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PubMed2003

Serotonergic and histaminergic mechanisms involved in intralipid drinking?

Some newer antipsychotic agents are associated with weight gain in humans and a hyperphagic response to intralipid solutions in rodents. To examine the possible contribution of serotonin (5-HT) and histamine (H) receptor blockade in antipsychotic-associated hyperphagia, rats were trained to drink a palatable, high-calorie fat emulsion (10% intralipid) during 30-min sessions and were tested following pretreatment with mepyramine (H1 receptor antagonist), metergoline (5-HT(1/2) receptor antagonist), cyproheptadine (H1 and 5-HT(2A/2B/2C) and muscarinic receptor antagonist), SB 242084 (5-HT2C receptor antagonist) and an SB 242084-mepyramine combination. Total intake and ingestive behaviour microstructure were measured. Mepyramine (10 mg/kg) reduced intake, as did metergoline (3.0 mg/kg). Cyproheptadine (0.1-1.0 mg/kg) increased intake and microstructural analysis suggests that this was due to increased numbers of clusters of licking. SB 242084 (3 mg/kg) reduced intake, either when administered alone, or in combination with mepyramine (1 mg/kg). In conclusion, simple antagonism of either H1 (mepyramine) or 5-HT(1/2) receptors (metergoline) alone was not sufficient to increase intake. Furthermore, combined blockade of H1 and 5-HT2C receptors (SB 242084 and mepyramine) was also insufficient to produce hyperphagia. Conversely, simultaneous blockade of H1, 5-HT(2A/2C) and muscarinic receptors (cyproheptadine) led to a substantial hyperphagia and pattern of ingestive behaviour that was similar to that previously observed with some newer antipsychotic agents.

Aminopyridines↗
PubMed1985

Drug and environmentally induced manipulations of the opiate and serotonergic systems alter nociception in neonatal rat pups.

The influence of drug- and environmentally induced alterations in serotonergic and opiate activity on pain sensitivity was assessed in 6-day-old Sprague-Dawley-derived rat pups using tail flick-testing procedures. The opiate agonist morphine was observed to induce tail flick analgesia that was blocked by concurrent administration of the opiate antagonist naloxone. Similarly, the serotonergic agonist quipazine induced analgesia that was blocked by pretreatment with the serotonergic antagonist metergoline. Naloxone alone did not alter tail flick responsivity in non-isolated, nondeprived neonates, suggesting that the opiate system may not exert a significant tonic inhibition of pain sensitivity in neonates. In contrast, the serotonergic system may exert some tonic analgesic influence at this age, given that metergoline was observed to induce slight hyperalgesia in nondeprived, non-isolated neonates. Twenty four hours of food and maternal deprivation, shown previously to increase brain serotonin and 5-hydroxyindole acetic acid and their ratio in neonates (L. P. Spear & F. M. Scalzo, 1984, Developmental Brain Research, in press) was observed to induce tail flick analgesia, an effect blocked by metergoline. Isolation from siblings and the dam and nest for 30 min also induced tail flick analgesia; this analgesia was blocked by treatment with naloxone prior to testing. Together, these experiments support the suggestion that the serotonergic and opiate systems may regulate pain sensitivity even in neonatal rat pups, with agonist- or environmentally precipitated increases in serotonergic or opiate activity inducing significant analgesia during the early postnatal period.

Animals↗
PubMed2000

MDP and 5-HT receptors. Does MDP interact with 5-HT(7) receptors?

A possible interaction of immunomodulator muramyl dipeptide (MDP) with 5-HT(7) (5-hydroxytryptamine) receptors was investigated. The activation of 5-HT(7) receptors relaxes the guinea-pig distal ileum. The whole ileum segments were, therefore, cut and placed into the bath. The preparations were precontracted by substance P and potently relaxed by adding incremental concentrations of 5-carboxamidotryptamine (5-CT) (0.01-3.2 microM), less potently by 5-hydroxytryptamine (5-HT) (1-100 microM). The preparations most sensitive to 5-CT were also relaxed by MDP (1-100 microM). Noncumulative concentration-response curves (CRCs) for 5-HT or 5-CT were established in the absence or presence of 5-HT antagonist metergoline (320 nM). Metergoline inhibited the relaxations and shifted the CRCs to the right. In the preparations most sensitive to the effects of both 5-CT and metergoline, the latter substance also inhibited the effect of the highest concentration (100 microM) in CRCs for MDP. In another type of experiments, CRCs for 5-HT or 5-CT were constructed in the presence of low concentrations of MDP (5-500 nM). The relaxations evoked by either drug remained unchanged. These results suggest that low concentrations of MDP do not interact with activation of 5-HT(7) receptors. In higher concentrations MDP acts on this receptor type as a very weak partial agonist.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2006

