Topic
Indalpine
About: Indalpine is a research topic. Over the lifetime, 70 publications have been published within this topic receiving 2679 citations. The topic is also known as: LM-5008 & Indalpine.
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Papers
TL;DR: Extracellular levels of endogenous serotonin (5‐HT) and its major metabolite, 5‐HIAA, were measured in the caudate‐putamen of anesthetized and awake rats using intracerebral microdialysis coupled to HPLC with fluorimetric detection to suggest that the high 5‐HT levels recovered in association with probe implantation were blood‐derived.
Abstract: Extracellular levels of endogenous serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured in the caudate-putamen of anesthetized and awake rats using intracerebral microdialysis coupled to HPLC with fluorimetric detection. A dialysis probe (of the loop type) was perfused with Ringer solution at 2 μl/min, and samples collected every 30 or 60 min. Basal indole levels were followed for up to 4 days in both intact and 5,7-dihydroxytryptamine (5,7-DHT) lesioned animals. Immediately after the probe implantation, the striatal 5-HT levels were about 10 times higher than the steady-state levels that were reached after 7-8 h of perfusion. The steady-state baseline levels, which amounted to 22.5 fmol/30 min sampling time, remained stable for 4 days. In 5,7-DHT-denervated animals, the steady-state levels of 5-HT, measured during the second day after probe implantation, were below the limit of detection (<10 fmol/60 min). However, during the first 6h post-implantation, the 5-HT output was as high as in intact animals, which suggests that the high 5-HT levels recovered in association with probe implantation were blood-derived. As a consequence, all other experiments were started after a delay of at least 12 h after implantation of the dialysis probe. In awake, freely moving animals, the steady-state 5-HT levels were about 60% higher than in halothane-anesthetized animals, whereas 5-HIAA was unaffected by anesthesia. KCI (60 and 100 mM) added to the perfusion fluid produced a sharp increase in 5-HT output that was eight-fold at the 60 mM concentration and 21-fold at the 100 mM concentration. In contrast, 5-HIAA output dropped by 43 and 54%, respectively. In 5,7-DHT-lesioned animals, the KCl-evoked (100 mM) release represented less than 5% of the peak values obtained for the intact striata. Omission of Ca2+ from the perfusion fluid resulted in a 70% reduction in baseline 5-HT output, whereas the 5-HIAA levels remained unchanged. High concentrations of tetrodotoxin (TTX) added to the perfusion medium (5-50 μM) resulted in quite variable results. At a lower concentration (1 μM), however, TTX produceda 50% reduction in baseline 5-HT release, whereas the 5-HIAA output remained unchanged. The 5-HT reuptake blocker, indalpine, increased the extracellular levels of 5-HT sixfold when added to the perfusion medium (1 μM), and threefold when given intraperitoneally (5 mg/kg). By contrast, the 5-HIAA level remained unaffected during indalpine infusion. Application of TTX (1 μM) under simultaneous 5-HT uptake blockade induced a decrease in 5-HT output by 62–71%. p-Chloroamphetamine (2.5 mg/kg, i.p.) induced a 12-fold increase in 5-HT release and reduced the 5-HIAA output by about 50%. The p-chloroamphetamine-induced increase in 5-HT release was 10 times lower in the 5,7-DHT-denervated striatum. Pargyline (75 mg/kg, i.p.) increased the extracellular levels of 5-HT 11-fold within 6 h, and reduced the 5-HIAA levels by 80%. The 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (1 mg/kg, i.p.), produced an immediate reduction of about 50% in 5-HT release and a small (11 %) decrease in 5-HIAA output. It is concluded (1) that intracerebral microdialysis coupled to HPLC with fluorimetric detection provides a useful method for the study of extracellular 5-HT and 5-HIAA levels; (2) that steady-state levels of 5-HT and 5-HIAA recovered in the dialysis perfusate are neuronally derived, but these steady-state levels are reached only after a minimum of 7–8 h after probe implantation; (3) that changes in striatal extracellular levels of 5-HT are closely related to changes in serotonergic synaptic activity; and (4) that extracellular levels of 5-HIAA are a poor indicator of synaptic activity, and instead primarily reflect intraneuronal metabolism.
247 citations
TL;DR: A computerized version of this test (ITEMATIC-TST) which in addition to recording immobility measures the power of the movements, suggesting that the automated test system is not only sensitive to antidepressants but could also be useful for generating activity profiles for different kinds of psychotropic agent.
