Doses Of Serotonin Research Articles

Abstract MP19: Endogenous 5-hydroxytryptamine May Regulate Skeletal Muscle Vascular Resistance In Normal Healthy Rats

Infusing low doses of 5-hydroxytryptamine (5-HT) into normal rats causes chronic (weeks to months) hypotension and a fall in total peripheral resistance. These effects are mediated by activation of 5-HT 7 receptors. Therefore, we generated 5-HT 7 receptor knockout rats (5-HT 7 KO) to explore possible cardiovascular effects of 5-HT 7 receptors under normal and pathophysiological conditions. We previously reported that healthy 5-HT 7 KO rats have normal blood pressure and total peripheral resistance at rest. This suggested that 5-HT 7 receptors plays no role in cardiovascular regulation under normal conditions. But total peripheral resistance is determined by multiple vascular beds that differ in their sensitivity to 5-HT. Others have indicated that 5-HT 7 receptors in the skeletal muscle vasculature are particularly sensitive to the effects of 5-HT. Therefore, we hypothesized that 5-HT 7 KO rats would show both reduced responsiveness to exogenous 5-HT and increased resting skeletal muscle vascular resistance. Experiments were performed in isoflurane-anesthetized, male Sprague-Dawley (SD) (n=6), 5-HT 7 wild-type (5-HT 7 WT) (n=5) and 5-HT 7 KO (n=6) rats at 7-8 months of age. Arterial pressure was measured with an aortic catheter. Blood flow to the hindquarters (mostly skeletal muscle) was measured with transit-time, ultrasound flowmetry. After 10 minutes of baseline hemodynamic measurements were obtained, 5-HT was infused iv at a rate of 25 μg/kg/min for 15 minutes, followed by a 15-minute recovery period. As expected, 5-HT 7 KO rats did not show a significant fall in hindquarter vascular resistance (HQVR) during 5-HT infusion, while SD and 5-HT 7 WT did. More importantly, HQVR at baseline was significantly (p < 0.05) higher in 5-HT 7 KO rats (16.0 ± 2.0 mmHg/ml/min) than in 5-HT 7 WT rats (10.9 ± 0.06 mmHg/ml/min) or SD rats (7.0 ± 0.03 mmHg/ml/min). These results support our hypothesis that in healthy (albeit anesthetized) rats, 5-HT 7 receptors reduce skeletal muscle vascular resistance.

Effect of 5-hydroxytryptamine on neurogenic vasoconstriction in the isolated, autoperfused hindquarters of the rat

1. In the present study, we analysed the effect of different doses of 5-hydroxytryptamine (5-HT; intravenous infusions of 0.001-40 microg/kg per min) in the autoperfused hindquarters of the rat subjected to electrical stimulation (frequencies of 0.5-20 Hz) of the lumbar chains, investigating the relationship between the adrenergic and serotonergic systems in this vascular bed. 2. Because we observed that 5-HT inhibited the increases in perfusion pressure induced by electrical stimulation of the lumbar chains, we used different agonists and antagonists to analyse the mechanism of action of 5-HT. 3. The effect of 5-HT was inhibited by methiothepin (a non-specific 5-HT receptor antagonist), but not by ritanserin (a selective 5-HT2 receptor antagonist). The effects of 5-HT were mimicked by 5-carboxamidotryptamine (a 5-HT1 receptor agonist) and L-694 247 (a selective 5-HT1D receptor agonist), but not by 8-hydroxy-2-dipropylaminotetralin (a 5-HT1A receptor agonist), CGS-12066B (a 5-HT1B receptor agonist), alpha-methyl-5-HT (a 5-HT2 receptor agonist), 1-(3-chlorophenyl) piperazine (a 5-HT2C receptor agonist) or 1-phenylbiguanide (a 5-HT3 receptor agonist). The selective 5-HT1D/1B receptor antagonist BRL 15572 inhibited the effect of the agonist L-694 247. 4. Our data suggest that 5-HT inhibits the increases in perfusion pressure induced by the electrical stimulation of the lumbar chains, acting on presynaptic 5-HT1D receptors and decreasing the release of noradrenaline from the sympathetic nerves in the hindquarter vascular bed of the rat.

