Administration Of Metergoline Research Articles

Dual-mode dopamine increases mediated by 5-HT1B and 5-HT2C receptors inhibition, inducing impulsive behavior in trained rats

Patients with eating disorders exhibit problems with appetitive impulse control. Interactions between dopamine and serotonin (5-HT) neuron in this setting are poorly characterized. Here we examined 5-HT receptor-mediated changes in extracellular dopamine during impulsive appetitive behavior in rats. Rats were trained to perform a cued lever-press (LP) task for a food reward such that they stopped experiencing associated dopamine increases. Trained rats were administered the mixed 5-HT1B/2C-receptor antagonist metergoline, the 5-HT2A/2C-receptor antagonist ketanserin, and p-chlorophenylalanine (PCPA). We measured dopamine changes in the ventral striatum using voltammetry and examined the number of premature LPs, reaction time (RT), and reward acquisition rate (RAR). Compared with controls, metergoline increased premature LPs and shortened RT significantly; ketanserin decreased premature LPs and lengthened RT significantly; and PCPA decreased premature LPs, lengthened RT, and decreased RAR significantly. Following metergoline administration, rats exhibited a fast phasic dopamine increase for 0.25–0.75 s after a correct LP, but only during LP for an incorrect LP. No dopamine increases were detected with ketanserin or PCPA, or in controls. After LP task completion, metergoline also caused dopamine to increase slowly and remain elevated; in contrast, ketanserin caused dopamine to increase slowly and decrease rapidly. No slow dopamine increase occurred with PCPA. Inhibition of 5-HT1B- and 5-HT2C-receptors apparently induced dual modes of extracellular dopamine increase: fast phasic, and slow long-lasting. These increases may be associated with the suppression of acquired prediction learning and retention of high motivation for reward, leading to impulsive excessive premature LPs.

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

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. 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. 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. 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.

Abortifacient and endocrine effects of metergoline in beagle bitches during the second half of gestation

The purpose of this study was to investigate the abortifacient effects of high doses of metergoline when administered to pregnant beagle bitches during the second half of gestation and to define the endocrine effects of this treatment as represented by plasma progesterone and estradiol concentrations. Previously, metergoline had been shown to be incompletely luteolytic and induced abortion in only one of eight pregnant bitches when 0.4–0.5 mg/kg were administered twice daily for 5 days from Days 18 to 20 of diestrus. Nine pregnancies in six beagle bitches were used for the present study. Three bitches were treated in each of two consecutive pregnant cycles. Metergoline was administered at a dose of 0.6 mg/kg per os twice daily, starting on Day 28 after the cytological onset of diestrus. Abortion was induced in eight of the nine treated pregnancies and started after 3–23 days of treatment (mean 12.5 days, S.D. 6.4 days). The abortions were completed within 0.5–8 days (mean 2.2 days, S.D. 2.7 days). There were no side effects associated with metergoline treatment and none of the abortions was associated with complications that required intervention. In the single bitch that did not abort, an ovarian granulosa cell tumor was discovered when the single fetus had to be removed surgically at term. Plasma progesterone concentrations declined after the start of metergoline administration in all pregnancies but levels below 4.8 nmol/l were required for successful abortions. Plasma estradiol concentrations showed a tendency to decline and fluctuate concurrently with the plasma progesterone levels. However, suppression of plasma estradiol concentrations by metergoline was not as complete as the suppression of progesterone and did not seem a prerequisite for abortion. The hormone profiles and treatment period required for abortion tended to be similar for both cycles of the three bitches that were treated during two consecutive pregnancies. This suggests a bitch effect on the factors that determine the efficacy of metergoline to induce abortion. The large variation and length of the treatment period that was required until abortion commenced was probably related to the relatively early start of treatment compared to other studies. The results of this investigation suggest that, similar to other prolactin suppressing ergot derivatives, metergoline causes complete luteolysis and can be used to reliably induce abortion only during the last 3 weeks of gestation.

Influence of the serotonin antagonist, metergoline, on the anxiogenic effects of carbon dioxide, and on heart rate and neuroendocrine measures, in healthy volunteers.