Abstract: 1. Mice when suspended by the tail will alternate between active attempts to escape and immobility. Immobility like that measured in the behavioral despair test is reduced by a wide variety of antidepressant agents. 2. The present paper describes a computerized version of this test (ITEMATIC-TST) which in addition to recording immobility measures the power of the movements. 3. Various tricyclic (amitriptyline, desipramine, imipramine), MAOI (clorgyline, moclobemide, nialamide, pargyline, toloxatone) and atypical antidepressants (bupropion, citalopram, indalpine, mianserin, nomifensine, viloxazine) were tested and compared with psychostimulants (d-amphetamine, caffeine), neuroleptics (chlorpromazine, haloperidol, sulpiride), anxiolytics (clobazam, diazepam) and agents acting on the cholinergic system (atropine, oxotremorine). 4. All antidepressants decreased the duration of immobility and most increased the power of movements. 5. The psychostimulants also decreased immobility but only amphetamine increased the power of movements. 6. Neuroleptics increased immobility without affecting the power of movements, whereas anxiolytics increased immobility but decreased the power of movements. 7. Atropine had a profile similar to antidepressants whereas oxotremorine tended to have opposite effects. 8. The results suggest that the automated test system with its two parameters is not only sensitive to antidepressants but could also be useful for generating activity profiles for different kinds of psychotropic agent.
238 citations
TL;DR: It is concluded that serotonin release in the mouse brain cortex is inhibited via CB1 receptors, which may be located presynaptically and are not activated by endogenous cannabinoids.
Abstract: We studied whether serotonin release in the CNS is inhibited via cannabinoid receptors. In mouse brain cortex slices preincubated with [3H]serotonin and superfused with medium containing indalpine and metitepine, tritium overflow was evoked either electrically (3 Hz) or by introduction of Ca2+ (1.3 mM) into Ca2+-free K+-rich (25 mM) medium containing tetrodotoxin. The effects of cannabinoid receptor ligands on the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [3H]choline and on the binding of [3H]WIN 55,212-2 and [35S]GTPgammaS to mouse brain cortex membranes were examined as well. In superfused mouse cortex membranes preincubated with [3H]serotonin, the electrically evoked tritium overflow was inhibited by the cannabinoid receptor agonist WIN 55,212-2 (maximum effect of 20%, obtained at 1 microM; pEC50=7.11) and this effect was counteracted by the CB1 receptor antagonist SR 141716 (apparent pA2=8.02), which did not affect the evoked tritium overflow by itself. The effect of WIN 55,212-2 was not shared by its enantiomer WIN 55,212-3 but was mimicked by another cannabinoid receptor agonist, CP-55,940. WIN 55,212-2 also inhibited the Ca2+-evoked tritium overflow and this effect was antagonized by SR 141716. Concentrations of histamine, prostaglandin E2 and neuropeptide Y, causing the maximum effect at their respective receptors, inhibited the electrically evoked tritium overflow by 33, 69 and 73%, respectively. WIN 55,212-2 (1 microM) inhibited the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [3H]choline by 49%. [3H]WIN 55,212-2 binding to mouse cortex membranes was inhibited by CP-55,940, SR 141716 and WIN 55,212-2 (pKi=9.30, 8.70 and 8.19, respectively) but not by the auxiliary drugs indalpine, metitepine and tetrodotoxin (pKi<4.5). [35S]GTPgammaS binding was increased by WIN 55,212-2 (maximum effect of 80%, pEC50=6.94) but not affected by WIN 55,212-3. In conclusion, serotonin release in the mouse brain cortex is inhibited via CB1 receptors, which may be located presynaptically and are not activated by endogenous cannabinoids. The extent of inhibition is smaller than that obtained (1) via another three presynaptic receptors on serotoninergic neurones and (2) via CB1 receptors on cholinergic neurones in the same tissue.
203 citations
TL;DR: Generality suggests that elevated synaptic 5‐HT could be responsible for the effects of these latter agents and selective inhibition of marble burying was not found to be a property of 5‐ HT‐related putative and actual anxiolytic agents.