Systemic morphine produce antinociception mediated by spinal 5-HT7, but not 5-HT1A and 5-HT2 receptors in the spinal cord.

BACKGROUND AND PURPOSE: The serotonergic system within the spinal cord have been proposed to play an important role in the analgesic effects of systemic morphine. Currently, seven groups of 5-HT receptors (5-HT1-7) have been characterized. One of the most recently identified subtypes of 5 HT receptor is the 5-HT7 receptor. We aimed to examine the role of spinal 5-HT7 receptors in the antinociceptive effects of systemic morphine. EXPERIMENTAL APPROACH: The involvement of spinal 5-HT7 receptor in systemic morphine antinociception was compared to that of the 5-HT1A and 5-HT2 receptors by using the selective 5-HT7 receptor antagonist, SB-269970, the selective 5-HT1A receptor antagonist, WAY 100635, the selective 5-HT2 antagonist ketanserin as well as the non-selective 5-HT1,2,7 receptor antagonist, metergoline. Nociception was evaluated by the radiant heat tail-flick test. KEY RESULTS: I.t. administration of SB-269970 (10 microg) and metergoline (20 microg) completely blocked the s.c. administered morphine-induced (1, 3, 5 and 10 mg kg(-1)) antinociception in a time-dependent manner. Additionally, i.t. administration of SB-269970 (1, 3, 10 and 20 microg) and metergoline (1, 5, 10 and 20 microg) dose dependently inhibited the antinociceptive effects of a maximal dose of morphine (10 mg kg(-1), s.c.). I.t. administration of WAY 100635 (20 microg) or ketanserine (20 microg) did not alter morphine-induced (1, 3, 5 and 10 mg kg(-1), s.c.) antinociception. CONCLUSION AND IMPLICATIONS: These findings indicate that the involvement of spinal 5-HT7, but not of 5-HT1A or of 5-HT2 receptors in the antinociceptive effects of systemic morphine.

Analgesics, Opioid↗
PubMed1993

Reciprocal interaction of 5-hydroxytryptamine and cholecystokinin in the control of feeding patterns in rats.

1. The effect of the CCKA receptor antagonist, devazepide (100 mg kg-1) on meal parameters during the initial phase of the dark period was studied in free-feeding rats by use of a procedure for continuously monitoring feeding patterns. 2. In a second experiment, the effect of devazepide on the reduction in meal parameters induced by the 5-hydroxytryptamine (5-HT) releaser and uptake inhibitor, (+)-fenfluramine (1.5 mg kg-1) in 4 h food-deprived rats was examined. 3. The hypophagic effect of an intraperitoneal injection of cholecystokinin (CCK-8, 4 micrograms kg-1) was studied in rats treated with the 5-HT receptor antagonist, metergoline (1 and 2 mg kg-1). 4. Devazepide increased the size of the first meal in free-feeding, but not in 4 h food-deprived rats and partially antagonized the effect of (+)-fenfluramine on the size and duration of the first meal. The reduction in eating rate induced by (+)-fenfluramine was not modified by devazepide. No changes in (+)-fenfluramine or (+)-norfenfluramine levels were found in the brain of rats treated with devazepide. 5. The effect of CCK-8 on meal size was completely antagonized by 2 mg kg-1 metergoline. A significant interaction was also found between 2 mg kg-1 metergoline and CCK-8 as regards their effect on the inter-meal interval. 6. The results suggest a reciprocal interaction between 5-HT and CCK-8 in enhancing the satiating effect of food in rats.

Animals↗
PubMed1994

The 5-HT1-like receptor mediating the increase in canine external carotid blood flow: close resemblance to the 5-HT1D subtype.

