Comparison of EEG effects of chlorpromazine, octoclothepin and methiothepin in rabbits.
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Animals↗
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Effect of serotonin receptor antagonist on phosphate excretion.
To determine whether endogenous intrarenal 5-hydroxytryptamine affects phosphate excretion, the serotonin receptor antagonist methiothepin (20 microgram/kg, +6 microgram/kg per h) was infused into the renal interstitium of rats fed a normal phosphate diet (0.7% phosphate [Pi]) in the presence of endogenous parathyroid hormone (PTH). Renal interstitial infusion of methiothepin significantly increased fractional phosphate excretion (FE(Pi)) from 23 +/- 4 to 30 +/- 4% (n = 8, P < 0.05). To determine whether serotonin modulates the phosphaturic response to PTH during conditions of dietary phosphate excess or deprivation, rats were fed either a high (1.8% Pi, HPD) or low (0.07% Pi, LPD) phosphate diet, and methiothepin (100 microgram/kg, +30 microgram/kg per h) or saline vehicle was infused intravenously before and during PTH infusion (33 U/kg, +1 U/kg per min). Methiothepin infusion significantly increased FE(Pi) in thyroparathyroidectomized rats fed a HPD from 25 +/- 4 to 32 +/- 4% (n = 9, P < 0.05), and the subsequent administration of PTH further increased the FE(Pi) to 64 +/- 3% (P < 0.05). The increase in FE(Pi) during PTH infusion was similar in the absence (Delta27 +/- 5%, n = 7) and presence (Delta33 +/- 6%) of methiothepin, P > 0.05. In thyroparathyroidectomized rats fed a LPD, methiothepin infusion did not increase phosphate excretion (0.8 +/- 0.4 to 1.3 +/- 0.9%, n = 7, P > 0.05). However, the increase in FE(Pi) during PTH infusion was significantly greater in the presence of methiothepin (1.3 +/- 0.9 to 20.0 +/- 4.0%, Delta18.7 +/- 3.5%) than in the vehicle-infused rats (0.5 +/- 0.2 to 8.8 +/- 1.1%, Delta8.3 +/- 1.2%; n = 8, P < 0.05). In conclusion, these observations suggest that endogenous intrarenal serotonin enhances phosphate reabsorption in phosphate-replete rats, and attenuates the phosphaturic response to PTH in phosphate-deprived rats.
Animals↗
5-HT antagonists suppress sleep and delay its restoration after 5-HTP in p-chlorophenylalanine-pretreated cats.
When injected intraperitoneally (i.p.) into normal cats, methiothepin (1-7.5 mg/kg) or metergoline (0.5-8 mg/kg) induced total insomnia. The duration of suppression of deep slow-wave sleep (SWS2) and paradoxical sleep (PS) was dose-related for methiothepin (10-30 h), but was shorter and not dose-related for metergoline (3-5 h). When injected into the fourth ventricle, methiothepin (20 microgram) induced a selective suppression of PS for 6-7 h). In rho-chlorophenyl-alanine (PCPA)-pretreated, insomniac cats, i.p. injection of 5 mg/kg of DL-5-hydroxytryptophan(5-HTP) was followed by SWS and PS after latencies of 25 and 62 min. When methiothepin (2.5 mg/kg) or metergoline (4 mg/kg) were given before 5-HTP, the latency for the first PS episode increased dramatically to 7 h. Thereafter PS occurred periodically for 10 h but no SWS appeared. These results suggest that a 'PS factor' induced by 5-HTP and different from indolamines is preserved during the antagonistic effect of methiothepin or metergoline until it can act upon the executive mechanisms of PS. Our data also suggest that metergoline and methiothepin suppress but do not delay the mechanism responsible for SWS2 in the PCPA-5-HTP paradigm.
5-Hydroxytryptophan↗
h5-HT(1B) receptor-mediated constitutive Galphai3-protein activation in stably transfected Chinese hamster ovary cells: an antibody capture assay reveals protean efficacy of 5-HT.