Dipeptidyl peptidases in the soleus muscle of the rat before and after treatment with 5-hydroxytryptamine.

A moderate peptidase activity against L-lysyl-L-proline-4-methoxy-beta-napththylamide was detected histochemically in unfixed sections of soleus muscle fibres of inbred male Wistar rats using two variants of the semipermeable membrane technique. One variant involved simultaneous coupling with tetrazotised 3,3'-dimethoxybenzidine, the other post-coupling. The activity at pH 6 increased approximately three-fold in many fibres showing signs of insult in rats that had been given a single low dose of 5-hydroxytryptamine (10 mg/kg body weight) 48-72 h earlier. The hydroxytryptamine treatment was found to induce a selective myopathy. Some of the increased peptidase activity within insulted muscle fibres appeared to arise from invading mononuclear cells, but the majority seemed endogenous to muscle fibres. The peptidase activity persisted in some fibres 21-28 days after 5-hydroxytryptamine administration, by which time the whole muscle appeared histologically normal. The variation of the activity of the peptidase with pH in the presence of various inhibitors was investigated in both control and insulted muscle fibres. From its sensitivity and behaviour towards Zn2+, Hg2+, Cu2+, puromycin, benzethonium chloride and phenylmethylsulphonyl fluoride and its indifference towards Co2+, Cd2+, Mn2+ and o-phenanthroline, it is concluded that the activity can be attributed to a mixture of at least two peptidases, dipeptidyl peptidase II and an unidentified neutral dipeptidyl peptidase. The possible role of the peptidase(s) in muscle regeneration in discussed.

The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, attenuates the Bezold-Jarisch reflex in the anaesthetized rat

The effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, on the Bezold-Jarisch reflex elicited by i.v. doses of 5-hydroxytryptamine (5-HT) was investigated in urethane-anaesthetized rats. Activation of the Bezold-Jarisch reflex with 5-HT (0.5–16 ug kg ) produced pronounced dose-dependent hypotensive and bradycardic responses which were attenuated by MK-801 (1 mg kg i.v.) but not by saline. The data suggests that activation of the Bezold-Jarisch reflex by 5-HT involves a glutamatergic synapse presumably located within the brainstem vagal reflex arc.

Lack of effect of antagonists on serotonin-induced inhibition in rat hippocampus.

Four putative central nervous system 5-hydroxytryptamine antagonists, methysergide, cyproheptadine, metergoline, and ketanserin and also lysergic acid diethylamide were applied by iontophoresis to firing CA1 hippocampal pyramidal cells to test their action on the inhibition produced by 5-hydroxytryptamine. In contrast to a previous report, none of these peripherally active 5-hydroxytryptamine antagonists altered the inhibitory response to submaximal doses of 5-hydroxytryptamine, but they did block after-excitations that followed the inhibitions. All the antagonists and lysergic acid diethylamide produced a depression of firing. When picrotoxin was used to drive the cells, 5-hydroxytryptamine was still able to produce a normal inhibition. The results of this study suggest that CA1 hippocampus is another structure, innervated by serotonergic neurones, where all (peripherally active) serotonin antagonists tested to date are ineffective against 5-hydroxytryptamine induced inhibition.

Complete blockade and attenuation of 5-hydroxytryptamine induced analgesia following NA depletion in rats and mice.

The effect of pretreatment with the noradrenaline neurotoxin, N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), upon the analgesia induced by various doses of 5-hydroxytryptamine (5-HT) was examined in rats and mice. DSP4 treatment (2 X 50 mg/kg, intraperitoneally) of rats caused a complete blockade of 5-HT induced analgesia in the tail-flick, hot-plate and shock titration tests. DSP4 treatment (1 X 50 mg/kg, intraperitoneally) of mice caused a partial blockade of 5-HT induced analgesia in the hot-plate test, but no significant blockade in the tail-flick test. These results are discussed with regard to serotonergic-noradrenergic interactions and the species discrepancy in nociceptive testing.