1. It has recently been shown that the increase in external carotid blood flow induced by 5-hydroxy-tryptamine (5-HT) in the anaesthetized dog, being mimicked by 5-carboxamidotryptamine (5-CT), inhibited by methiothepin, vagosympathectomy and sympatho-inhibitory drugs, and resistant to blockade by ritanserin and MDL 72222, is mediated by stimulation of prejunctional 5-HT1-like receptors leading to an inhibitory action on carotid sympathetic nerves; these 5-HT1-like receptors are unrelated to either the 5-HT1A, 5-HT1B or 5-HT1C (now 5-HT2C) receptor subtypes. Inasmuch as 5-CT, 5-methoxytryptamine, sumatriptan and metergoline display high affinity, amongst other 5-HT binding sites, for the 5-HT1D subtype, in the present study we have used these drugs in an attempt to determine whether the above inhibitory prejunctional 5-HT1-like receptors correlate with the 5-HT1D subtype. 2. One-minute intracarotid (i.c.) infusions of 5-HT (0.3, 1, 3 and 10 micrograms), 5-CT (0.01, 0.03, 0.1 and 0.3 micrograms), 5-methoxytryptamine (1, 3, 10 and 30 micrograms) and sumatriptan (1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent increases in external carotid blood flow (without changes in mean arterial blood pressure or heart rate) with the following rank order of agonist potency: 5-CT >> 5-HT > 5-methoxytryptamine > or = sumatriptan. Interestingly, sumatriptan-induced vasodilatation was followed by a more pronounced vasoconstriction. 3. The external carotid vasodilator effects of 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan were dose-dependently and specifically antagonized by metergoline (10, 30 and/or 100 micrograms kg-1, i.v.). In addition, 5-methoxytryptamine- and sumatriptan-induced vasodilator effects were, respectively, markedly inhibited or abolished after vagosympathectomy, as previously shown for 5-CT and 5-HT.4. Sumatriptan showed tachyphylaxis in its vasodilator component and antagonized 5-HT-induced external carotid vasodilatation in a specific manner, suggesting that a common site of action may be involved.5. Taken together, the above results support our contention that 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan produce external carotid vasodilatation in the dog by an action that might primarily involve a prejunctional inhibition on carotid sympathetic nerves; a secondary component of this vasodilator response may be postsynaptic (endothelium-dependent and/or even directly on the vasculature).Based on the rank order of agonist potency, inhibition by vagosympathectomy and blockade by metergoline, we suggest that the inhibitory prejunctional 5-HT1-like receptors mediating external carotid vasodilatation in the dog closely resemble the 5-HTID receptor subtype. The pharmacological profile of these receptors is similar (sympathetic nerves of the rat kidney and human saphenous vein, as well as porcine coronary endothelium) to other putative 5-HTID receptors mediating vascular responses.

Animals↗
PubMed1995

Characterization of prejunctional 5-HT receptors mediating inhibition of sympathetic vasopressor responses in the pithed rat.

1. It has recently been shown that continuous infusions of 5-hydroxytryptamine (5-HT) are able to inhibit, in a dose-dependent manner, the pressor responses induced by preganglionic (T7-T9) sympathetic stimulation in pithed rats pretreated with desipramine (50 micrograms kg-1, i.v.). This inhibitory effect, besides being significantly more pronounced at lower frequencies of stimulation (0.03-I Hz) and devoid of tachyphylaxis, is reversible after interrupting the infusions of 5-HT (up to 5.6 micrograms kg-1 min-1). In the present study we have characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5-HT. 2. The inhibition induced by 5.6 micrograms kg-1 min-1 of 5-HT on sympathetically-induced pressor responses was not blocked after i.v. treatment with physiological saline (1 ml kg-1), ritanserin (0.1 mg kg-1), MDL 72222 (0.15 mg kg-1) or tropisetron (3 mg kg-1), which did not modify the sympathetically-induced pressor responses per se, but was significantly antagonized by the 5-HT1-like and 5-HT2 receptor antagonist, methysergide (0.3 mg kg-1), which also produced a slight attenuation of the pressor responses to 0.03 and 0.1 Hz per se. 3. Unexpectedly and contrasting with methysergide, the 5-HT1-like and 5-HT2 receptor antagonists, methiothepin (0.01, 0.03 and 0.1 mg kg-1) and metergoline (1 and 3 mg kg-1), apparently failed to block the above 5-HT-induced inhibition. Nevertheless, it is noteworthy that these antagonists also blocked the electrically-induced pressor responses per se, presumably by blockade of vascular alpha 1-adrenoceptors and, indeed, this property might have masked their potential antagonism at the inhibitory 5-HT1-like receptors. 4. Consistent with the above findings, 5-carboxamidotryptamine (5-CT, a potent 5-HT1-like receptor agonist), metergoline and methysergide mimicked the inhibitory action of 5-HT with the following rank order of agonist potency: 5CT > > 5-HT > metergoline > or = methysergide. 5. Taken together, the above results suggest that the inhibitory action of 5-HT on the electrically-induced pressor responses is primarily mediated by an action on inhibitory prejunctional 5-HT1-like receptors leading to a decrease in the sympathetic nerve discharge. Interestingly, 5-HT-induced excitatory mechanisms could be made manifest once the inhibitory action of 5-HT had been antagonized.