The mechanism of action of carbon dioxide (CO(2)) angiogenesis is unknown; only recently have possible serotonergic (5-HT) influences begun to be studied. In separate double-blind challenges 1 week apart, 14 healthy volunteers received two vital capacity inhalations each of 35% CO(2) and of air, once after a single capsule of placebo and once after a single capsule containing 4 mg of the 5-HT antagonist metergoline in a randomized crossover design. The inhalations were repeated 1 and 2 days after the ingestion of capsules, to investigate possible delayed effects of metergoline, and possible tolerance to repeated CO(2) after placebo. We observed increased anxiety, and a trend for increased plasma noradrenaline (NA), after CO(2). CO(2) anxiogenesis was significantly enhanced by metergoline. Heart rate increased after both gas mixtures following metergoline administration. Plasma prolactin levels were lower after metergoline. Responses to CO(2) did not differ between the day of placebo administration and the two subsequent days; on the days following metergoline administration there were almost no delayed effects. We hypothesize that 5-HT may function as an inhibitor of CO(2) anxiogenesis, and that this is opposed by the 5-HT antagonist, metergoline. Absence of tolerance after repeated CO(2) argues against psychological explanations of tolerance after other panicogens. Copyright 2001 John Wiley & Sons, Ltd.

S.19.03 Is there a specific psychopharmacology for eating disorders?

The diagnosis, treatment, and pathophysiology of obsessive-compulsive disorder (OCD) were examined in a series of studies utilizing psychobiological approaches. Putative biological markers previously reported in depression were studied in this disorder and revealed that on some measures [Dexamethasone Suppression Test and rapid eye movement (REM) latency on sleep electroencephalogram (EEG)], OCD patients resemble those with major depressive disorder (MDD), whereas on others [REM density, platelet serotonin uptake, probably platelet 3H-imipramine binding, and 5-hydroxy-indoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF)] they do not. The relationship between OCD and MDD was further explored in a double-blind, randomized crossover study designed to compare the antiobsessional effects of two tricyclic antidepressants, clomipramine (CMI) and desipramine (DMI), in a nondepressed cohort of OCD patients. CMI was found to have significant antiobsessional effects in this group, whereas in the same patients, DMI lacked therapeutic effects. These results suggest that not all antidepressants are antiobsessive and that some property of CMI, such as its potent serotonergic effects, may be of pathophysiological relevance for OCD. The role of serotonin in this disorder was then tested using the pharmacological challenge strategy. A novel serotonin postsynaptic receptor (5HT-1) agonist, m-chlorophenylpiperazine (m-CPP), was administered orally (0.5 mg/kg) under double-blind, placebo-controlled conditions to OCD patients and controls. In addition, a serotonergic receptor antagonist, metergoline (4 mg), was given to a subset of OCD patients. Relative to healthy volunteers, the OCD patients became significantly more anxious, depressed, and dysphoric after m-CPP administration. Moreover, in the OCD patients, obsessive-compulsive symptoms increased markedly after m-CPP and decreased significantly following metergoline administration. These results demonstrate that agents that bind to the 5HT-1 receptor can acutely affect the symptoms of OCD patients. The striking behavioral effects of these direct postsynaptic receptor ligands and the relative specificity of clomipramine as an antiobsessional agent suggest

Mediation of 5-HT-induced external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs by the putative 5-HT7 receptor.

1. The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 micrograms kg-1, i.v.). 2. One-minute intracarotid (i.c.) infusions of 5-HT (0.3-30 micrograms min-1), 5-carboxamidotryptamine (5-CT; 0.01-0.3 microgram min-1), 5-methoxytryptamine (1-100 micrograms min-1) and lisuride (3-1000 micrograms min-1) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5-CT > > 5-HT > or = 5-methoxytryptamine > lisuride, whereas cisapride (100-1000 micrograms min-1, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85 +/- 7 micrograms kg-1, i.c.), but not cisapride (mean dose of 67 +/- 7 micrograms kg-1, i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8-OH-DPAT (3-3000 micrograms min-1) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200 +/- 33 micrograms kg-1, i.c.) the agonist-induced vasodilator responses. 3. The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (+/-)-pindolol (4 mg kg-1) or ritanserin (100 micrograms kg-1) plus granisetron (300 micrograms kg-1), but were dose-dependently blocked by i.v. administration of methiothepin (10 and 30 micrograms kg-1, given after ritanserin plus granisetron), mesulergine (10 and 30 micrograms kg-1), metergoline (1 and 3 mg kg-1), methysergide (1 and 3 mg kg-1) or clozapine (0.3 and 1 mg kg-1). Nevertheless, the blockade of the above responses, not significant after treatment with the lower of the two doses of metergoline and mesulergine, was nonspecific after administration of the higher of the two doses of methysergide and clozapine. 4. Based upon the above rank order of agonist potencies and the antagonism produced by a series of drugs showing high affinity for the cloned 5-ht7 receptor, our results indicate that the 5-HT receptor mediating external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs is operationally similar to the putative 5-HT7 receptor mediating relaxation of vascular and non-vascular smooth muscles (e.g. rabbit femoral vein, canine coronary artery, rat systemic vasculature and guinea-pig ileum) as well as tachycardia in the cat.