1. Serotonin 5-HT(1B) receptors couple to G-proteins of the Gi/o family. However, their activation of specific G-protein subtypes is poorly characterised. Using an innovative antibody capture/guanosine-5'-0-(3-[(35)S]thio)-triphosphate ([(35)S]GTPgammaS) binding strategy, we characterised Galpha(i3) subunit activation by h5-HT(1B) receptors stably expressed in Chinese hamster ovary (CHO) cells. 2. The agonists, 5-HT, alniditan and BMS181,101, stimulated Galpha(i3), whereas methiothepin and SB224,289 behaved as inverse agonists. The selective 5-HT(1B) receptor ligand, S18127, modestly stimulated Galpha(i3) and reversed the actions of both 5-HT and methiothepin. S18127 (1 micro M) also produced parallel, dextral shifts of the 5-HT and methiothepin isotherms. 3. Isotopic dilution experiments ([(35)S]GTPgammaS versus GTPgammaS) revealed high-affinity [(35)S]GTPgammaS binding to Galpha(i3) subunits in the absence of receptor ligands indicating constitutive activity. High-affinity [(35)S]GTPgammaS binding was increased 2.8-fold by 5-HT with an increase in the affinity of GTPgammaS for Galpha(i3) subunits. In contrast, methiothepin halved the number of high-affinity binding sites and decreased their affinity. 4. h5-HT(1B) receptor-mediated Galpha(i3) subunit activation was dependent on the concentration of NaCl. At 300 mM, 5-HT stimulated [(35)S]GTPgammaS binding, basal Galpha(i3) activation was low and methiothepin was inactive. In contrast, at 10 mM NaCl, basal activity was enhanced and the inverse agonist activity of methiothepin was accentuated. Under these conditions, 5-HT decreased Galpha(i3) activation. 5. In conclusion, at h5-HT(1B) receptors expressed in CHO cells: (i) inverse agonist induced inhibition of Galpha(i3), and its reversal by S18127, reveals constitutive activation of this Galpha subunit; (ii) constitutive Galpha(i3) activation can be quantified by isotopic dilution [(35)S]GTPgammaS binding and (iii) decreasing NaCl concentrations enhances Galpha(i3) activation and leads to protean agonist properties of 5-HT: that is a switch to inhibition of Galpha(i3).
Animals↗
Pharmacological characterization of an adenylyl cyclase-coupled 5-HT receptor in aplysia: comparison with mammalian 5-HT receptors.
We attempted to identify compounds that are effective in blocking the serotonin (5-hydroxytryptamine, 5-HT) receptor(s) that activate adenylyl cyclase (AC) in Aplysia CNS. We call this class of receptor 5-HT(apAC). Eight of the 14 antagonists tested were effective against 5-HT(apAC) in CNS membranes with the following rank order of potency: methiothepin > metergoline approximately fluphenazine > clozapine > cyproheptadine approximately risperidone approximately ritanserin > NAN-190. GR-113808, olanzapine, Ro-04-6790, RS-102221, SB-204070, and spiperone were inactive. Methiothepin completely blocked 5-HT stimulation of AC with a K(b) of 18 nM. Comparison of the pharmacological profile of the 5-HT(apAC) receptor with those of mammalian 5-HT receptor subtypes suggested it most closely resembles the 5-HT(6) receptor. AC stimulation in Aplysia sensory neuron (SN) membranes was also blocked by methiothepin. Methiothepin substantially inhibited two effects of 5-HT on SN firing properties that are mediated by a cAMP-dependent reduction in S-K(+) current: spike broadening in tetraethylammonium/nifedipine and increased excitability. Consistent with cyproheptadine blocking 5-HT stimulation of AC, cyproheptadine also blocked the 5-HT-induced increase in SN excitability. Methiothepin was less effective in blocking AC-mediated modulatory effects of 5-HT in electrophysiological experiments on SNs than in blocking AC stimulation in CNS or SN membranes. This reduction in potency appears to be due to effects of the high ionic strength of physiological saline on the binding of this antagonist to the receptor. Methiothepin also antagonized AC-coupled dopamine receptors but not AC-coupled small cardioactive peptide receptors. In conjunction with other pharmacological probes, this antagonist should be useful in analyzing the role of 5-HT in various forms of neuromodulation in Aplysia.
Adenylyl Cyclases↗
5-HT1-receptor-mediated vasoconstriction in bovine isolated pulmonary arteries: influences of vascular endothelium and tone.