Animals↗
PubMed1985

Effects of serotonin receptor agonists and antagonists on schedule-controlled behavior of squirrel monkeys.

The behavioral effects of the serotonin (5-HT) precursor l-5-hydroxytryptophan (l-5-HTP) and the phenylpiperazine 5-HT agonists 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), 1-(m-trifluromethylphenyl) piperazine (TFMPP), 1-(m-chlorophenyl)piperazine (CPP) and 2-(1-piperazinyl)quinoline (quipazine) were compared with those of the putative 5-HT antagonists metergoline, methysergide, cyproheptadine, cinanserin and ketanserin under a multiple 5-min fixed-interval schedule of food or electric shock presentation in squirrel monkeys. Intramuscular administration of l-5-HTP (0.3-17 mg/kg), MK-212 (0.01-1.0 mg/kg), TFMPP and CPP (0.03-10 mg/kg) produced dose-related decreases in responding under both the food- and shock-presentation schedules. Quipazine differed from the other 5-HT agonists in that it increased shock-maintained behavior at doses (0.1-1.0 mg/kg) that decreased responding maintained by food. The 5-HT antagonists produced mixed behavioral effects. Metergoline (0.03-1.0 mg/kg), cyproheptadine (0.1-1.0 mg/kg) and cinanserin (1.0-10 mg/kg) produced dose-related increases in responding maintained by food, whereas only metergoline and methysergide increased behavior maintained by shock presentation. The prototype 5-HT2-receptor ligand ketanserin (0.3-10 mg/kg) differed from the other 5-HT antagonists in that it decreased behavior maintained by either event. Thus, performances maintained by food or shock presentation reveal both qualitative and quantitative differences in the behavioral effects of 5-HT receptor agonists and antagonists.

5-Hydroxytryptophan↗
PubMed1987

Effect of diet and fenfluramine on thermogenesis in the rat: possible involvement of serotonergic mechanisms.

A single injection of 5-hydroxytryptamine (5HT, 1 mg/kg, s.c.) in rats stimulated resting oxygen consumption (Vo2) by 21 percent; this was reduced (to 8 percent) by pretreatment with hexamethonium (5 mg/kg, s.c.). DL-fenfluramine injection (20 mg/kg, s.c.) stimulated metabolic rate (Vo2) by about 40 percent, but caused only 11 and 15 per cent increases in animals pretreated with hexamethonium or metergoline (5 mg/kg, s.c.), respectively. Interscapular brown adipose tissue (BAT) activity, assessed from mitochondrial GDP-binding, was increased by 96 per cent in intact tissue 1 h after fenfluramine injection; this response was completely prevented by surgical sympathectomy of interscapular BAT. Metergoline significantly inhibited (by 46 percent) the acute thermic response (postprandial rise in Vo2) to a 40-kJ meal in normal rats, and depressed resting Vo2 in protein-deficient rats by 18 percent, but did not affect resting Vo2 in control animals. BAT activity (mitochondrial GDP-binding) was elevated by 56 per cent in rats fed the low-protein diet, but this difference was almost completely abolished by prior treatment with metergoline. These data demonstrate a potent thermogenic effect of fenfluramine which apparently involves serotonergic pathways and activation of sympathetic outflow to BAT, and indicate that acute thermic responses to food and chronic thermogenic responses to low-protein diets may also involve serotonergic mechanisms.