The effects of metergoline combined with PGF 2α treatment on luteal function and gestation in pregnant bitches

This study was designed to determine the nature of the antiluteotrophic effect of metergoline on pregnant bitches, the occurrence of clinically evident side-effects, and the efficacy of PGF 2α in initiating abortion after a course of metergoline therapy. Starting on Days 18 to 20 after the onset of diestrus, 8 adult pregnant beagle bitches were treated twice daily with 0.4 to 0.5 mg/kg po metergoline for 5 d. After receiving no treatment for the next 5 d, metergoline administration was repeated for a further 3 d, followed by twice-daily intramuscular injections of dinoprost tromethamine at 250 μg/kg. There was an overall trend for the plasma progesterone concentration to decrease during the first and second course of metergoline therapy and to rise during the intervening period of no treatment. None of the bitches aborted during or after the first 5 d of metergoline administration. No side-effects were evident during the metergoline therapy. After pretreatment with metergoline a mean of 4.8 injections of PGF 2α was necessary to ensure complete abortion. All abortions were rapid and uneventful, except for the usual side-effects associated with PGF 2α. The plasma progesterone concentration at the onset of PGF 2α treatment was positively correlated to the number of PGF 2α injections needed to complete the abortion process. The plasma progesterone concentration was < 8 nmol/l for several days as a result of metergoline therapy in 6 of the 8 bitches. Only 1 bitch, however, aborted before PGF 2α therapy was initiated. In the other 7 bitches PGF 2α appeared to be necessary for abortion. The results suggest that the effect of metergoline has to be considered incompletely luteolytic at the doses used in this study. Even prolonged suppression of luteal function in early to mid-gestation, however, did not cause abortion without the previously documented luteolytic and/or ecbolic effects of PGF 2α. The average interestrus interval of cycles treated with metergoline and PGF 2α was shorter (mean 182.2 d, SD 7.9 d, n = 6) than expected for this group of bitches (mean 211.4 d, SD 31.5 d, n = 7).

M-CPP challenge response as predictor of reponse to clozapine in neuroleptic resistant schizophrenia patients

The diagnosis, treatment, and pathophysiology of obsessive-compulsive disorder (OCD) were examined in a series of studies utilizing psychobiological approaches. Putative biological markers previously reported in depression were studied in this disorder and revealed that on some measures [Dexamethasone Suppression Test and rapid eye movement (REM) latency on sleep electroencephalogram (EEG)], OCD patients resemble those with major depressive disorder (MDD), whereas on others [REM density, platelet serotonin uptake, probably platelet 3H-imipramine binding, and 5-hydroxy-indoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF)] they do not. The relationship between OCD and MDD was further explored in a double-blind, randomized crossover study designed to compare the antiobsessional effects of two tricyclic antidepressants, clomipramine (CMI) and desipramine (DMI), in a nondepressed cohort of OCD patients. CMI was found to have significant antiobsessional effects in this group, whereas in the same patients, DMI lacked therapeutic effects. These results suggest that not all antidepressants are antiobsessive and that some property of CMI, such as its potent serotonergic effects, may be of pathophysiological relevance for OCD. The role of serotonin in this disorder was then tested using the pharmacological challenge strategy. A novel serotonin postsynaptic receptor (5HT-1) agonist, m-chlorophenylpiperazine (m-CPP), was administered orally (0.5 mg/kg) under double-blind, placebo-controlled conditions to OCD patients and controls. In addition, a serotonergic receptor antagonist, metergoline (4 mg), was given to a subset of OCD patients. Relative to healthy volunteers, the OCD patients became significantly more anxious, depressed, and dysphoric after m-CPP administration. Moreover, in the OCD patients, obsessive-compulsive symptoms increased markedly after m-CPP and decreased significantly following metergoline administration. These results demonstrate that agents that bind to the 5HT-1 receptor can acutely affect the symptoms of OCD patients. The striking behavioral effects of these direct postsynaptic receptor ligands and the relative specificity of clomipramine as an antiobsessional agent suggest

