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At least 217 records · Page 12Linked to original sources
PubMed1984

Modulation of cardiovascular and electrocortical activity through serotonergic mechanisms in the nucleus tractus solitarius of the rat.

The nucleus tractus solitarius (NTS) is an integral part of the baroreceptor reflex arc. Thus, stimulation of the NTS elicits changes in arterial pressure and heart rate as well as in numerous other physiologic parameters including electrocortical activity. Serotonin (5-HT), which has been implicated in cardiovascular and electrocortical control, is present in nerve terminals within the NTS. Therefore, this study was designed to determine whether 5-HT may effect that control within the NTS. Serotonin injected into the NTS of anesthetized rats produced marked changes in the EEG, arterial pressure, and heart rate. EEG activity changed from irregular 1-5 Hz, 350-500 microV waves with an overlying 13-15 Hz, low voltage rhythm to a regular, 5 Hz, 250-300 microV rhythm. The dose-dependent cardiovascular changes were maximal at a dose of 400 pmol which produced a fall of mean arterial pressure of 48 +/- 2 mm Hg from a baseline of 96 +/- 4 mm Hg and of heart rate of 90 +/- 9 bpm from a baseline of 400 +/- 18 bpm (n = 6; P less than 0.001). Both the cardiovascular and EEG effects of 5-HT injected into the NTS were blocked by the prior injection of the 5-HT antagonist metergoline at the same site. However, the bilateral microinjection of metergoline into the NTS did not affect the baroreceptor reflex. Thus, although serotonergic mechanisms in the NTS may be involved in the modulation of electrocortical and cardiovascular activity, they are not integral to the baroreceptor reflex arc.

Animals↗
PubMed1991

The effects of serotonergic stimulation on hippocampal and neocortical slow waves and behavior.

The effect of central serotonergic stimulation on hippocampal and neocortical electrical activity and behavior was studied in freely moving rats by administering: (a) tranylcypromine followed by tryptophan, (b) fluoxetine followed by 5-hydroxytryptophan, or (c) p-chloroamphetamine alone. In all rats, scopolamine-resistant hippocampal rhythmical slow activity (RSA), thought to be dependent on brain serotonin, maintained its normal relation to behavior, occurring in close correlation with Type 1 behaviors (postural changes, turning of the head, walking). This RSA was generally absent during stereotyped behavior (head weaving, forepaw treading, hindlimb splaying and tremor). Scopolamine-resistant neocortical low-voltage fast activity (LVFA), also though to be dependent on brain serotonin, was present during Type 1 behaviors and also during stereotyped behavior. Most rats that developed a full stereotyped behavior syndrome had behavioral and electrocortical seizures which were associated with a reduction in the amplitude of hippocampal activity. These seizures were suppressed by methysergide or benserazide. Metergoline (and methysergide to a lesser extent) suppressed the stereotypic behaviors of the serotonin syndrome, resulting in a striking increase in the locomotion caused by central serotonergic stimulation. Such locomotion was accompanied by RSA and LVFA. It was concluded that increased serotonergic activity in the CNS causes an increase in motor activity and a correlated increase in scopolamine-resistant hippocampal RSA and scopolamine-resistant neocortical LVFA and suggested that metergoline blocks serotonin receptors mediating stereotyped behaviors, thereby permitting the expression of serotonin-mediated locomotion.

5-Hydroxytryptophan↗
PubMed1994

Effects of serotonergic agonists on firing rates of photically responsive cells in the hamster suprachiasmatic nucleus.