Vasoconstrictor responses to 5-hydroxytryptamine (5-HT) and the 5-HT1D receptor agonist sumatriptan were studied in isolated bovine pulmonary artery rings. The effects of the antagonists, ketanserin (5-HT2A-receptors) and methiothepin (5-HT1- and 5-HT2A-receptors) on these responses were determined. The influences of vascular tone and the effect of removal of the vascular endothelium and pretreatment with the inhibitor of nitric oxide synthase, N omega-nitro-L-arginine methylester, were also studied. In the absence of tone, in the majority of vessels, sumatriptan did not induce significant contractions. 5-HT-induced responses were concentration-dependent and ketanserin and methiothepin antagonized these in a competitive fashion. Removal of the endothelium or inclusion of L-NAME potentiated responses to sumatriptan. The sensitivity to sumatriptan was increased by L-NAME only in the presence of the endothelium whilst maximum responses to sumatriptan were potentiated in both unrubbed and rubbed vessels. Removal of the endothelium and/or inclusion of L-NAME had no significant effect on responses to 5-HT. U46619-induced tone markedly increased sumatriptan-induced responses which were competitively antagonized by methiothepin but were relatively resistant to ketanserin, verifying activation of a 5-HT1D receptor. Responses to 5-HT were also potentiated and competitively antagonized by ketanserin, and further antagonized by methiothepin. With tone present, lower concentrations of 5-HT were ketanserin-resistant and methiothepin-sensitive, indicating activation of a 5-HT1-like receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Oxidoreductases↗
Dihydroergocristine-induced stimulation of the 5-HT autoreceptor in the hypothalamus of the rat.
In slices of the hypothalamus of the rat, prelabelled with [3H]5-hydroxytryptamine ([3H]5-HT), dihydroergocristine (DHEC) decreased in a concentration-dependent manner (0.01-1 microM) the release of [3H]transmitter elicited by stimulation. In the presence of phentolamine (1 microM), sulpiride (1 microM), atropine (1 microM) or methiothepin (0.1 microM), the effect of DHEC remained unchanged. However, methiothepin at 1 microM and citalopram at 1 microM antagonized the inhibition induced by DHEC. Methiothepin at 0.1 microM has been shown to be sufficient to shift to the right the concentration-effect curve of D-lysergic acid diethylamide (LSD) on the stimulation-evoked release of [3H]5-HT by a factor of 10. However, in the present experiments, 1 microM methiothepin was required to antagonize the effect of DHEC. Thus, the alpha adrenergic, dopaminergic and cholinergic activities of DHEC do not seem to be responsible for its effect on the release of 5-HT. The lower potency of methiothepin suggests, however, that stimulation of the 5-HT autoreceptor by DHEC may not fully explain the results.
Animals↗
Vascular actions of MDMA involve alpha1 and alpha2-adrenoceptors in the anaesthetized rat.
We have investigated the effects of methylenedioxymethamphetamine (MDMA, 'ecstasy'), i.v., on diastolic blood pressure (DBP) in pithed and pentobarbitone anaesthetized rats. In pithed rats, the non-selective 5-HT receptor antagonist methiothepin (0.1 mg kg(-1)) and the alpha2-adrenoceptor antagonists methoxyidazoxan and yohimbine (1 mg kg(-1)) showed significant alpha1-adrenoceptor antagonist potency, but methiothepin did not show alpha2-adrenoceptor antagonist potency. MDMA (1 and 5 mg kg(-1)) produced pressor responses which were significantly reduced by the alpha(1)-adrenoceptor antagonist prazosin (0.1 mg kg(-1)), yohimbine (1 mg kg(-1)) or methiothepin (0.1 mg kg(-1)), but not by the 5-HT2 receptor antagonist ritanserin (1 mg kg(-1)). In anaesthetized rats, antagonists revealed two phases with three components to the effects of MDMA (5 mg kg(-1)) on DBP: an initial pressor response, a later pressor component at 1 min, the sustained depressor response. Methoxyidazoxan, methiothepin or the combination ritanserin/prazosin significantly reduced the initial pressor response, although neither of the latter compounds alone had any effect. The pressor response to MDMA (5 mg kg(-1)) at 1 min was converted to a depressor response by prazosin and to a lesser extent methiothepin and methoxyidazoxan. The depressor response to MDMA (5 mg kg(-1)) was significantly reduced by methoxyidazoxan (0.1 mg kg(-1)), and by the noradrenaline re-uptake blocker cocaine 10 mg kg(-1) but not 1 mg kg(-1). However, the most marked reduction in the depressor response was produced by the combination of methoxyidazoxan and cocaine. It is concluded that the initial pressor response to MDMA (5 mg kg(-1)) in anaesthetized rats involves alpha2- and possibly alpha1-adrenoceptors and 5-HT2 receptors, the pressor component at 1 min is largely alpha1-adrenoceptor mediated, and the sustained depressor response involves alpha2-adrenoceptors.