Moclobemid and maprotiline in chronic neurogenic pain syndromes

The diagnosis, treatment, and pathophysiology of obsessive-compulsive disorder (OCD) were examined in a series of studies utilizing psychobiological approaches. Putative biological markers previously reported in depression were studied in this disorder and revealed that on some measures [Dexamethasone Suppression Test and rapid eye movement (REM) latency on sleep electroencephalogram (EEG)], OCD patients resemble those with major depressive disorder (MDD), whereas on others [REM density, platelet serotonin uptake, probably platelet 3H-imipramine binding, and 5-hydroxy-indoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF)] they do not. The relationship between OCD and MDD was further explored in a double-blind, randomized crossover study designed to compare the antiobsessional effects of two tricyclic antidepressants, clomipramine (CMI) and desipramine (DMI), in a nondepressed cohort of OCD patients. CMI was found to have significant antiobsessional effects in this group, whereas in the same patients, DMI lacked therapeutic effects. These results suggest that not all antidepressants are antiobsessive and that some property of CMI, such as its potent serotonergic effects, may be of pathophysiological relevance for OCD. The role of serotonin in this disorder was then tested using the pharmacological challenge strategy. A novel serotonin postsynaptic receptor (5HT-1) agonist, m-chlorophenylpiperazine (m-CPP), was administered orally (0.5 mg/kg) under double-blind, placebo-controlled conditions to OCD patients and controls. In addition, a serotonergic receptor antagonist, metergoline (4 mg), was given to a subset of OCD patients. Relative to healthy volunteers, the OCD patients became significantly more anxious, depressed, and dysphoric after m-CPP administration. Moreover, in the OCD patients, obsessive-compulsive symptoms increased markedly after m-CPP and decreased significantly following metergoline administration. These results demonstrate that agents that bind to the 5HT-1 receptor can acutely affect the symptoms of OCD patients. The striking behavioral effects of these direct postsynaptic receptor ligands and the relative specificity of clomipramine as an antiobsessional agent suggest

Action of serotonin in the medial prefrontal cortex: mediation by serotonin3-like receptors.

In the present study, we investigated the effects of various serotonin (5-HT) antagonists on 5-HT's action on medial prefrontal cortical cells (mPFc) using the techniques of single cell recording and microiontophoresis. The microiontophoretic application of 5-HT (10-80 nA) produced a current-dependent suppression of mPFc cell firing and this effect was blocked by the selective 5-HT3 receptor antagonists (+/-)-zacopride, ICS 205930 and granisetron at currents of 5-20 nA. Furthermore, the intravenous (i.v.) administration of (+/-)-zacopride (5-50 micrograms/kg) markedly attenuates the suppressive action of 5-HT on mPFc cell firing. In contrast, the microiontophoresis of 5-HT1 and 5-HT2 receptor antagonists such as (+/-)-pindolol, spiperone, metergoline, and ritanserin (10-20 nA) failed to block 5-HT's effect. In fact, in some cells, spiperone and ritanserin potentiated 5-HT's action and prolonged neuronal recovery. In addition, the intravenous administration of either ritanserin (5-2,000 micrograms/kg) or metergoline (4-2,400 micrograms/kg) failed to alter 5-HT's action. The electrical stimulation of the caudal linear raphe nucleus (CLi) suppressed the spontaneous activity of 83% of the mPFc cells tested by 45 +/- 2%. This suppression was significantly attenuated by the iontophoresis of granisetron (2.5-5 nA) but not by the 5-HT2 and 5-HT1C receptor antagonist ritanserin or the relatively selective 5-HT2 receptor antagonist (+)-MDL 11,939 (10-40 nA). However, the i.v. administration of ritanserin (0.5-1.5 mg/kg) or S-zacopride (0.1 mg/kg) significantly blocked the suppression of mPFc cell firing produced by CLi stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of chronic hindlimb flexion in rat: evidence for mediation by 5-hydroxytryptamine