Serotonergic neurons from the midbrain raphe nuclei innervate the suprachiasmatic nucleus (SCN) of the hypothalamus, which functions as the dominant pacemaker for mammalian circadian rhythms. We investigated the effects of serotonin (5-HT) on firing rates of light-activated SCN cells in urethane-anesthetized hamsters. Micro-iontophoretic application of 5-HT or 5-HT1A agonists (8-OH-DPAT and 5-CT) caused a dose-dependent inhibition of spontaneous activity and photic responses in the majority of SCN cells tested. Application of metergoline alone, a non-selective 5-HT antagonist, slightly increased firing rates during darkness and light exposure, suggesting a tonic serotonergic suppression of SCN activity. Metergoline also effectively attenuated suppression induced by the three 5-HT agonists. In addition, the effects of 8-OH-DPAT were blocked by a 5-HT1A antagonist, SDZ 216-525. However, other putative 5-HT antagonists were weak (propranolol and NAN-190) or ineffective (ketanserin) in blocking the action of 8-OH-DPAT. These results indicate that serotonin has a potent role in reducing photic effects on retinally activated SCN cells in hamsters, and that these effects are mediated by a receptor with properties similar to those of the 5-HT1A subtype.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1984

Prolongation of rat tail bleeding time by ketanserin: mechanisms of action.

Serotonin (5-HT) may play a regulatory role in platelet-vessel wall interaction. This can be reliably investigated by measuring bleeding time. Ketanserin is a recently developed selective 5-HT2 receptor antagonist, reportedly effective against both platelet and vascular 5-HT activation. Ketanserin (5-10 mg/kg) significantly prolonged tail bleeding time measured in conscious rats by two different techniques. While mianserin (a 5-HT2 receptor antagonist exhibiting alpha-adrenolytic activity) also prolonged bleeding time, methysergide, metergoline and cyproheptadine did not. All three compounds acted as 5-HT2 receptor antagonists with appreciable affinity for 5-HT1 receptors. On the other hand, bleeding time was prolonged by either prazosin (a selective alpha 1-adrenoceptor antagonist) or labetalol (an alpha 1- and beta-receptor antagonist). In contrast it was not affected by phentolamine or nicergoline (alpha 1-alpha 2-receptor antagonists) nor by propranolol (a beta-receptor antagonist). The effect of prazosin was significantly increased by combining it with either ketaserin or metergoline. Depletion of platelet serotonin by reserpine did not result in any modification of bleeding time, unless reserpine was combined with an inhibitor of 5-HT synthesis. Platelet activation by 5-HT was neither potentiated by norepinephrine nor prevented by prazosin or phentolamine whereas ketanserin and methysergide were equally effective inhibitors. These findings argue against a role of platelet and/or vascular 5-HT2 receptors in the antihemostatic effect of ketanserin in rats. This drug prolongs bleeding time by antagonising vascular adrenoceptors (prazosin-like effect) and/or by preventing a synergistic interaction between 5-HT and catecholamines at the vascular level.

Animals↗
PubMed1985

Alpha 2-adrenoceptors modulate kainic acid-induced limbic seizures.

We have tested several compounds interfering with the brain monoamine (noradrenaline, dopamine, serotonin) and acetylcholine systems for their effects on limbic seizures produced by systemically (s.c.) injected kainic acid as well as on neurochemical changes in amygdala/pyriform cortex resulting from the kainic acid treatment. The characteristic neurochemical changes induced by s.c. kainic acid were a decrease in noradrenaline and an increase in 5-hydroxyindoleacetic acid in the acute (3 h after kainic acid injection) suggesting strongly increased neurotransmitter turnover in noradrenergic and serotonergic neurons. This was followed by a reduction of glutamic acid decarboxylase and choline acetyltransferase activities during the chronic phase (3 days) of the kainic acid action, indicating destruction of GABAergic and cholinergic neurons. The compounds tested in this model of limbic epilepsy included 1-propranolol, prazosin, clonidine, yohimbine, metergoline, atropine and haloperidol. Among these compounds the alpha 2-adrenergic agonist clonidine (0.1 mg/kg, i.p.) exhibited a powerful protective action on kainic acid-induced limbic seizures as well as on the neurochemical changes in the amygdala and pyriform cortex. In addition, the adrenoceptor antagonists prazosin (alpha 1) and propranolol (beta) as well as the dopamine receptor antagonist haloperidol had significant but less potent - protective actions upon kainic acid-induced seizures and subsequent neurochemical changes. On the other hand, yohimbine (alpha 2-antagonist) and metergoline (serotonin-antagonist) potentiated the limbic seizure syndrome and no effect was found with atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Studies on the role of 5-HT receptors in satiation and the effect of d-fenfluramine in the runway test.