Adrenergic Uptake Inhibitors↗
Sleep/waking and EEG power spectrum effects of a nonselective serotonin (5-HT) antagonist and a selective 5-HT reuptake inhibitor given alone and in combination.
Sleep/waking stages, electroencephalogram (EEG) power spectra and behavior were studied in rats for 8 hours following intraperitoneal administration of a nonselective serotonin (5-HT) antagonist (0.1 and 2.0 mg/kg methiothepin) and a selective 5-HT reuptake inhibitor (20 mg/kg zimeldine), given alone and in combination. Consistent with earlier studies, zimeldine gave a biphasic effect on sleep and waking. Waking was increased and slow wave sleep (SWS)-2 decreased initially, followed by an increase in SWS-2 in the second 2-hour period. Rapid eye movement (REM) sleep was reduced throughout the experiment. EEG power densities were generally reduced in the higher frequencies, but the effect differed somewhat in the different vigilance states and between the fronto-frontal and fronto-parietal EEG leads. Zimeldine did not change behavior. Methiothepin, at 0.1 mg/kg, gave only minor effects by itself, but it blocked the initial waking increase of zimeldine. So did 2.0 mg/kg methiothepin, but this dose markedly changed sleep/waking stages by itself: SWS-1 was profoundly increased, whereas waking, SWS-2 and REM sleep were reduced. Total SWS (TSWS) was markedly increased due to the SWS-1 increase. Because TSWS was increased while SWS-2 was decreased following 2.0 mg/kg methiothepin, it is concluded that spindle activity was facilitated, whereas slow wave activity was antagonized. Methiothepin, at 2.0 mg/kg, also markedly changed EEG power densities within TSWS and induced cataleptic behavior. It is concluded that the initial waking increase of zimeldine depends on simultaneous activation of several different 5-HT receptor subtypes. The other zimeldine effects were not consistently antagonized, thus the mechanisms behind these effects remain unclear.
Animals↗
Serotonin receptor antagonists discriminate between PKA- and PKC-mediated plasticity in aplysia sensory neurons.
Highly selective serotonin (5-hydroxytryptamine, 5-HT) receptor antagonists developed for mammals are ineffective in Aplysia due to the evolutionary divergence of neurotransmitter receptors and because the higher ionic strength of physiological saline for marine invertebrates reduces antagonist affinity. It has therefore been difficult to identify antagonists that specifically block individual signaling cascades initiated by 5-HT. We studied two broad-spectrum 5-HT receptor antagonists that have been characterized biochemically in Aplysia CNS: methiothepin and spiperone. Methiothepin is highly effective in inhibiting adenylyl cyclase (AC)-coupled 5-HT receptors in Aplysia. Spiperone, which blocks phospholipase C (PLC)-coupled 5-HT receptors in mammals, does not block AC-coupled 5-HT receptors in Aplysia. In electrophysiological studies, we explored whether methiothepin and spiperone can be used in parallel to distinguish between the AC-cAMP and PLC-protein kinase C (PKC) modulatory cascades that are initiated by 5-HT. 5-HT-induced broadening of the sensory neuron action potential in the presence of tetraethylammonium/nifedipine, which is mediated by modulation of the S-K+ currents, was used an assay for the AC-cAMP cascade. Spike broadening initiated by 5 microM 5-HT was unaffected by 100 microM spiperone, whereas it was effectively blocked by 100 microM methiothepin. Facilitation of highly depressed sensory neuron-to-motor neuron synapses by 5-HT was used as an assay for the PLC-PKC cascade. Spiperone completely blocked facilitation of highly depressed synapses by 5 microM 5-HT. In contrast, methiothepin produced a modest, nonsignificant, reduction in the facilitation of depressed synapses. Interestingly, these experiments revealed that the PLC-PKC cascade undergoes desensitization during exposure to 5-HT.