Adipose Tissue, Brown↗
PubMed1982

Involvement of serotonin in the central regulation of blood pressure: evidence for a facilitating effect on sympathetic nerve activity.

The effects of serotonin (5-HT) receptor agonists and antagonists on sympathetic nervous discharge (SND) recorded from the external carotid and splanchnic nerves were studied in baroreceptor-denervated cats. Intravenous administration of the 5-HT antagonists methysergide (0.025-1.6 mg/kg), metergoline (0.01-0.32 mg/kg), cyproheptadine (0.05-1.6 mg/kg) and cinanserin (0.2-6.4 mg/Kg) was associated with a prolonged dose-related inhibition of SND. Maximum reductions in SND produced by methysergide, metergoline, cyproheptadine and cinanserin were 90, 72, 71 and 50%, respectively. In contrast, a progressive increase in SND was observed in vehicle control animals. Methysergide, metergoline and cyproheptadine failed to reduce SND in cats pretreated with the 5-HT synthesis inhibitor p-chlorophenylalanine. Clonidine (20 micrograms/kg i.v.) significantly inhibited SND (-73%) in p-chlorophenylalanine-treated cats. The selective 5-HT agonists 5-methoxydimethyltryptamine and lisuride also reduced SND in a dose-dependent manner. The time course of the depressor effects of 5-methoxydimethyltryptamine and lisuride correlate well to their ability to inhibit 5-HT cell firing. These data indicate that 5-HT agonists which act presynaptically to inhibit 5-HT cell firing and antagonists which act postsynaptically to block the effect of synaptically released 5-HT both mediate a central reduction in SND. It is concluded that central 5-HT neurons facilitate transmission in central sympathetic pathways.

Animals↗
PubMed1982

Accumulation of hypothalamic endorphins after repeated injections of anorectics which release serotonin.

Two anorectic drugs which stimulate serotonin neuronal activity by releasing serotonin from nerve terminals, d-fenfluramine and CM 57 277 (4-amino-[6-chloro-2-pyridyl]-1-piperidine HCl), were studied in rats. Both drugs, when given for 5 days at doses of 15 mg of d-fenfluramine per kg/day and 20 mg of CM 57 277 per kg/day, decreased body weight gain and increased content of Met5-enkephalin and beta-endorphin in hypothalamus, but not in frontal cortex or pituitary. The increase in the hypothalamic content of the two opioid peptides elicited by d-fenfluramine was reversed by metergoline and p-chlorophenylalanine, suggesting that it is mediated by serotonin. The content of two other hypothalamic neuropeptides, cholecystokinin and substance P, were not affected by d-fenfluramine. Although Met5-enkephalin content in striatum was increased transiently by d-fenfluramine, this was not a serotonin-mediated effect because it was not abolished by metergoline. The decrease in body weight gain was prevented by metergoline, but not by i.p. injection of p-chlorophenylalanine. The effect of p-chlorophenylalanine on intestine may contribute to its failure in reversing the anorectic effect of d-fenfluramine. Naltrexone, an antagonist of opiate receptor, decreased body weight gain but exerted no effect on hypothalamic Met5-enkephalin or beta-endorphin content. Taking into consideration that the increase in Met5-enkephalin and beta-endorphin may have resulted from accumulation due to decreased utilization, the anorectic effects of serotonin releasing drugs may be mediated by a reduction in the functional role of hypothalamic opioid peptides.

Animals↗
PubMed1997

Functional subsensitivity of 5-HT2A and 5-HT2C receptors mediating hyperthermia following acute and chronic treatment with 5-HT2A/2C receptor antagonists.