d-Fenfluranine has previously been shown to reduce food-rewarded runway behaviour in the rat, an effect thought to be mediated through activation of central 5-HT pathways. We now examined in more detail the mechanism by which d-fenfluramine reduces runway performance and food intake in the 15-trial runway test. The non-selective 5-HT receptor antagonist, metergoline (1.0 mg/kg), significantly antagonised the effect of d-fenfluramine (2.5 mg/kg) in the runway test. In contrast, neither ritanserin, the potent 5-HT2 and 5-HT1C receptor antagonist (0.5 mg/kg), nor the peripheral 5-HT receptor antagonist, xylamidine (3.0 mg/kg), attenuated the effect of d-fenfluramine in this test situation. Metergoline, but not ritanserin or xylamidine significantly increased runway performance when administered alone. These data indicate that d-fenfluramine reduces runway performance and food intake through activation of 5-HT1 receptors. In addition, blockade of 5-HT1 receptors can attenuate the development of satiation normally observed under control conditions in the runway test.

Amidines↗
PubMed1992

Role of 5-HT receptors in the effect of d-fenfluramine on feeding patterns in the rat.

The effect of d-fenfluramine, 1.5 mg/kg i.p., on meal patterns was studied in rats treated i.p. with 1 mg/kg metergoline or 0.5 mg/kg ritanserin or s.c. with 3 mg/kg (+/-)cyanopindolol. d-Fenfluramine significantly reduced eating rate, meal size and total intake in the first 4 h of testing and the effects were antagonized by metergoline. (+/-)Cyanopindolol reduced total intake and the effect of d-fenfluramine on this measure; the effect of d-fenfluramine on meal size (but not on eating rate) was also reduced by (+/-)cyanopindolol. Ritanserin only reduced the rate of eating and the effect of d-fenfluramine on this measure. The results suggest that 5-HT1 receptors, possibly of the 5-HT1B type, are involved in the ability of d-fenfluramine to cause satiety in freely feeding rats.

Animals↗
PubMed1994

On the mechanisms by which theophylline changes core body temperature in mice.

In the present work, the effects of neurotransmitter antagonists on theophylline-induced changes in body temperature were investigated. Intraperitoneal (i.p.) administration of a low dose of theophylline (25 mg/kg) induced slight hyperthermia, while high doses (75 and 100 mg/kg) induced hypothermia. The hypothermic effect of theophylline was decreased by pretreatment of animals with the dopamine D2 receptor antagonists sulpiride (15 and 30 mg/kg i.p.) and pimozide (0.125 and 0.25 mg/kg i.p.), the muscarinic receptor antagonist atropine (2.5 and 5 mg/kg i.p.) and the 5-HT receptor antagonist metergoline (0.25 mg/kg i.p.). However, the dopamine D1 receptor antagonist SCH 23390 (0.05 and 0.5 mg/kg i.p.), the alpha-adrenoceptor antagonist phenoxybenzamine (2.5 and 5 mg/kg i.p.) and the beta-adrenoceptor antagonist propranolol (5 and 10 mg/kg i.p.) did not after the theophylline response. In reserpinized mice, theophylline caused a dose-dependent rise in body temperature. The response was blocked in animals pretreated with phenoxybenzamine, propranolol and atropine. Single treatment of animals with either SCH 23390 or sulpiride, and also with a combination of the two drugs, decreased the hyperthermia induced by theophylline in reserpinized mice. Pimozide or metergoline did not have any effect in this respect. These data suggest that the hypothermic response to theophylline may be mediated through dopaminergic, cholinergic and serotonergic mechanisms. The hyperthermic action of theophylline in reserpinized animals may be mediated through dopaminergic, cholinergic and adrenergic systems. Overall it seems likely that theophylline interacts with modulatory mechanisms involved in thermoregulation.

Animals↗
PubMed1987

M-chlorophenylpiperazine increases blood pressure and heart rate in pithed and conscious rats.

