The 5-HT hypothesis of depression revisited.
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Carrier Proteins↗
Biomedical subjects
C Routledge
Publications and source records attributed to C Routledge.
Differential effects of WAY-100135 on the decrease in 5-hydroxytryptamine release induced by buspirone and NAN-190.
1-(2-Methoxyphenyl)-4-[(phthalimido)butyl] piperazine (NAN-190) and 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5] decane-7,9-dione (buspirone) are 5-HT1A receptor partial agonists which decrease 5-hydroxytryptamine (5-HT) release in vivo. In order to assess whether these ligands decrease 5-HT release by stimulating 5-HT1A receptors we examined the ability of the selective 5-HT1A receptor antagonist N-tert-butyl 3-4-(2-methoxyphenyl) piperazin-1-yl-2-phenylpropanamide dihydrochloride (WAY-100135) to block their inhibitory effects on 5-HT. NAN-190 (0.1 mg/kg s.c.) and buspirone (1.0 mg/kg s.c.) significantly decreased extracellular levels of 5-HT in hippocampal dialysates. WAY-100135 (10.0 mg/kg s.c.) attenuated the effect of buspirone but had no significant effect on the NAN-190-induced decreased in 5-HT release. These data demonstrate that buspirone is an agonist at the somatodendritic 5-HT1A receptor but that the inhibitory effects of NAN-190 on 5-HT release may be mediated via a mechanism other than, or in addition to, 5-HT1A receptor agonism.
Animals↗
Differential effects of potassium channel blockers on extracellular concentrations of dopamine and 5-HT in the striatum of conscious rats.
1. The selective Ca(2+)-activated K+ channel blocker apamin increased extracellular 5-hydroxytryptamine (5-HT) concentrations in the striatum when administered through the microdialysis probe at doses of 0.1 mM and 1 mM. Extracellular dopamine concentrations increased only at the highest dose administered (1 mM). 2. Mast cell degranulating peptide (MCDP), which blocks the dendrotoxin sensitive delayed rectifier (DR) current, increased extracellular concentrations of dopamine at dose of 10 microM-100 microM but had no effect on 5-HT. 3. The non selective K+ channel blocker tetraethylammonium (TEA) induced a dose-dependent (1 mM-10 mM) increase in extracellular dopamine concentrations and an increase in 5-HT which showed little or no dose-dependency. 4. 4-Aminopyridine (4-AP), a blocker with some similar characteristics to MCDP, increased extracellular dopamine concentrations at doses of 10 microM-1 mM, but had no effect on 5-HT. 5. These findings suggest that dopamine release may be modulated by DR-like current and/or A-current K+ channels. However, in view of the similar effects of MCDP and 4-AP at the concentrations used it is more likely that the dendrotoxin-sensitive DR-like current is involved. In contrast, 5-HT release appears to be modulated by Ca(2+)-activated K+ channels.
4-Aminopyridine↗
Neurochemical profile of the selective and silent 5-HT1A receptor antagonist WAY100135: an in vivo microdialysis study.
The neurochemical profile of the selective 5-HT1A receptor antagonist WAY100135 [N-tert-butyl 3-4-(2-methoxyphenyl) piperazin-1-yl-2-phenylpropanamide dihydrochloride] and its enantiomers at the somatodendritic 5-HT1A receptor was determined by studying the effects of these compounds on 5-HT (5-hydroxytryptamine, serotonin) release in the rat hippocampus using in vivo microdialysis. (+/-)-WAY100135, (+)-WAY100135 and (-)-WAY100135 (all at 10 mg/kg s.c.) had no significant effect on extracellular levels of 5-HT in the hippocampus demonstrating that these compounds are devoid of 5-HT1A receptor agonist properties. In contrast, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.1 mg/kg s.c.) and the partial agonists BMY 7378 (1.0 mg/kg s.c.) and buspirone (5 mg/kg s.c.) significantly decreased hippocampal 5-HT. Pretreatment with (+/-)-WAY100135 (at 10 mg/kg s.c.) and (+)-WAY100135 (at 1.0-10 mg/kg s.c.) completely blocked the 8-OH-DPAT-induced decrease in 5-HT release demonstrating that these compounds are antagonists at the somatodendritic 5-HT1A autoreceptor. (-)-WAY100135 at a dose of 10 mg/kg s.c. had no significant effect on the 8-OH-DPAT-induced inhibition of 5-HT release. (+/-)-WAY100135 had no significant effect on extracellular levels of dopamine in the rat hippocampus but significantly increased extracellular levels of noradrenaline. The mechanism underlying the increase in noradrenaline is unknown at present.(ABSTRACT TRUNCATED AT 250 WORDS)
8-Hydroxy-2-(di-n-propylamino)tetralin↗
(S)-N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide [(S)-WAY-100135]: a selective antagonist at presynaptic and postsynaptic 5-HT1A receptors.