In the present study, we investigated the duration of attenuation of the temperature increases produced by (+/-) 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and m-chlorophenylpiperazine (m-CPP) which followed pretreatment with four serotonin (5-HT) antagonists; metergoline, mesulergine, mianserin and ritanserin. The duration of attenuation of m-CPP-induced hyperthermia lasted less than 1 day for ritanserin, more than 1 day for the 5 mg/kg doses of both mianserin and metergoline and more than 2 days for the 5 mg/kg dose of mesulergine. The duration of attenuation of DOI-induced hyperthermia lasted less than 1 day for ritanserin, more than 1 day for mianserin, more than 2 days for the 5 mg/kg dose of metergoline and more than 4 days for mesulergine. Daily administration of a low (1.0 mg/kg per day) dose of ritanserin for 14 days led to an attenuation of the temperature increases produced by m-CPP given 24 h after the last dose of ritanserin, but did not cause a similar desensitization of DOI-induced hyperthermia. On the other hand, daily administration of both low (1.0 mg/kg per day) and high (5.0 mg/kg per day) doses of mianserin for 14 days caused desensitization of DOI-induced hyperthermia but did not cause desensitization of m-CPP-induced hyperthermia when these agonists were administered 48 h after the last dose of mianserin. These findings demonstrate functional subsensitivity of both 5-HT2A and 5-HT2C receptors mediating hyperthermia following both acute and chronic administration of 5-HT2A/5-HT2C receptor antagonists; some differences in time course and in responses to individual antagonists at 5-HT2A versus 5-HT2C sites were also observed.

Amphetamines↗
PubMed1990

Complex actions of serotonergic agonists on cold-stimulated TSH secretion in male rats.

The effects of serotonergic activation on cold-stimulated thyrotropin (TSH) and prolactin secretion were studied in male rats. Peripheral injections of both 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, and 1-(3-chlorophenyl)piperazine (m-CPP), a 5-HT1 agonist, decreased TSH levels. The action of 8-OH-DPAT was antagonized by (+/-)-pindolol, which is known to have 5-HT1 antagonist activity, but not by metergoline or ketanserin. The action of m-CPP was antagonized by ketanserin but not by metergoline. TSH levels were not affected by a 5-HT3 receptor agonist, 2-methyl-5-HT, or by a 5-HT3 antagonist, MDL 72222. Infusion of 8-OH-DPAT into the anterior third ventricle increased TSH levels; 5-HT tended to increase TSH levels, but the effect was not significant. Inversely, infusion of 5-HT, 8-OH-DPAT or m-CPP into the posterior third ventricle decreased TSH levels. The action of 5-HT was counteracted by metergoline, ketanserin and (+/-)-pindolol. Unexpectedly, m-CPP infusion into the anterior third ventricle also inhibited TSH secretion. The prolactin-elevating effects of 5-HT, 8-OH-DPAT and m-CPP were neither consistent nor site-specific. In conclusion, stimulation of both 5-HT1 and 5-HT2 receptors may inhibit TSH secretion, but the exact mechanism underlying the site-dependent action of 5-HT and 8-OH-DPAT on TSH secretion remains to be identified.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

5-Hydroxytryptamine-induced vasodilatation in the isolated perfused rat kidney: are endothelial 5-HT1A receptors involved?

Left kidneys obtained from male Wistar rats were perfused with Tyrode solution; the perfusion pressure was measured continuously and taken as an index of vascular resistance in the kidneys. 5-Hydroxytryptamine (5-HT; 3-50 nmol) caused dose-dependent dilator responses in kidneys preconstricted with noradrenaline (0.6 microM) and pretreated with ritanserin (10 nM) and ICS 205930 (10 nM). The 5-HT1 agonist 5-carboxamidotryptamine (5-CT; 16-64 nmol) also caused renal dilatations under similar conditions. The dilator responses to both 5-HT and 5-CT were antagonized by the non-selective 5-HT receptor antagonist metergoline (0.2 microM) and by the selective 5-HT1A receptor antagonist BMY 7378 (0.4 microM). The guanylate cyclase inhibitor methylene blue (30 microM) and the nitric oxide (NO) synthase inhibitor nitro-L-arginine (L-NNA; 100 microM) significantly attenuated the dilator responses to 5-HT and 5-CT. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.5-16 nmol) also caused dose-dependent dilator responses in preconstricted rat kidneys. These responses were antagonized by metergoline and BMY 7378 and significantly attenuated by the NO inhibitors hemoglobin (10 microM) and L-NNA. The renal dilator responses noted with the beta-adrenoceptor blocker tertatolol (1-32 nmol) were also antagonized by metergoline and BMY 7378 and significantly reduced by L-NNA and hemoglobin. Both 8-OH-DPAT and tertatolol (1-30 microM) significantly reduced the vasoconstrictor responses to angiotensin II (20 pmol). Our data indicate that 5-HT receptors located on the vascular endothelium of the renal circulation are involved in the dilator actions of 5-HT, 5-CT, 8-OH-DPAT and tertatolol, and suggest that these receptors resemble the 5-HT1A subtype.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Role of 5-HT1-like receptors in the increase in intragastric pressure induced by 5-hydroxytryptamine in the rat.