Action Potentials↗
Serotonergic modulation of ethanol-induced electrophysiological depression in young and aged rats.
BACKGROUND: Ethanol (EtOH)-induced electrophysiological depressions in cerebellar Purkinje neurons have been shown to be potentiated by exogenously applied serotonin (5HT). In this study, we determined whether this modulatory action can be activated by endogenous release from presynaptic serotonergic terminals, and whether such a response is altered by age or rat strain. METHODS: Extracellular 5HT levels in cerebellar cortex were measured in real time by in vivo chronoamperometry, by using Nafion-coated carbon fiber electrodes, in anesthetized young (3-5 months old) or aged (18-24 months old) Sprague Dawley and Fischer 344 rats. Some animals were prelesioned with 5,7 dihydroxytryptamine (5,7 DHT). Single unit electrophysiological activity was recorded from cerebellar Purkinje neurons. Serotonin or its presynaptic antagonist methiothepin was applied directly to cerebellar neurons through multibarrel pipettes. RESULTS: Local application of methiothepin dose-dependently induced 5HT overflow in young Sprague Dawley and Fisher 344 rats. Methiothepin-induced 5HT release was decreased significantly in aged or 5,7 DHT-lesioned rats. Local application of methiothepin or 5HT potentiated EtOH-induced electrophysiological depression of Purkinje neurons in young animals of both strains. Methiothepin-potentiated, EtOH-elicited neuronal inhibition was reduced greatly in aged or 5,7 DHT-lesioned rats. Serotonin-facilitated EtOH responses were reduced in the aged Sprague Dawley rats. CONCLUSIONS: EtOH-induced electrophysiological responses in cerebellum can be facilitated by endogenous 5HT release by using a 5HT autoreceptor antagonist. Such actions are attenuated in aged rats perhaps through a presynaptic serotonergic mechanism.
5,7-Dihydroxytryptamine↗
Differential effects of three 5-HT receptor antagonists on the performance of rats in attentional and working memory tasks.
The effects of three different serotonin (5-HT) receptor antagonists (ketanserin, methysegide, methiothepin) in the modulation of attention, working memory and behavioural activity were investigated in this study by assessing the performance of rats in two separate cognitive models; the 5-choice serial reaction time (5-CSRT) task, which measures attention, and the delayed non-matching to position (DNMTP) task, which measures working memory. Methysergide and methiothepin bind at the 5-HT1 and 5-HT2 as well as the 5-HT5-7 receptors, with varying degrees of selectivity, and ketanserin binds at the 5-HT2A receptors rather selectively. None of these agents bind to any significant extent to 5-HT3 or 5-HT4 receptors. In the 5-CSRT task, neither methiothepin (0.15 mg/kg) nor ketanserin (1.0 and 3.0 mg/kg) impaired the choice accuracy of rats, although they induced sedation. The low doses of methysergide (1.5 and 3.0 mg/kg) slightly increased the behavioural activity of rats, whereas the high dose of methysergide (15.0 mg/kg) reduced behavioural activity and slightly reduced choice accuracy of the rats in the attentional task (monitoring of visual stimuli) under the baseline conditions or curtailed stimulus duration. This effect was not augmented at the reduced stimulus intensity. These findings suggest that the high dose of methysergide did not interfere with the visual discrimination of rats. Furthermore, methysergide did not reduce motivation for this task, since it did not increase food collection latencies. In the DNMTP task, methiothepin (0.15 mg/kg) induced a delay non-dependent deficit in choice accuracy. This could be due to an impaired alternation ability or akinesia, which increases an actual delay between sample and choice. Methiothepin (0.15 mg/kg) also interfered with behavioural activity of rats. Interestingly, ketanserin (1.0 mg/kg and 3.0 mg/kg) and methysergide (3.0-15.0 mg/kg) neither impaired the choice accuracy nor reduced the behavioural activity of rats in the DNMTP task. These results suggest that the blockade of 5-HT2A receptors does not interfere with attention and working memory per se. However, all three serotonin receptor antagonists interfered with behavioural activity of rats in the 5-CSRT task more severely than in the DNMTP task. The possible role of serotonin and non-serotonin receptors underlying the influence of these antagonists on behavioural activity will be discussed.