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Animals↗
Comparison of the effects of selected drugs on the release of hypothalamic adrenaline and noradrenaline measured in vivo.
Intracerebral dialysis combined with high-performance liquid chromatography and electrochemical detection was used to monitor changes in extracellular posterior hypothalamic, noradrenaline, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) following administration of an inhibitor of phenylethanolamine-N-methyltransferase (LY87130); the alpha 2-antagonist idazoxan; the monoamine oxidase (MAO) inhibitor tranylcypromine, and a selective noradrenergic neurotoxin (DSP4) to the anaesthetised rat. LY87130 (50 mg/kg i.p.) decreased basal hypothalamic perfusate and whole-tissue levels of adrenaline by 100% and 64%, respectively, but was without effect on basal extracellular hypothalamic levels and whole-tissue levels of noradrenaline, DOPAC and 5-HIAA. Administration of the alpha 2-adrenoceptor antagonist idazoxan and the MAO inhibitor tranylcypromine elicited increases in hypothalamic extracellular levels of both adrenaline and noradrenaline by 208% and 229%, respectively. Idazoxan also increased hypothalamic extracellular 5-HIAA by 97% but was without effect on extracellular DOPAC. In contrast, tranylcypromine decreased hypothalamic extracellular levels of DOPAC and 5-HIAA by 72% and 50%, respectively. DSP4 depleted extracellular hypothalamic adrenaline and noradrenaline 360 min and 390 min postdrug, respectively, after causing an initial 3-fold increase in both these amines 150 min after drug administration. DSP4 was without effect on posterior hypothalamic extracellular DOPAC and 5-HIAA. These results demonstrate that the pharmacology of central adrenaline and noradrenaline is very similar and, with the exception of phenylethanolamine-N-methyl transferase inhibitors, none of the drugs investigated are able to differentiate between adrenergic and noradrenergic neurones.
3,4-Dihydroxyphenylacetic Acid↗
Adrenaline in the CNS: in vivo evidence for a functional pathway innervating the hypothalamus.
This article reviews the evidence, obtained from studies employing the technique of intracerebral dialysis, to monitor changes in extracellular adrenaline in the hypothalamus, that adrenaline is released from nerve endings in the hypothalamus and has a functional role. Studies using [3H] adrenaline to determine the specificity of uptake mechanisms for adrenaline indicate that labelled adrenaline is also taken up by noradrenergic nerve endings. This supports the need to develop techniques to monitor changes in endogenous release of adrenaline. In this study, it has been shown that inhibition of phenylethanolamine-N-methyltransferase selectively decreases tissue levels in the hypothalamus and in vivo release of adrenaline, while monoamine oxidase inhibition and antagonism of alpha 2-adrenoceptors increases the release of both adrenaline and noradrenaline. The "selective" noradrenergic neurotoxin DSP4 caused an initial increase in the release of both catecholamines, followed by a marked decrease in their release. Stimulation of the adrenaline-containing neurones in the rostral ventrolateral medulla (C1 region) increased the release of adrenaline in the posterior hypothalamus, but not that of noradrenaline, while also increasing mean arterial blood pressure. Pharmacological evidence indicates that B2-adrenoceptors in the hypothalamus and the spinal cord are involved in the rise in mean arterial pressure, as the response is reduced by a selective B2-antagonist (ICI 118551). The rise in mean arterial blood pressure during C1 stimulation is enhanced by the alpha 2-antagonist idazoxan, supporting observations that alpha 2-adrenoceptors are involved in the pre-synaptic regulation of release of adrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Antagonists↗
Electrical stimulation of the C1 region of the rostral ventrolateral medulla of the rat increases mean arterial pressure and adrenaline release in the posterior hypothalamus.
