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PubMed2002

5,7-DHT-induced hippocampal 5-HT depletion attenuates behavioural deficits produced by 192 IgG-saporin lesions of septal cholinergic neurons in the rat.

Adult Long-Evans male rats sustained injections of 5,7-dihydroxytryptamine into the fimbria-fornix (2.5 microg/side) and the cingular bundle (1.5 microg/side) and/or to intraseptal injections of 192 IgG-saporin (0.4 microg/side) in order to deprive the hippocampus of its serotonergic and cholinergic innervations, respectively. Sham-operated rats were used as controls. The rats were tested for locomotor activity (postoperative days 18, 42 and 65), spontaneous T-maze alternation (days 20-29), beam-walking sensorimotor (days 34-38), water maze (days 53-64) and radial maze (days 80-133) performances. The cholinergic lesions, which decreased the hippocampal concentration of ACh by about 65%, induced nocturnal hyperlocomotion, reduced T-maze alternation, impaired reference-memory in the water maze and working-memory in the radial maze, but had no effect on beam-walking scores and working-memory in the water maze. The serotonergic lesions, which decreased the serotonergic innervation of the hippocampus by about 55%, failed to induce any behavioural deficit. In the group of rats given combined lesions, all deficits produced by the cholinergic lesions were observed, but the nocturnal hyperlocomotion and the working-memory deficits in the radial maze were attenuated significantly. These results suggest that attenuation of the serotonergic tone in the hippocampus may compensate for some dysfunctions subsequent to the loss of cholinergic hippocampal inputs. This observation is in close concordance with data showing that a reduction of the serotonergic tone, by pharmacological activation of somatodendritic 5-HT(1A) receptors on raphe neurons, attenuates the cognitive disturbances produced by the intrahippocampal infusion of the antimuscarinic drug, scopolamine. This work has been presented previously [Serotonin Club/Brain Research Bulletin conference, Serotonin: From Molecule to the Clinic (satellite to the Society for Neuroscience Meeting, New Orleans, USA, November 2-3, 2000)].

5,7-Dihydroxytryptamine↗

PubMed1995

d-fenfluramine increases striatal extracellular dopamine in vivo independently of serotonergic terminals or dopamine uptake sites.

The effect of various doses of the serotonin (5-HT) release-inducing agent d-fenfluramine (d-fenf) on extracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) was studied in vivo in the striatum of halothane-anesthetized rats, following systemic and local administration. At 5 and 10 but not 2.5 mg/kg, d-fenf administered intraperitoneally significantly increased DA extracellular concentration and reduced DOPAC outflow. A concentration-dependent enhancement of DA dialysate content was also found following intrastriatal application (5, 10, 25, and 50 microM). The bilateral administration of 5,7-dihydroxytryptamine into the dorsal raphe nucleus, which markedly depleted 5-HT in the striatum, did not modify the effect on extracellular DA concentration of 25 microM d-fenf locally applied into the striatum. The enhancement of extracellular DA level induced by 25 microM d-fenf was slightly but significantly reduced by the local application of 25 microM citalopram. The blockade of DA uptake sites by nomifensine (0.1, 0.3, and 1 microM) did not modify significantly the effect of d-fenf. The rise of DA outflow induced by 25 microM d-fenf was strongly reduced in the presence of 1 microM tetrodotoxin (TTX) or by the removal of Ca2+ from the perfusion medium. The results obtained show that d-fenf increases the striatal extracellular DA concentration by a Ca(2+)-dependent and TTX-sensitive mechanism that is independent of striatal 5-HT itself or DA uptake sites.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Serotonin-mediated increases in the extracellular levels of beta-endorphin in the arcuate nucleus and nucleus accumbens: a microdialysis study.

