release), the antiserotonergic component in its PRL-inhibiting effect was evident but less clearly separable from the dopaminergic component in experiments with 5HTP and with fluoxetine plus 5HTP, whereas in experiments with quipazine the entire action could be accounted for by its dopaminergic activity. CYP was the least potent among the three blockers (ED50 0.6, 0.4, and 1.37 mg/kg, respectively, for the three serotonergic stimuli of PRL release), but appropriate tests indicated that it acted only as a serotonin receptor blocker and not by virtue of its antihistaminic, anticholinergic properties or by a direct action on the pituitary lactotrophs. SQ 10,631, another serotonin receptor blocker that was also tested, had no PRL-inhibiting activity. Because of the dual nature of the PRL-inhibiting mechanism of ME and MS and the low effectiveness of CYP, combined possibly with other actions, the serotonin receptor blockers have limited value in studies concerning the role of the central serotonergic system in the regulation of PRL secretion.

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.

Chlordiazepoxide and two serotonin receptor antagonists showed opposite effects when tested for their influence on morphine-induced locomotor stimulation in mice. Chlordiazepoxide enhanced morphine-induced hyperactivity, which was antagonized by cyproheptadine and mianserin. The results indicate that the enhancement of morphine-induced locomotor stimulation is not attributable to an antiserotonergic action of the benzodiazepine compound.

The effects of local intra-arterial infusions of serotonin (5 or 25 micrograms base/min) or norepinephrine (1 or 5 micrograms base/min) on cutaneous (skin) and skeletal muscle vasculatures were investigated in canine forelimbs perfused at constant flow in dogs anesthetized with pentobarbital. Norepinephrine produced dose-related constriction of the skin and skeletal muscle vasculatures. In the cutaneous vascular circuit, norepinephrine produced large artery, small vessel, and large vein constriction. The increase in cutaneous vascular resistance was primarily due to an increase in small vessel resistance. Serotonin did not increase skeletal muscle vascular resistance but produced marked cutaneous vasoconstriction subsequent to large artery and large vein constriction. The small vessels, if anything, tended to dilate. The skin and skeletal muscle vascular responses to serotonin and norepinephrine were similar in innervated and acutely denervated forelimbs. Phentolamine pretreatment completely blocked all vascular actions of norepinephrine, and largely inhibited the cutaneous vasoconstriction produced by the infusion of the low dose of serotonin. However, the cutaneous large artery and large vein constriction produced by the infusion of the high dose of serotonin was not affected by phentolamine pretreatment. Cyproheptadine pretreatment blocked or largely inhibited the cutaneous vasoconstriction produced by serotonin only in doses which also inhibited norepinephrine and vasopressin cutaneous vasoconstriction. Pretreatment with methysergide blocked or largely inhibited the cutaneous large artery and large vein constriction produced by infusions of serotonin. Norepinephrine and vasopressin produced significant vasoconstriction in the presence of methysergide. These data suggest that the cutaneous large artery and large vein constriction produced by serotonin is not due to the activation of postjunctional alpha-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

In male Wistar rats overheated by an infrared lamp, intraperitoneal serotonin administration led to a more rapid overheating than in control, the effect of serotonin being dose-dependent and reduced after i.p. administration of cyproheptadine. Stimulation of the brain serotonin receptors did not affect the development of hyperthermia, whereas the blockade of brain serotonin receptors by intraventricular injections of cyproheptadine or the depletion of brain serotonin by p-chlorophenylalanine resulted in significantly more obvious hyperthermia than in control.

Electrical stimulation (2 Hz for 2 min) of dog isolated saphenous vein strips pre-incubated with tritiated noradrenaline increased the overflow of tritium of which about 80% was noradrenaline. 5-Hydroxytryptamine (5-HT; 1.0 x 10-9-1.0 x 10-7 mol litre-1) and methysergide (3.0 x 10-8-3.0 x 10-6 mol litre-1) inhibited the induced overflow of total tritium by a maximum of 78 +/- 4% and 47 +/- 7% respectively (mean +/- s.e. mean, n=6 for each). Methysergide was about 30 times less potent than 5-HT and the maximum inhibition obtained was less than with 5-HT. Both compounds inhibited electrically-induced contractions and overflow of tritiated noradrenaline. Their inhibitory actions on tritium overflow were little affected by phentolamine (1.0 x 10-6 mol litre-1) or cyproheptadine (1.0 x 10-6 mol litre-1), nor was the inhibitory effect of methysergide on electrically induced contractions antagonized by atropine, mepyramine, cimetidine or propranolol. The findings suggest that the prejunctional inhibitory effect of methysergide may be mediated via stimulation of a 5-HT receptor which, unlike the D-receptor, is not blocked by cyproheptadine. The possibility that the pre-junctional 5-HT receptor in the dog saphenous vein is the same as the post-junctional receptor in this preparation is discussed.