In pithed rats, m-chlorophenylpiperazine (m-CPP) produced marked, dose-dependent (ED50 = 0.18 mumol) increases in mean arterial blood pressure which peaked within 1 minute and were sustained over 15 minutes. Two serotonin antagonists, metergoline and ritanserin, completely blocked the pressor responses to 2.5 mg/kg m-CPP in pithed adrenal demedullated rats, while alpha-adrenergic blockade by prazosin plus yohimbine was without effect, suggesting that the doubling in blood pressure produced by m-CPP was mediated via serotonin receptors within blood vessels. Somewhat smaller increases in blood pressure over baseline values were observed after m-CPP administration to conscious, freely moving rats. A small but statistically significant increase in heart rate peaked 5 minutes after m-CPP and also was blocked by metergoline but was only minimally affected by ritanserin or the prazosin-yohimbine combination. These results with m-CPP support other evidence for two or more separable effects of serotonergic agonists on the peripheral cardiovascular system.

Adrenal Medulla↗
PubMed1982

Responses of cortical neurones to stimulation of the nucleus raphé medianus: a pharmacological analysis of the role of indoleamines.

Single shock stimulation of the nucleus raphé medianus evoked complex responses from the large majority of neurones tested. These responses consisted of a short-latency (mean 21 msec) inhibition of firing followed by a longer latency (mean 160 msec) increase in firing rate. Occasionally, cells were encountered which exhibited pure inhibitory or pure excitatory responses. Prior treatment with the tryptophan hydroxylase inhibitor rho-chlorophenylalanine reduced the excitatory effects of raphé stimulation but greatly increased the inhibitory effects. Pretreatment with 5,7-dihydroxytryptamine (5,7-DHT), on the other hand, reduced both inhibitory and excitatory effects of raphé stimulation. Methysergide was found to be an effective antagonist of excitatory responses to iontophoretically applied 5-hydroxytryptamine (5-HT) but less effective against depressant responses to either 5-HT or tryptamine. In contrast metergoline consistently antagonized 5-HT and tryptamine-induced depressions but not 5-HT elicited excitations. When tested against stimulation evoked responses of cortical neurones methysergide antagonized the excitatory effects of raphé stimulation but had much less effect on the inhibitory responses, while the reverse held true for metergoline. The present results may be compatible with a mediation of the excitatory effects of stimulation by 5-HT and the inhibitory effects by tryptamine.

5,7-Dihydroxytryptamine↗
PubMed1983

Behavioural responses induced by intrathecal injection of 5-hydroxytryptamine in mice are inhibited by a substance P antagonist, D-Pro2, D-Trp7,9-substance P.

Intrathecal injection of 5-hydroxytryptamine (5-HT) in mice produced a behavioural syndrome consisting of reciprocal hindlimb scratching and biting or licking of the hindquarters. Pretreatment with either metergoline or morphine given intrathecally inhibited the 5-HT-induced behaviour. The response to 5-HT was similar to the effect of substance P (SP), and it was found that the blocker of the substance P receptor, D-Pro2, D-Trp7,9-SP, not only reduced the effect of substance P, but also that of 5-HT. The behaviour induced by substance P was also significantly reduced by intrathecal injection of either morphine or metergoline. These findings indicate a functional interaction between substance P and 5-HT in the modulation of sensory input at the spinal level.

Animals↗
PubMed1984

Test-dependent variations in the antinociceptive effect of p-chloroamphetamine-induced release of 5-hydroxytryptamine.

p-Chloroamphetamine (PCA), in doses that did not significantly impair motor performance in a rotating-wheel task, induced marked analgesia in rats tested with the hot-plate and flinch-jump methods. In the tail-flick test, moderate hyper- or hypo-analgesia was found to be dependent on dose. In hot-plate experiments the analgesia was attenuated by inhibition of uptake of 5-HT (with zimelidine), depletion of stores of 5-HT (with PCPA) and by lesioning of 5-HT-containing terminals (long-term PCA treatment). Blockade of serotonin receptors by metergoline produced hyperalgesia, but failed to reduce the analgesia induced by p-chloroamphetamine. Manipulation of catecholaminergic and opioid systems did not reduce the effect of p-chloramphetamine. It is concluded that induction of release of 5-HT by chloroamphetamine induces antinociception which varies in magnitude between tests, suggesting that different serotonergic mechanisms modulate complex and reflex responses to noxious stimulation. The failure of metergoline to antagonize the analgesia induced by p-chloroamphetamine suggests an involvement of 5-HT receptors different from the ones implicated in other types of behaviour mediated by 5-HT.