Prolonged high-intensity stimulation of the rat hindlimb produces a persistent unilateral flexion. 5-Hydroxytryptamine (5-HT) has been implicated in the modulation of spinal cord mechanisms. Electrical stimulation across the upper hindlimb was used to induce a persistent hindlimb flexion. The flexion was measured after stimulation and at 72 h, both before and after spinal transection at T 7. Transection of the spinal cord typically resulted in an increase in flexion of 3–5 g (rebound). Pretreatment with para-chlorophenylalanine (pCPA) to deplete 5-HT, or the administration of metergoline, a non-specific 5-HT antagonist, had no significant effect on flexion at 72 h in the intact rat but abolished rebound. The 5-HT 1A agonist,(±)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide (8-OH-DPAT) and 5-HT 1B agonist, m-trifluoromethylphenylpiperazine-HCl (TFMPP), had no effect on flexion at 72 h in the intact rat but reduced rebound. The 5-HT 2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-HCl (DOI), suppressed post-stimulation flexion and flexion subsequent to spinal section. Furthermore, ketanserin, a 5-HT 2 antagonist, restored flexion suppressed by DOI in the acutely spinalized rat. These results suggest that chronic hindlimb flexion is suppressed in the intact rat by descending, serotonergic fibers which exert an effect through spinal 5-HT 2 receptors. Moreover, 5-HT 1 agonist suppression of rebound implicates these receptors as well in the modulation of chronic hindlimb flexion.

Muscarinic cholinergic, but not serotoninergic mediation of arginine vasopressin response to metoclopramide in man.

The possibility that metoclopramide (MCP) stimulates arginine vasopressin (AVP) secretion in man through a serotoninergic and/or a cholinergic muscarinic pathway was studied. Twenty normal male subjects were tested with MCP (10 mg in an i.v. bolus) alone or in the presence of the 5HT1 serotoninergic antagonist metergoline (10 mg/day p.o. in five divided doses for 4 days), the 5HT2 receptor blocker ketanserin (10 mg i.v. 5 min before MCP) (n = 10), the M1 and M2 muscarinic antagonist atropine (1.2 mg i.v. just before MCP administration) or the M1 muscarinic receptor blocker pirenzepine (40 mg i.v. 10 min before MCP) (n = 10). AVP doubled in response to MCP. the MCP-induced AVP rise did not change after metergoline, ketanserin or pirenzepine administration, whereas it was abolished by atropine. Additional experiments were performed in order to evaluate the effect of 1.2 mg atropine, given alone, on circulating AVP levels and whether the effect of atropine on the AVP response to MCP depends on the amount of the muscarinic antagonist (dose-response study). For these purposes, atropine was given alone to the same subjects previously tested with MCP plus atropine; furthermore, eight additional male subjects were tested with MCP plus atropine given in doses ranging from 0.8 to 1.4 mg. The results of these additional studies failed to show an effect of atropine alone on AVP secretion and demonstrated a dose-related inhibition of MCP-induced AVP rise by increasing atropine administration from 0.8 mg to 1.2 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment, and pathophysiology

The diagnosis, treatment, and pathophysiology of obsessive-compulsive disorder (OCD) were examined in a series of studies utilizing psychobiological approaches. Putative biological markers previously reported in depression were studied in this disorder and revealed that on some measures [Dexamethasone Suppression Test and rapid eye movement (REM) latency on sleep electroencephalogram (EEG)], OCD patients resemble those with major depressive disorder (MDD), whereas on others [REM density, platelet serotonin uptake, probably platelet 3H-imipramine binding, and 5-hydroxy-indoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF)] they do not. The relationship between OCD and MDD was further explored in a double-blind, randomized crossover study designed to compare the antiobsessional effects of two tricyclic antidepressants, clomipramine (CMI) and desipramine (DMI), in a nondepressed cohort of OCD patients. CMI was found to have significant antiobsessional effects in this group, whereas in the same patients, DMI lacked therapeutic effects. These results suggest that not all antidepressants are antiobsessive and that some property of CMI, such as its potent serotonergic effects, may be of pathophysiological relevance for OCD. The role of serotonin in this disorder was then tested using the pharmacological challenge strategy. A novel serotonin postsynaptic receptor (5HT-1) agonist, m-chlorophenylpiperazine (m-CPP), was administered orally (0.5 mg/kg) under double-blind, placebo-controlled conditions to OCD patients and controls. In addition, a serotonergic receptor antagonist, metergoline (4 mg), was given to a subset of OCD patients. Relative to healthy volunteers, the OCD patients became significantly more anxious, depressed, and dysphoric after m-CPP administration. Moreover, in the OCD patients, obsessive-compulsive symptoms increased markedly after m-CPP and decreased significantly following metergoline administration. These results demonstrate that agents that bind to the 5HT-1 receptor can acutely affect the symptoms of OCD patients. The striking behavioral effects of these direct postsynaptic receptor ligands and the relative specificity of clomipramine as an antiobsessional agent suggest

Water intake induced in rats by serotonin and 5-hydroxytryptophan: Different mechanisms?