Although the involvement of both endogenous opioid and serotonergic systems in modulation of pain and emotion was suggested, the neurochemical interaction between these systems in the brain has not previously been studied directly. Herein, the effects of the local application of serotonin (5-HT) and fluoxetine (a 5-HT reuptake inhibitor) on extracellular levels of beta-endorphin in the arcuate nucleus and nucleus accumbens were assessed in freely moving rats using in vivo microdialysis. The mean basal concentrations of beta-endorphin in dialysates obtained from the arcuate nucleus and nucleus accumbens were 259.9 and 143.3 pM, respectively. Specific lesion of the serotonergic system by 5,7-dihydroxytryptamine (5,7-DHT) caused a significant decrease in these dialysate beta-endorphin levels. When 5-HT (0.25-5 microM) was added to the perfusion solution, the levels of beta-endorphin in the dialysate from the arcuate nucleus increased (186-296% of baseline), in a concentration-dependent manner. In the nucleus accumbens, 0.5 and 2 microM 5-HT in the perfusion fluid did not affect the levels of beta-endorphin in the dialysate, whereas 5 and 10 microM 5-HT caused an increase of approximately 190% of baseline. When fluoxetine (250 microM) was present in the perfusing solution, the levels of beta-endorphin in the dialysates from the arcuate nucleus and nucleus accumbens increased two- to threefold. This effect was not obtained in the 5,7-DHT-lesioned rats. Thus, 5-HT, either endogenously or exogenously delivered, appears to facilitate the release of beta-endorphin in the arcuate nucleus and nucleus accumbens. This indication of an interaction between serotonergic and endorphinic systems may be relevant for assessing pain and mood disorder circuits and the mode of action of antidepressant drugs.

5,7-Dihydroxytryptamine↗

PubMed2001

Serotonin depletion produces long lasting increase in striatal glutamatergic transmission.

The ability of serotonin (5-HT) to influence striatal glutamatergic transmission was examined by determining changes over time in glutamate extracellular levels, transporter expression and synaptosomal uptake in rats with lesion of serotonergic neurones. By 8 days after intraraphe injections of 5,7-dihydroxytryptamine, producing 80% decreases in striatal tissue 5-HT levels, no changes were observed in the glutamatergic transmission. When 5-HT depletion was almost complete (21 days post-lesion), high affinity glutamate uptake in striatal synaptosomal preparations was significantly increased (156% of control), although no changes in striatal GLT1, GLAST and EAAC1 mRNAs, and GLT1 protein were detected by in situ hybridization and immunohistochemistry. Meanwhile, the serotonin lesion produced large increases in basal extracellular levels of glutamate and glutamine (364% and 259%, respectively) determined in awake rats by in vivo microdialysis, whereas no change was observed in dopamine levels as compared with control rats. High potassium depolarization as well as L-trans-pyrrolidine-2,4-dicarboxylate, also induced larger increases in extracellular levels of glutamate in lesioned rats than in controls. Finally, similar changes in glutamate transmission were observed by 3 months post-lesion. These results suggest that 5-HT has a long lasting and tonic inhibitory influence on the striatal glutamatergic input, without affecting the basal dopaminergic transmission.

5,7-Dihydroxytryptamine↗

PubMed2003

Serotonin (5-HT) transporter (SERT) function after graded destruction of serotonergic neurons.

The degree of occupancy of the serotonin transporter (SERT) by selective serotonin reuptake inhibitors (SSRIs) appears to be critical in determining therapeutic response. To gain insight into the extent of occupancy required to alter serotonergic neurotransmission we used high-speed chronoamperometry to determine the extent of serotonergic destruction required to reduce the clearance of exogenously administered serotonin from extracellular fluid in the CA3 region of the hippocampus. Rats were pretreated with various doses of 5,7-dihydroxytryptamine to produce either a low, intermediate or high loss of SERTs. Clearance of 5-HT was reduced only in rats with > 90% loss of SERT. In these rats, there was also a trend for peak signal amplitudes to be greater. There was no significant difference in these parameters between the sham group and those with low or intermediate loss of SERTs. The SSRI, fluvoxamine, prolonged clearance of 5-HT in sham, low and intermediate groups, whereas there was no effect of fluvoxamine in those rats with > 90% loss of SERT. Functional loss of SERT activity occurs when destruction of serotonergic innervation is greater than 90% but serotonin clearance and efficacy of fluvoxamine is maintained with as few as one fifth of a full complement of SERTs.