The study concerned the effects of 5-hydroxytryptamine (5-HT) on intragastric pressure in bilaterally vagotomized spinal rats. Intravenous (i.v.) bolus injections of 5-HT (2.5, 5.0 and 10 micrograms/kg) produced dose-dependent increases in intragastric pressure; these effects were not modified by atropine (up to 0.2 mg/kg) or mepyramine (1 mg/kg), but were blocked by the mixed 5-HT1-like and 5-HT2 receptor antagonists, methiothepin (0.1, 0.3 and 0.5 mg/kg i.v.) and methysergide (0.5, 1 and 2.5 mg/kg i.v.). However, metergoline (0.5, 1 and 2 mg/kg i.v.) did not markedly modify this effect of 5-HT; only the response induced by 5 micrograms/kg 5-HT was significantly antagonized by the highest dose of metergoline. In contrast, neither the 5-HT2 receptor antagonist, ketanserin (0.5, 1 and 1.5 mg/kg i.v.), nor the 5-HT3 receptor antagonist, ICS 205-930 (0.5, 1 and 3 mg/kg i.v.), influenced the 5-HT-induced increase in intragastric pressure. In addition, 5-carboxamidotryptamine (25, 50 and 100 micrograms/kg i.v.) and RU 24969 (50, 100 and 200 micrograms/kg i.v.) mimicked the aforementioned effects of 5-HT but were weaker than 5-HT. These data suggest that the 5-HT-induced increase in intragastric pressure in the spinal and bilaterally vagotomized rat is mediated by an atypical 5-HT1-like receptor, which, based on the low agonist potency of 5-carboxamidotryptamine and RU 24969 and the resistance to blockade by metergoline, does not seem to correspond to either the 5-HT1A, 5-HT1B, 5-HT1C or the 5-HT1D receptor subtypes.

Animals↗
PubMed1984

Negative feedback control of serotonin release in vivo: comparison of 5-hydroxyindolacetic acid levels measured by voltammetry in conscious rats and by biochemical techniques.

All evidence that serotonin release from central neurones is controlled by a negative feedback mechanism comes from in vitro studies. To study this problem in vivo we performed differential pulse voltammetry in conscious rats, in which carbon fibre electrodes had been implanted 2-15 weeks previously. The effects of monoamine oxidase inhibition (which decreases the amount of 5-hydroxyindoleacetic acid), as well as that of probenecid (which increases 5-hydroxyindoleacetic acid), suggests that 5-hydroxyindoleacetic acid rather than serotonin is measured. Blockade of the presynaptic serotoninergic autoreceptors by methiothepin, metergoline or quipazine led to an increase in differential current of the peak attributed to 5-hydroxyindoleacetic acid in hippocampus, hypothalamus and striatum. Stimulation of these receptors by m-chlorophenylpiperazine, MK-212 or LSD decreased the signal attributed to 5-hydroxyindoleacetic acid. A decrease in the signal was also seen with cinanserin. Stimulation of presynaptic alpha 2-adrenoreceptors by clonidine decreased the signal. Metergoline, quipazine and cinanserin showed biphasic effects, and no effect was observed with methysergide. In general, a reasonable agreement with the results of Baumann & Waldmeier obtained in vitro with electrically stimulated [3H]serotonin prelabelled cortex slices was achieved with differential pulse voltammetry. Only partial agreement with the results of voltammetry was obtained if 5-hydroxyindoleacetic acid was determined biochemically under comparable conditions. Qualitatively, the effects observed with methiothepin, m-chlorophenylpiperazine, clonidine and LSD were in good agreement with those measured with voltammetry as well as with the in vitro effects obtained in electrically stimulated cortex slices. No, or only partial correlation with the results obtained with voltammetry was found with MK 212, cinanserin, metergoline and quipazine. It is concluded that voltammetry preferentially measures extraneuronal 5-hydroxyindoleacetic acid rather than overall changes of this metabolite.