The present studies were designed to investigate further the mechanism by which water intake is induced in rats by peripheral administration of either serotonin (5HT) or its precursor 5-hydroxytryptophan (5HTP). Consistent with previous studies that have implicated mediation by the renal renin-angiotensin system (RAS), we now report that bilateral nephrectomy completely abolishes the drinking response to various doses of 5HT. In contrast, nephrectomy had little effect on the drinking induced by 5HTP. Thus, 5HTP may induce drinking by mechanisms other than its peripheral conversion to 5HT and subsequent activation of the RAS. The drinking responses to both 5HT and 5HTP were blocked by peripheral administration of the 5HT receptor antagonist, metergoline, but the drug was at least ten-fold more potent against 5HTP than 5HT. Intracerebroventricular (ICV) administration of metergoline also prevented the drinking response to peripherally-administered 5HTP. The drinking responses to both 5HT and 5HTP were enhanced by peripheral administration of low doses of an angiotensin I converting enzyme inhibitor, captopril. Collectively, these findings support previous conclusions that 5HT-induced intake of water is mediated exclusively by the renal RAS. However, 5HTP-induced drinking may additionally involve a renin-independent, serotonin-mediated mechanism, possibly in the brain.

Involvement of serotonin in the excitation of phrenic motoneurons evoked by stimulation of the raphe obscurus

Short-latency averaged responses in the C5 phrenic nerves to electrical stimulation (2.5-80 microA; 5-80 Hz; 150 microseconds pulse duration) of raphe pallidus (RP) and raphe obscurus (RO) were investigated in anesthetized, paralyzed, and artificially ventilated cats. The responses to stimulation of RO were excitatory, whereas a mixture of inhibitory and excitatory responses of lesser magnitude were observed after stimulating in RP. The maximal response was obtained from the ventral part of RO and consisted of early and delayed excitatory responses that were of equal magnitude in both left and right C5 phrenic nerve roots. The mean latency for the early response was 2.5 +/- 0.1 msec and for the delayed response was 7.0 +/- 0.2 msec. Both responses were elicited during inspiratory phase stimulation, but only the delayed response was present during expiratory phase stimulation. The stimulus threshold of the early response was 5 microA; the delayed response was elicited at currents as small as 2.5 microA. Early and delayed responses were affected in different ways by increasing stimulus current and by increasing stimulus frequency. Intravenous administration of serotonin receptor antagonists methysergide (0.1-0.7 mg/kg), metergoline (33-244 micrograms/kg), and cinanserin (1.5-9.0 micrograms/kg) caused significant dose-related reductions in the magnitude of the delayed response, but did not significantly affect the early response. These data suggest that the early and delayed excitatory responses are mediated by different neuronal pathways. The early response does not involve serotonin release, while the later response is mediated at least in part by activation of a serotonergic pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of the Cyclic Motor Activity of the Ovine Small Intestine by Lysergic Acid Derivatives

The effects of a variety of substances influencing the initiation of cyclic motor events at the gastroduodenal junction were studied in conscious sheep. A significant and long-lasting decrease in the frequency of cyclic events from approximately 100 min to 30-40 min was elicited by the intraduodenal bulb administration of the lysergic acid derivatives methylergonovine and methysergide. This effect was dose-dependent and occurred with smaller dosages than those effective when administered parenterally or more distal in the jejunum. Intraluminal administration of cyproheptadine, fonazine, and metergoline into the duodenal bulb increased the interval between phase III activity. At higher dosages, however, cyproheptadine and metergoline reduced the spiking activity of the antroduodenal junction, without significantly changing the cycle duration of the migrating myoelectric complex on the duodenal bulb or jejunum. After administration of cyproheptadine, fonazine, and metergoline, the cycling activity of the duodenojejunum was irregular for 1-2 days. These findings are compatible with a resetting of the enteric biological clock at a faster rhythm and suggest a selective action via an enteric serotoninergic mechanism involved in the normal pacing of the cyclic motor events of the gut.