Opposite effects of intraventricular serotonin and bufotenin on rat startle responses

Rat startle responses to air puffs were monitored in a stabilimeter during the intraventricular infusion of various doses of 5-hydroxytryptamine (5-HT) or the putative hallucinogenic congener of 5-HT, 5-hydroxy-N, N-dimethyltryptamine (5-HDMT) or saline. Qualitatively opposite effects were observed, with 5-HT producing a dose-dependent decrease in responsivity and 5-HDMT increasing the magnitude of startle responses. No specific effects of either compound could be demonstrated on the presumably separable processes of sensitization and habituation. The results are discussed in the context of a central serotonergic system which facilitates behavioral inhibition and which antagonized by indoleamine hallucinogens.

The effects of potassium, 5-hydrocytryptamine, adrenocorticotrophin and angiotensin II on the concentration of adenosine 3':5'-cyclic monophosphate in suspensions of dispersed rat adrenal zona glomerulosa and zona fasciculata cells.

Dispersed rat adrenal cells prepared from both the capsule and the decapsulated gland were used to investigate the effects on cyclic AMP accumulation of known stimuli of steroidogenesis [ACTH (adrenocorticotrophin), angiotensin II, K(+) ions and 5-hydroxytryptamine]. Since glomerulosa-cell preparations from capsular strippings are normally contaminated with a proportion of fasciculata cells, cells purified by fractionation on a bovine serum albumin gradient were also used. The results showed that: (1) ACTH and angiotensin II stimulated cyclic AMP accumulation in both fractionated and unfractionated zona fasciculata cells; (2) 5-hydroxytryptamine and an increased extracellular K(+) concentration (from 3.6 to 8.4mm) had no effect on cyclic AMP concentrations in fasciculata cell preparations; (3) the addition of ACTH, angiotensin II, 5-hydroxytryptamine or K(+) to the incubation medium resulted in increased cyclic AMP concentrations in unpurified zona glomerulosa cell preparations; (4) fractionation and hence the virtual elimination of fasciculata contamination, did not affect the response to 5-hydroxytryptamine and increased K(+) concentration. However, the responses to ACTH and angiotensin II were markedly lowered but not abolished. These results strongly suggest a link between cyclic AMP production and steroidogenesis in the zone of the adrenal gland that specifically secretes aldosterone. All four agents used stimulated both steroid output and cyclic AMP accumulation. However, at certain doses of 5-hydroxytryptamine, K(+) and angiotensin II the significant increases in corticosterone output were not accompanied by measurable increases in cyclic AMP accumulation.

Cardiovascular Responses to Radioprotective Compounds in Rats

Heart rate and blood pressure were measured in anesthetized rats after the intraperitoneal administration of radioprotective doses of 5-hydroxytryptamine (5-HT), 2-mercaptoethylamine (MEA), 2-aminoethylisothiouronium (AET), and their mixtures. All of the chemicals produced a slowing of the heart rate in most of the animals. Both doses of 5-HT (7 and 14 mg/kg) consistently elicited a marked depressor response. While a low dose of AET (100 mg/kg) had little effect, higher doses (175 and 250 mg/kg) tended to increase blood pressure. On the other hand, low doses of MEA (60 and 120 mg/kg) tended to lower blood pressure, while a high dose (165 mg/kg) produced no significant change. The blood pressure response after the administration of the mixtures of the chemicals appeared to be the resultant effect of the action of each component. The mixture of all three chemicals (7 mg/kg 5-HT, 100 mg/kg AET, 60 mg/kg MEA) elicited the most consistent response in all animals, slowing the heart rate by 20% and decreasing th...

UPTAKE OF 5-HYDROXYTRYPTAMINE AND ADRENALINE IN THE LIVER.

A dose of 5-hydroxytryptamine caused a greater contraction of the cat nictitating membrane when injected into the jugular vein than when injected into the portal vein. The difference is attributed to uptake or destruction of 5-hydroxytryptamine by the liver. The effects of portal and jugular injections became equal after administration of the monoamine oxidase inhibitors iproniazid or harmaline. Isoniazid, which does not inhibit monoamine oxidase, did not have this effect. Similarly, the effect of a portal injection of adrenaline was less than the effect of an equal jugular injection of adrenaline. Iproniazid and harmaline increased the effect of a portal injection, but not to equal the effect of a jugular injection. Isoniazid had no effect. Pyrogallol did not alter the ratio between the effects of portal and jugular injections of adrenaline, but increased the responses to both.