Animals↗
A behavioural and biochemical study in rats of 5-hydroxytryptamine receptor agonists and antagonists, with observations on structure-activity requirements for the agonists.
1 The effect of the putative 5-hydroxytryptamine (5-HT) receptor antagonists, methysergide, methergoline, mianserin, cyproheptadine, cinanserin (all at 10 mg/kg), methiothepin (5 mg/kg) and (-)-propranolol (20 mg/kg) on the behavioural responses to tranylcypromine (10 mg/kg) followed 30 min later by L-tryptophan (100 mg/kg) was examined.2 Methysergide, methergoline, methiothepin and (-)-propranolol inhibited head weaving, forepaw treading and hind-limb abduction. Methysergide and methergoline increased reactivity. In contrast, cypropheptadine, cinanserin and mianserin had no effects on the behaviour.3 Similar findings were obtained when the behaviours were elicited by administration of tranylcypromine (10 mg/kg) followed by the putative 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (2 mg/kg).4 When the behaviours were elicited by the putative 5-HT receptor agonist, quipazine (50 mg/kg), all the drugs effectively inhibited head weaving and forepaw treading.5 When the dose of cypropheptadine was doubled to 20 mg/kg an inhibition of the tranylcypromine/L-tryptophan induced behaviours was seen.6 Methiothepin produced a marked inhibition of apomorphine-induced locomotor activity whilst all the others enhanced this response, suggesting that only methiothepin inhibits the 5-HT behaviours by dopamine antagonism and that the increased reactivity seen following tranylcypromine/L-tryptophan after pretreatment with methysergide or methergoline might be due to enhanced dopamine function.7 Pretreatment with p-chlorophenylalanine resulted in enhanced behavioural responses to both 5-MeODMT and quipazine.8 Both methergoline and methiothepin decreased the rate of 5-HT synthesis in whole brain but not spinal cord and methergoline decreased spinal cord 5-HIAA concentration. None of the other drugs had any significant effects on the concentration of 5-HT, 5-HIAA or 5-HT synthesis rate in brain or spinal cord.9 Experiments with compounds structurally related to quipazine and with molecular models suggested that quipazine produces behavioural changes probably by stimulating the 5-HT receptor in a similar way to 5-HT but that it would bind weakly, in agreement with ligand-receptor binding studies.10 It is suggested, therefore, that cyproheptadine, cinanserin and mianserin fail to inhibit 5-HT and 5-MeODMT-induced behaviours because they are weak antagonists whilst they are able to inhibit the same behaviours induced by quipazine because it is a weak agonist.11 These data indicate that extreme care should be taken in accepting or rejecting 5-HT as a mediator of behaviours or of other responses unless several antagonists or agonists have been examined.
Animals↗
Inhibition and sex specific induction of spawning by serotonergic ligands in the zebra mussel Dreissena polymorpha (Pallas).
Serotonin (5-hydroxytryptamine, 5-HT) stimulates spawning in the zebra mussel (Dreissena polymorpha), a macrofouling European bivalve that has recently invaded North America. To develop methods of controlling zebra mussel spawning, two vertebrate serotonin antagonists, methiothepin and metergoline, known to bind with high affinity to snail 5-HT receptors, were tested for their ability to block 5-HT-induced spawning in zebra mussels. Methiothepin inhibited 5-HT-induced spawning at concentrations as low as 10(-6) M. Metergoline (10(-4) M) inhibited 5-HT-induced spawning; however, at lower concentrations (10(-8) to 10(-5) M), metergoline by itself significantly induced spawning in male, but not female zebra mussels. Metergoline (10(-5) M)-induced male spawning was inhibited by 10(-5) M methiothepin. Thus, methiothepin is the most effective inhibitor and metergoline the most powerful inducer of spawning yet tested in zebra mussels.