Amphetamines↗
PubMed1986

Effects of MK-212 (6-chloro-2[1-piperazinyl]pyrazine) on schedule-controlled behavior and their reversal by 5-HT antagonists in the pigeon.

The effects of MK-212 (6-chloro-2[1-piperazinyl]pyrazine), a centrally-active 5-hydroxytryptamine (5-HT; serotonin) agonist, were studied alone and in combination with the 5-HT antagonists, methysergide (0.01-0.1 mg/kg), metergoline (0.01-1.0 mg/kg) and ketanserin (0.01-3.0 mg/kg). Pigeons were maintained under a procedure where key pecks were reinforced under a multiple fixed-interval (FI) fixed-ratio (FR) schedule of food presentation. In the fixed-interval component, the first response after 3 min had elapsed, produced food, while in the fixed-ratio component, the thirtieth response was reinforced. The drug MK-212 (0.1-3.0 mg/kg) produced dose-related decreases in response rates under both components of the schedule. In smaller doses of MK-212 (0.3 and 1.0 mg/kg), the decrease in the response rate was greater in the fixed-interval component than in the fixed-ratio component. Small doses of methysergide (0.03 mg/kg) and metergoline (0.1 mg/kg), which had little effect when given alone, partially blocked the effects of MK-212 (1.7 and 3.0 mg/kg) in decreasing rate. Larger doses of these compounds, which sometimes increased the response rate when given alone, resulted in a more complete restoration of response rates when administered with MK-212. Ketanserin, a selective 5-HT2 antagonist, reversed the effects of MK-212 in some cases, but the patterning of responses remained disturbed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Effects of serotonin receptor antagonists and agonists on the tail-flick response in mice involve altered tail-skin temperature.

Tail-flick latency and tail-skin temperature were measured in mice after administration of serotonin (5-HT) receptor antagonists (metergoline and metitepin) and agonists [5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)]. Metergoline (4 mg/kg) and metitepin (0.5 mg/kg) reduced the tail-flick latencies and increased the tail-skin temperatures, but the effect on the tail-flick latencies was non-significant when the effect of temperature was taken into account. Both 5-MeODMT (3 mg/kg) and 8-OH-DPAT (1 mg/kg) reduced the tail-skin temperature but only 5-MeODMT increased the tail-flick latencies. The effect of 5-MeODMT on tail-flick latencies was still highly significant when the effect of temperature was taken into account. The results show that the apparent hyperalgesia elicited by 5-HT receptor antagonists in the tail-flick test in the mouse is secondary to increased tail-skin temperature and not due to increased nociceptive sensitivity. The antinociceptive effect of 5-MeODMT in the tail-flick test can, however, not be explained by effects of temperature.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1983

Time course of changes in nociception after 5,6-dihydroxytryptamine lesions of descending 5-HT pathways.

Intrathecal injection of 5,6-dihydroxytryptamine (5,6-DHT) in rats produced selective lesions of the descending 5-HT pathways. Spinal 5-HT levels gradually fell to less than 10% of controls within 10 days of 5,6-DHT administration with no recovery evident within 4 weeks. The uptake of 14C-5-HT into crude spinal synaptosomes was similarly reduced. The uptake of 3H-NA into spinal synaptosomes was unaffected, as was the uptake of 14C-5-HT and 3H-NA into cortical synaptosomes. Following 5,6-DHT, tail-flick latencies were reduced by 20-30% during the first post-injection week, but returned to control levels during the second week. Intrathecal or systemic administration of the 5-HT receptor antagonist metergoline significantly reduced latencies of normal rats and of 5,6-DHT treated rats tested after the second week when the response was normalized. Metergoline did not, however, further reduce the latencies of lesioned rats during the first post-injection week. It is concluded that functional adaptation involving 5-HT neurotransmission compensated for the selective lesion of descending 5-HT pathways induced by 5,6-DHT.