By using intracerebral dialysis in combination with high performance liquid chromatography and electrochemical detection, extracellular posterior hypothalamic adrenaline, noradrenaline, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid were measured in the anaesthetized rat and changes in their levels monitored following administration of tranylcypromine and electrical stimulation of the rostral ventrolateral medulla. Tranylcypromine (10 mg/kg i.p.) administration decreased basal extracellular 3,4-dihydroxyphenylacetic acid and 5-hydroxyindole acetic acid levels with a simultaneous increase in adrenaline and noradrenaline levels. Electrical stimulation of the C1 area of the rostral ventrolateral medulla increased (+56.6%) extracellular adrenaline levels in the posterior hypothalamus with a simultaneous increase in mean arterial pressure (+48 mm Hg) compared to prestimulation control values. No change was seen in posterior hypothalamic extracellular levels of noradrenaline, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindole acetic acid during the stimulation period. Electrical stimulation of areas close to but outside the C1 region had no effect on either mean arterial pressure or posterior hypothalamic extracellular levels of the amines or the metabolites. The increase in adrenaline levels in the hypothalamus during stimulation of the C1 region supports the evidence for an adrenergic pathway from the rostral ventrolateral medulla to the hypothalamus and suggests that the increase in mean arterial pressure during electrical stimulation to the C1 region may relate to a specific increase in adrenaline levels.
3,4-Dihydroxyphenylacetic Acid↗
Lack of selectivity between the uptake of [3H]adrenaline and [3H]noradrenaline into rat hypothalamic slices.
The uptake of [3H]adrenaline and [3H]noradrenaline into rat hypothalamic slices was compared for determination of whether adrenaline uptake was independent of uptake into noradrenergic neurones. Kinetic analysis revealed a similar high-affinity uptake process for both adrenaline and noradrenaline, with Km and Vmax values within similar ranges. These uptakes were inhibited by desipramine and maprotiline in a dose-dependent manner, but the selective dopamine and 5-hydroxytryptamine uptake inhibitors benztropine and fluoxetine, respectively, were without effect. Competition for uptake sites by unlabelled adrenaline with [3H]adrenaline and [3H]-noradrenaline and by unlabelled noradrenaline with [3H]-adrenaline and [3H]noradrenaline was very similar. Lesioning of the major adrenaline-containing cell group (C1 cell group) decreased the hypothalamic adrenaline concentration but had no effect on hypothalamic [3H]adrenaline or [3H]noradrenaline uptake. The results suggest that exogenous adrenaline is largely taken up by high-affinity sites on noradrenergic nerve terminals.
Animals↗
Application of intracerebral dialysis and in vivo voltammetry to pharmacological and physiological studies of amine neurotransmitters.
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3,4-Dihydroxyphenylacetic Acid↗
Recent advances in high-performance liquid chromatographic analysis of small molecules. Application of high-performance liquid chromatography with electrochemical detection to the study of neurotransmitters in vivo.
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3,4-Dihydroxyphenylacetic Acid↗
The 5-HT1 receptor agonist RU-24969 decreases 5-hydroxytryptamine (5-HT) release and metabolism in the rat frontal cortex in vitro and in vivo.