Effect of Metergoline on Prolactin, Follicle Stimulating Hormone, Luteinizing Hormone and Thyroid Stimulating Hormone Response to TRH and LHRH in Normal Men and Women

Metergoline, a prolactin (PRL)-lowering drug with an antiserotoninergic activity, is known to restore menstruations and fertility in hyper-PRL patients even when PRL levels are not normalized. This suggests that metergoline might also affect gonadotropins release. In a double-blind cross-over study in 8 normal males, repeated administration of metergoline enhanced the LH response to LHRH and reduced the PRL response to TRH; for females, three different tests were performed on days 5, 8 and 21 of two different menstrual cycles, each test being preceded by metergoline or by placebo administration. Metergoline always reduced the PRL response to TRH; on the 5th day, metergoline reduced the FSH response to LHRH and on the 21st day enhanced the LH response to LHRH. Basal levels of LH, FSH, T3, T4, Testosterone, 17 beta-estradiol and progesterone as well as the FSH response to LHRH (in males) and the TSH response to TRH (in both males and females) were not modified by metergoline. The data suggest that tests with TRH and LHRH can yield different results when performed during metergoline administration and that metergoline, acting through an unknown mechanism, can modify gonadotropins release.

Effects of serotonergic and cholinergic antagonists on suckling behavior of neonatal, infant, and weanling rat pups

In Experiment 1, Sprague-Dawley rat pups at postnatal days 3-4, 7-8, 10-11, 15-16, and 23-24 were tested for suckling behavior on their anesthesized multiparous dams following administration of metergoline or scopolamine. The serotonergic antagonist, metergoline, inhibited suckling in 3- to 4- and 7- to 8-day-old rat pups, but was not found to influence suckling in older pups. Scopolamine, a cholinergic antagonist, reduced suckling primarily in 3- to 4-day-old pups. In Experiment 2, parity of the maternal female was manipulated to assess whether this variable would influence suckling behavior and the effects of metergoline on suckling of weanlings. Baseline levels of suckling were reduced in 23- to 24-day-old pups of primiparous dams when compared with multiparous-derived offspring. Administration of metergoline increased the amount of time that these primiparous-derived pups spent attached to nipples, but did not influence suckling of offspring of multiparous dams, perhaps as a result of a ceiling effect on suckling behavior in these animals.

Failure to antagonize the 8-hydroxy-2-(Dl-n-propylamino)tetralin-induced facilitation of male rat sexual behavior by the administration of 5-HT receptor antagonists

The administration of the putative 5-hydroxytryptamine (5-HT) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-hydroxytryptophan (5-HTP) produced a facilitation and an inhibition of male rat sexual behavior, respectively. The 5-HTP-induced inhibitory effects were at least partially antagonized by the administration of metergoline, methiothepine or pirenperone. However, none of these agents were able to counteract any facilitatory effects produced by 8-OH-DPAT. It is concluded that 8-OH-DPAT does not facilitate the expression of masculine sexual behavior in the rat by stimulation of 5-HT 1 or 5-HT 2 receptors.

Serotonin receptor antagonists induce hyperalgesia without preventing morphine antinociception

5-Hydroxytryptamine (5-HT) receptor blockade by administration of mianserin (1 mg/kg) or metergoline (0.25 mg/kg) shortened the response latencies of rats in the hot-plate (hind-paw lick response) and tail-flick tests, but did not consistently attenuate the antinociceptive effect of morphine (1.25–5.0 mg/kg). Injection of the opiate receptor antagonist naloxone (1 mg/kg) did not change tail-flick response latencies and did not interfere with the antinociceptive action of the 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). The antinociceptive effect of morphine was reduced in chronically spinal rats, although significant increases in tail-flick latencies were observed after 2.5 and 5.0 mg/kg. Concomitant administration of 5-MeODMT failed to restore the effect of morphine in spinal rats. In the hot-plate test, morphine did not reliably prolong latencies to forepaw lick, indicating that this response is not a useful measure of pain sensitivity. The results suggest that different mechanisms underlie the analgesia induced by systemic administration of morphine and 5-HT mediated tonic inhibition of nociception.