Animals↗
In vivo control of 5-hydroxytryptamine release by terminal autoreceptors in rat brain areas differentially innervated by the dorsal and median raphe nuclei.
Selective serotonin reuptake inhibitors (SSRIs) reduce the 5-HT release in vivo. This effect is due to the activation of somatodendritic 5-HT1A receptors and it displays a regional pattern comparable to that of selective 5-HT1A agonists, i.e., preferentially in forebrain areas innervated by the dorsal raphe nucleus (DRN). However, despite a comparatively lower 5-HT1A-mediated inhibition of 5-HT release and a greater density of serotonergic uptake sites in hippocampus, the net elevation produced by the systemic administration of SSRIs is similar in various forebrain areas, regardless of the origin of serotonergic fibres. As terminal autoreceptors may also limit the SSRI-induced elevations of 5-HT in the extracellular brain space, we reasoned that a differential control of 5-HT release by terminal autoreceptors in DRN- and median raphe-innervated areas might be accountable. To examine this possibility, we have conducted a regional microdialysis study in the DRN, MRN and four forebrain regions preferentially innervated either by the DRN (frontal cortex, striatum) or the median raphe nucleus (MRN; dorsal and ventral hippocampus) using freely moving rats. Dialysis probes were perfused with 1 microM of the SSRI citalopram to augment the endogenous tone on terminal 5-HT autoreceptors. The non-selective 5-HT1 antagonist methiothepin (10 and 100 microM, dissolved in the dialysis fluid) increased extracellular 5-HT in frontal cortex and dorsal hippocampus in a concentration-dependent manner. The 5-HT(1B/1D) antagonist GR 127935 was ineffective at 10 microM and tended to reduce 5-HT in dorsal hippocampus at 100 microM. The local infusion of 100 microM methiothepin significantly elevated the extracellular 5-HT concentration to 142-173% of baseline (mean values of 260 min post-administration) in the DRN, MRN, frontal cortex, striatum and hippocampus (dorsal and ventral). Comparable elevations were noted in the four forebrain regions examined. As observed in frontal cortex and dorsal hippocampus, the perfusion of 10 microM GR 127935 did not elevate 5-HT in DRN. MRN, striatum or ventral hippocampus. Because the stimulated 5-HT release in the DRN has been suggested to be under control of 5-HT(1B/1D) receptors, we examined the possible contribution of these receptor subtypes to the effects of methiothepin in the DRN. The perfusion of sumatriptan (0.01-10 microM) or GR 127935 (0.01-10 microM) did not significantly modify the 5-HT concentration in dialysates from the DRN. Thus, the present data suggest that the comparable effects of SSRIs in DRN- and MRN-innervated forebrain regions are not explained by a preferential attenuation of 5-HT release by terminal 5-HT1B autoreceptors in hippocampus, an area with a low inhibitory influence of somatodendritic 5-HT1A receptors. Methiothepin-sensitive autoreceptors (possibly 5-HT1B) appear to play an important role not only in the projection areas but also with respect to the control of 5-HT release in the DRN and MRN. In addition, our findings indicate that GR 127935 is not an effective antagonist of the actions of 5-HT at rat terminal autoreceptors.
Animals↗
Serotonin antagonists and central hyperthermia produced by biogenic amines in conscious rabbits.
Previous studies have shown that the hyperthermia produced by intracerebroventricular injection of 5-hydroxytryptamine (5-HT) to conscious rabbits was antagonized by cyproheptadine and increased by LSD. Other putative antagonists, i.e. cinanserin, methiothepin, 2-bromo LSD, methysergide and dimetiotazine are investigated in the present report. Cinanserin and methiothepin resembeld cyproheptadine, 2-bromo LSD had almost the same effects as LSD and methysergide exhibited a mixed pattern of action, being depressant or potentiating as a function of dose. Dimetiotazine had no specific action. Cinanserin, however, differed from cyproheptadine in selectively antagonizing and early component of the 5-HT rise, unmasking an important fall and leaving a late hyperthermic component unaffected, thus disclosing three distinct effects of 5-HT action. The cinanserin, methiothepin and methysergide antagonism of the 5-HT-induced temperature rise was greater than the antagonism of the noradrenaline (NA)-induced rise. Methiothepin and methysergide inhibited both the 5-HT and DA hyperthermia; cinanserin--like cyproheptadine--was more effective on the 5-HT rise. The potentiation of the 5-HT temperature rise by 2-bromo LSD and methysergide was more developed than was the potentiation of the NA and DA rises. The effects of the drugs studied on 5-HT action argue in favour of the existence of several types of central 5-HT receptors. The dissociation observed between the antagonism to 5-HT and that to DA does not favour a mediation of DA hyperthermia by 5-HT; antiserotonin drug antagonism of DA hyperthermia is more simply accounted for by interactions at the level fo specific DA receptors. The potentiation of the 5-HT-induced temperature rise by 2-bromo LSD and methysergide might result from an antagonism of the hypothermic component. As with LSD, 2-bromo LSD and methysergide alone also produced hyperthermia, the origin of which is briefly discussed.