K+-stimulated release of [3H]-5-hydroxytryptamine ( [3H]-5-HT) from rat frontal cortex slices was decreased by the 5-HT receptor agonists 5-methoxy-n1N-dimethyltryptamine and 5-methoxy-3(1,2,3,6,-tetrahydro-4-pyrindinyl)-1H-indole (RU-24969) (1 X 10(-5)M). RU-24969 (10 mg kg-1, i.p.) decreased extracellular 5-HT and its metabolite 5-hydroxyindoleacetic acid measured in vivo by use of intracerebral dialysis combined with high performance liquid chromatography and electrochemical detection. The decrease in extracellular 5-hydroxyindoleacetic acid in vivo after RU-24969 (10 mg kg-1, i.p.) was also observed by in vivo voltammetry. The non-selective 5-HT antagonist metergoline prevented the RU-24969-induced decrease in 5-HT release and metabolism in vivo while the 5-HT2 receptor antagonist R-55669 (ritanserin) did not. The results support the view that RU-24969 stimulates a 5-HT1 receptor that is involved in the autoregulation of 5-HT release and metabolism.
Animals↗
In vivo characterization of the putative 5-HT1A receptor antagonist SDZ 216,525 using two models of somatodendritic 5-HT1A receptor function.
SDZ 216,525 has been proposed to be a silent 5-HT1A receptor antagonist. The present study examined the potential intrinsic agonist action of SDZ 216,525 using two in vivo models of somatodendritic 5-HT1A autoreceptor function: 5-HT release using microdialysis and feeding behaviour of satiated animals. SDZ 216,525 (1 mg/kg s.c.) and the alpha 1-adrenoceptor antagonist prazosin (1 mg/kg s.c.) significantly decreased hippocampal 5-HT release. In addition, SDZ 216,525 (3 and 10 mg/kg s.c.) and prazosin (3 and 10 mg/kg s.c.) significantly increased food intake in satiated rats. The selective 5-HT1A receptor antagonist (RS)-WAY100135 (10 mg/kg s.c.) which has been demonstrated to block the effects of 8-OH-DPAT on 5-HT release and food intake had no significant effect on the response induced by SDZ 216,525. In contrast, the non-selective 5-HT1A receptor antagonist (-)-pindolol (8 mg/kg s.c.) attenuated both SDZ 216,525 responses. The decrease in hippocampal 5-HT release and increase in food intake induced by SDZ 216,525 suggest that the compound may be a 5-HT1A receptor partial agonist. However, the failure of the 5-HT1A receptor antagonist (RS)-WAY100135 to block the SDZ 216,525 responses suggests that SDZ 216,525 decreases 5-HT release and increases food intake by a mechanism other than 5-HT1A receptor agonism. The high affinity of SDZ 216,525 for the alpha 1-adrenoceptor, and the ability of prazosin to decrease 5-HT release and increase food intake, suggest that the effects of SDZ 216,525 may be mediated via an alpha 1-adrenoceptor antagonist action.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity: an in vivo microdialysis study in the freely-moving guinea-pig.
The importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity was investigated with the selective h5-HT1B receptor ligands SB 219085, SB 220272, SB 224289 and SB 216641. The studies employed measurement of compound affinity and efficacy in vitro and the measurement of extracellular 5-HT in the frontal cortex of the freely-moving guinea-pig using in vivo microdialysis. All compounds had high affinity and selectivity for the h5-HT1B receptor, with SB 224289 the most selective for h5-HT1B over h5-HT1D receptors. Compounds exhibited a range of efficacies at both receptors: SB 224289 and SB 219085 were inverse agonists, SB 220272 was an antagonist and SB 216641 was a partial agonist. SB 220272, SB 216641 and SB 224289 had no effect on extracellular 5-HT following systemic administration, however, SB 219085 produced a significant increase. The SB 219085-induced increase in extracellular 5-HT was attributed to the compounds non-specific releasing properties as it was also demonstrated to increase basal release of [3H]5-HT from pre-loaded guinea-pig cortical slices. The lack of effect of the above h5-HT1B receptor selective compounds and the decrease in extracellular 5-HT elicited by the non-selective compounds GR 127935, GR125743 and methiothepin suggest that antagonism of 5-HT1D receptors may mediate this decrease in 5-HT levels. It is plausible that blockade of 5-HT1D receptors increases 5-HT levels in the raphe, this activates 5-HTtA receptors which results in an overall decrease in terminal 5-HT release. Definitive proof now awaits elucidation of the action of a selective 5-HT1D receptor antagonist.
Animals↗