Animals↗
PubMed2003

Further evidence that the discriminative stimulus properties of indorenate are mediated by 5-HT 1A/1B/2C receptors.

Indorenate (5-methoxytryptamine beta-methylcarboxylate, INDO) is a serotonin (5-hydroxytryptamine, 5-HT) agonist that has affinity for 5-HT(1A/1B/2C) receptors. Unlike other anxiolytics such as 5-HT receptor agonists, INDO may not share tolerance or dependency with the benzodiazepine anxiolytics. It has been reported that the discriminative stimulus properties of 5-HT(1A/1B/2C) agonists, but not those of 5-HT(3/4) agonists, generalize to INDO. Therefore, the aim of the present study was to obtain further evidence on the differential involvement of 5-HT(1A/1B/2C) receptors in the discriminative stimulus properties of INDO by evaluating its interactions with antagonists of the 5-HT(1A), 5-HT(1B), 5-HT(2C), and 5-HT(3/4) receptor subtypes. Rats were trained to discriminate INDO from saline in a conditioned taste aversion paradigm. For Group D(+)S(-), administration of INDO signalled that saccharin flavour was followed by LiCl, while injection of vehicle signalled safe consumption of saccharin solution. Group D(-)S(+) had the contingencies reversed. After this training, rats had generalization tests where INDO administration was preceded by different doses of the following antagonists: WAY100635 (5-HT(1A)), NAN190 (5-HT(1A)), methiothepin (5-HT(1A/1B/2C)), GR127935 (5-HT(1B/1D)), ketanserin (5-HT(2A/2C)), ritanserin (5-HT(2C/2A)), mesulergine (5-HT(2C/2A)), metergoline (5-HT(2C/2A)), SB206553 (5-HT(2B/2C)), and tropisetron (5-HT(3/4)). In Group D(+)S(-), the order of potency to block the discriminative stimulus properties of INDO was WAY100635>ketanserin>ritanserin>GR127935>mesulergine congruent with SB206553>metergoline>methiothepin>NAN190, while in Group D(-)S(+), the order was WAY100635>GR127935>ketanserin>ritanserin>mesulergine congruent with SB206553>metergoline>methiothepin>NAN190. Tropisetron did not produce any alteration of the discriminative control by INDO. These results suggest that the discriminative signal of INDO is mediated by 5-HT(1A/2C/1B) receptors and that blockade of any of its components produces a degradation of its discriminative effects.

5-Methoxytryptamine↗
PubMed1997

Cognitive and behavioral effects of cholinergic, dopaminergic, and serotonergic blockade in humans.

The purpose of this study was to investigate the cognitive and behavioral effects of anticholinergic, antidopaminergic, and antiserotonergic agents given alone and in combination to normal volunteers. Twelve young male volunteers took part in this double-blind, randomized, placebo-controlled, crossover study of six drug conditions, each administered on separate days [haloperidol (2 mg p.o.) +/-scopolamine (0.5 mg i.v.), metergoline (4 mg p.o.) +/-scopolamine (0.5 mg i.v.), placebo, and scopolamine alone (0.5 mg i.v.)]. Scopolamine-induced sedation (p < .01), slowed information processing (p < .01) and impaired new learning and memory (p < .01), but did not affect attention or retrieval from semantic memory. Given alone, haloperidol selectively impaired the ability to rapidly switch cognitive sets (p < .05), and metergoline decreased pupil size (p < .01) but did not induce cognitive deficits. In combination with scopolamine, neither haloperidol nor metergoline produced a worsening of the subjects' cognitive performance above and beyond that seen with scopolamine alone. On the contrary, a trend (p < .10) for haloperidol to reverse some of the scopolamine-induced exacerbation of verbal short-term forgetting was observed. The data indicate that scopolamine and haloperidol can independently and selectively affect cognition and that at the doses tested in this study no synergistic exacerbation of cognitive functioning was found when cholinergic blockage was coupled with dopaminergic or serotonergic blockade.

Adult↗