5,6-Dihydroxytryptamine↗
PubMed1984

Serotonergic mediation of habenular self-stimulation in the rat.

The possible involvement of serotonergic neurons in self-stimulation of the habenular complex was examined in 16 rats. Animals were implanted with bipolar electrodes into the habenula (Hb), lateral hypothalamus (LH), or median raphe (MR), and trained to touch a dry spout to receive electrical stimulation of the brain. Metergoline (5 mg/kg, IP), a serotonergic receptor blocking agent, produced a complete suppression of self-stimulation with Hb and MR electrodes, but significantly less suppression with LH electrodes, suggesting that the rewarding effect of habenular stimulation is mediated by serotonergic neurons. In contrast to the differential effects of metergoline, chlorpromazine (2 mg/kg, IP), a catecholamine receptor blocking agent, suppressed both Hb and LH self-stimulation in a similar manner.

Animals↗
PubMed1994

ICV injection of the serotonin 5-HT1B agonist CP-93,129 increases the secretion of ACTH, prolactin, and renin and increases blood pressure by nonserotonergic mechanisms.

This study tested whether a new serotonin (5-HT1B) agonist, 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxy-pyrrolo[3,2-b]pyridine (CP-93,129), could be used to study the potential role of 5-HT1B receptors in the secretion of adrenocorticotropic hormone (ACTH), prolactin, and renin. CP-93,129 has a high affinity for 5-HT1B receptors but low affinity for other 5-HT receptor subtypes. In addition, CP-93,129 does not readily cross the blood-brain barrier. The secretion of ACTH, prolactin, and renin is known to be increased after activation of 5-HT receptors. ICV injections of CP-93,129 (100 micrograms/kg) increased the plasma concentrations of ACTH, prolactin, and renin. CP-93,129 also increased blood pressure and reduced heart rate. To determine whether these effects of CP-93,129 are centrally mediated, we compared them with IP injection of the same dose of CP-93,129. IP-injected CP-93,129 did not alter blood pressure or heart rate and did not elevate plasma prolactin and renin concentrations. To determine whether 5-HT1B receptors mediate the central effects of CP-93,129, rats were pretreated with the 5-HT antagonists l-propranolol or metergoline prior to ICV injections of doses of CP-93,129 (0-100 micrograms/kg). The 5-HT1A/1B/2A/2C antagonist metergoline (0.5 mg/kg, IP) failed to inhibit the CP-93,129-induced elevation of ACTH, prolactin, or renin concentrations. In contrast, the 5-HT1A/1B/beta antagonist l-propranolol (20 micrograms/kg, ICV) inhibited the renin but not the ACTH or prolactin responses to ICV CP-93,129.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1990

Effects of serotonin antagonists on m-chlorophenylpiperazine-mediated responses in normal subjects.

The serotonin (5HT) agonist, m-chlorophenylpiperazine (MCPP), has been used as a challenge agent to assess central 5HT receptor sensitivity in normal subjects and patients with panic disorder, obsessive-compulsive disorder, and major depression. Adrenocorticotropin, cortisol, and prolactin responses to MCPP were among the variables measured. MCPP's usefulness as a probe of 5HT receptors, however, hinges on its 5HT selectivity. To address MCPP's selectivity for 5HT, this study tested whether two different 5HT antagonists, methysergide (4 mg p.o.) and metergoline (4 mg p.o.), could block the hormonal and behavioral effects of MCPP (0.5 mg/kg p.o.) in 10 normal male subjects in comparison to placebo. Both 5HT antagonists abolished the prolactin release to MCPP. Metergoline, the antagonist with the more potent 5HT binding affinity, significantly blocked MCPP's effect on cortisol release as compared to placebo, and methysergide showed a nonsignificant trend to that effect. MCPP alone did not have a significant effect on behavioral variables, perhaps explaining why neither 5HT antagonist affected these measures. The findings from this study suggest that both MCPP-induced prolactin release and cortisol release are indeed 5HT-mediated effects.

Administration, Oral↗