Abstract: 1. The effects of 5-hydroxytryptamine (5-HT) uptake inhibitors, agonists and antagonists have been evaluated on mouse marble-burying behaviour, a putative test for anxiolytic agents. The high levels of locomotor activity occurring on first exposure to a circular runway (runway were used as a separate test of non-specific drug effects. 2. Fluvoxamine, zimeldine, indalpine and citalopram dose-dependently inhibited burying without affecting runway activity. 5-Hydroxytryptophan (5-HTP, with carbidopa), 5-methoxy-N,N-dimethyltryptamine, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), buspirione, gepirone and ipsapirone reduced burying only at doses reducing runway activity. RU 24969 increased runway activity at all effective doses. 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 1,-(3-trifluoromethylphenyl) piperazine (TFMPP) and 1-(3-chlorophenyl)-piperazine (mCPP) potently and differentially reduced burying at doses below those affecting runway activity. 3. 5-HT antagonists only reduced burying at high doses which also reduced runway activity. Burying inhibition by DOI was antagonized by ritanserin, ICI 169,369 and cyproheptadine but not by pindolol or a low (0.25 mg kg-1) dose of metergoline. Burying inhibition by mCPP was not altered by any of these agents except that it was potentiated by pindolol 5 mg kg-1. 4. Zimeldine burying inhibition was potentiated by ritanserine, ICI 169,369, ICS 205-930, cyproheptadine and pindolol. Runway activity was not affected by these drug combinations. 5. Zimeldine was administered in drinking water at a dose of 10 mg kg-1 daily for 21 days. Burying inhibition had disappeared by day 14 and did not recur 24 or 48h after withdrawal at which times responses to DOI were at control levels.6. Selective inhibition of marble burying was not found to be a property of 5-HT-related putative and actual anxiolytics such as buspirone, gepirone, ipsapirone, ritanserin and ondansetron. Nevertheless it was a general property of both 5-HT uptake inhibitors and 5-HT releasing agents; this generality suggests that elevated synaptic 5-HT could be responsible for the effects of these latter agents. The action of DOI may be attributable to effects at the 5-HT2 receptor but those of the 5-HT agonist and releasing agent mCPP, and the uptake inhibitor zimeldine, could not be attributed to effects at any one 5-HT receptor subtype. This, together with the potentiating effect of several 5-HT antagonists on the response to zimeldine, raises the possibility of multiple interactions between 5-HT receptor subtypes.
191 citations
TL;DR: The selective serotonin uptake blocker indalpine, added to the perfusion fluid at 1 μM, increased the extracellular 5‐HT levels 6‐fold, with a similar correlation to behavioural activity state as without ind alpine.
Abstract: Hippocampal extracellular levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were monitored with the microdialysis technique in freely moving rats. In one experiment 30 min samples were collected during 24 h of continuous perfusion, and the monoamine output was compared to the behavioural activity state, as arbitrarily classified in three categories: sleep/rest, drowsiness and full alertness associated with complex behaviours. In the individual animal the hippocampal NA and 5-HT output showed pronounced fluctuations during the 24 h period, but the 30 min sampling times did not allow for a clear-cut correlation to behavioural activity state. However, the mean NA and 5-HT output for all animals during the dark period of the day was 43 and 38% higher, respectively, than during the light period, and the average NA and 5-HT levels in samples collected during periods of high behavioural activity was 34 and 45% higher, respectively, than during periods of rest or sleep. In contrast, there were no detectable changes in extracellular 5-HIAA. The selective serotonin uptake blocker indalpine, added to the perfusion fluid at 1 microM, increased the extracellular 5-HT levels 6-fold, with a similar correlation to behavioural activity state as without indalpine. In a second experiment the effect of handling and tail-pinch was studied in 15 min sample fractions. Gentle handling of the animals during the sampling period increased the hippocampal NA and 5-HT output by 32 and 72%, respectively, and a similar increase (63 and 48%) was obtained by application of tail-pinch. Maximum NA output was reached during the handling or tail-pinch period, whereas maximal 5-HT levels were detected in the subsequent 15 min sample fraction. No changes in extracellular 5-HIAA was observed. It is concluded (1) that intracerebral microdialysis provides a useful method for the study of extracellular NA and 5-HT in the hippocampal formation of conscious rats during active behaviour; (2) that there are substantial fluctuations in hippocampal NA and 5-HT output in freely moving rats which correlate with the light - dark cycle as well as with the activity state of the animals; (3) that the spontaneous variations in 5-HT output are maintained during reuptake blockade; and (4) that behavioural activation through gentle handling or tail-pinch elicits NA and 5-HT release. The present data support a role of the forebrain NA and 5-HT systems in behavioural state control and highlights the necessity of experimental designs in which the spontaneous fluctuations in transmitter release are controlled for in studies of, for example, drug effects on NA and 5-HT release in conscious animals.
179 citations
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| Year | Papers |
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| 2015 | 1 |
| 2011 | 1 |
| 2000 | 1 |
| 1997 | 1 |
| 1996 | 3 |
| 1993 | 1 |