Animals↗
Serotonin-glutamate interaction in rat cerebellum: involvement of 5-HT1 and 5-HT2 receptors.
The effects of serotonin (5-HT) on the release of endogenous glutamate (GLU) in rat cerebellum were investigated in slices depolarized with 35 mM K+. The Ca2+-dependent release of GLU was potently inhibited by 5-HT in a concentration-dependent way. Release was also inhibited by the 5-HT1 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and by the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). The inhibition by 10 nM 5-HT was partly (35-40%) counteracted by the 5-HT2 receptor antagonist ketanserin but was fully blocked by the mixed 5-HT1/5-HT2 receptor antagonist methiothepin. The effect of 8-OH-DPAT was not affected by ketanserin but was totally antagonized by methiothepin, while the effect of DOI was entirely suppressed by ketanserin. Ketanserin or methiothepin themselves increased (by 23 and 55%, respectively, at 10 nM) the K+-evoked release of GLU. In conclusion the release of endogenous GLU in rat cerebellum can be inhibited by 5-HT through receptors of the 5-HT1 and 5-HT2 type. The enhancement of GLU release by ketanserin or methiothepin could suggest a tonic inhibition. The possible localization of the 5-HT receptors involved in the interaction with the GLU systems is discussed.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Involvement of serotonin 5HT1 and 5HT2 receptors and nitric oxide synthase in the medial preoptic area on gonadotropin secretion.
Due to the stimulatory action of serotonin (5HT) and nitric oxide (NO) on the secretion of gonadotropins and PRL, this work aimed at investigating the participation of serotoninergic receptors 5HT(1) and 5HT(2) of the medial preoptic area (MPOA) in the control of luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL) secretion and the possible modulation by ovarian steroids as well as the possible participation of NO as a mediator of the stimulatory effects of serotonin in the MPOA on LH secretion. Microinjections of three different doses (0.02, 0.2, and 2 ug) of methiothepin, a serotoninergic 5HT(1) antagonist or ketanserin, a seretoninergic 5HT(2) antagonist, were carried out into the MPOA in ovariectomized rats treated or not with estrogen or estrogen plus progesterone. Other groups of ovariectomized rats treated with estrogen, estrogen plus progesterone or vehicle were prepared to evaluate NOS activity in the MPOA. Plasma LH, FSH, and PRL in ovariectomized rats were not altered by the microinjection of methiothepin or ketanserin in the MPOA. Methiothepin microinjection in the MPOA reduced LH but did not change plasma FSH and PRL in ovariectomized rats treated with estrogen or estrogen plus progesterone. On the other hand, ketanserin microinjection in the MPOA reduced plasma LH and FSH but did not change plasma PRL in the animals submitted to the same steroidal treatment. NOS activity in the MPOA was significantly reduced by methiothepin or ketanserin in ovariectomized rats treated with estrogen or estrogen plus progesterone. In conclusion, this work showed that in the studied conditions, serotonin in the MPOA: (1) does not work in the control of PRL secretion through 5HT(1) and 5HT(2) receptors; (2) integrates the control of FSH secretion by 5HT(2) receptors, but not 5HT(1); (3) in the presence of estrogen, stimulates LH secretion by 5HT(1) and 5HT(2) receptors, which can be differentially modulated by progesterone; (4) at least partly, stimulates LH secretion by nitric oxide activity.
Animals↗