5,7-Dihydroxytryptamine↗

PubMed1993

Serotonin 1B receptors in the developing somatosensory and visual cortices are located on thalamocortical axons.

Serotonin (5-HT)-immunoreactive axons are densely distributed in the primary visual and somatosensory cortices of rats, mice, and hamsters for the first 2 weeks of life, and a recent study from this laboratory has demonstrated that 5-HT1B receptors assume a pattern that exactly matches that of the serotoninergic axons. The differential distribution of these receptors is also transient. In the present study, we combined receptor binding autoradiography with neurochemical ablation of 5-HT axons or electrolytic lesions of the dorsal thalamus in an effort to determine the neural elements upon which the 5-HT1B receptors were located. Subcutaneous injections of the toxin 5,7-dihydroxytryptamine, made on the day of birth, totally eliminated the dense and patterned 5-HT innervation of the somatosensory and striate cortices of rats killed on postnatal day 8 but had no qualitative effect upon the distribution or density of 5-HT1B receptors in either of these cortical regions in animals killed at the same age. Conversely, electrolytic lesions of the dorsal thalamus made on postnatal day 6 resulted in a complete loss of the dense and patterned distribution of 5-HT1B receptors in rats killed on postnatal day 8. These results indicate that thalamocortical axons transiently express 5-HT1B receptors.

5,7-Dihydroxytryptamine↗

PubMed1985

Analysis of pre- and postsynaptic factors of the serotonin system in rabbit retina.

[3H]Serotonin is accumulated by a specific set of amacrine cells in the rabbit retina. These cells also accumulate the neurotoxin, 5,7-dihydroxytryptamine, and show signs of necrosis within 4 h of in vivo exposure to the drug. Biochemical analysis of [3H]serotonin uptake reveal a sodium- and temperature-dependent, high affinity uptake system with a Km of 0.94 microM and Vmax of 1.08 pmol/mg protein/min. [3H]Tryptophan is also accumulated in rabbit retinal homogenates by a high affinity process. Accumulated [3H]serotonin is released in response to potassium-induced depolarization of intact, isolated retinas. In vitro binding studies of rabbit retinal homogenate membranes demonstrate specific sets of binding sites with characteristics of the postsynaptic serotonin receptor. These data strongly suggest that rabbit retina contains virtually all of the molecular components required for a functional serotonergic neurotransmitter system. The only significant difference between the serotonin system in rabbit retina and that in the well-established serotonin transmitter systems in nonmammalin retinas and in brains of most species is the relatively low concentration of endogenous serotonin in rabbit retinas, as demonstrated by high-performance liquid chromatography, histofluorescence, or immunocytochemistry.

5,7-Dihydroxytryptamine↗

PubMedDate not supplied

Effects of a methanolic extract and a hyperforin-enriched CO2 extract of Hypericum perforatum on alcohol intake in rats.

Hypericum perforatum extracts (HPE) inhibit ethanol intake in rats. Hypericin and hyperforin have been proposed as major active principles of HPE. The present study compared the effect on ethanol intake in alcohol-preferring rats of two Hypericum perforatum extracts: a methanolic extract containing 0.3% hypericin and 3.8% hyperforin (HPE1) and a CO2 extract (HPE2) with 24.33% hyperforin and very low hypericin content. Freely feeding and drinking rats were offered 10% ethanol 2 h/day and HPE were given intragastrically 1 h before access to ethanol. Both extracts dose-dependently reduced ethanol intake, HPE2 being about eight times more potent than HPE1. Food and water intakes were not affected by doses that reduced ethanol intake. HPE2, unlike HPE1, reduced blood-alcohol levels (BAL) at doses of > or = 31.2 mg/kg, whereas the dose of 15.6 mg/kg, which reduced ethanol intake, did not significantly modify BAL; blood-acetaldehyde levels were never increased. As previously observed for HPE1, intracerebroventricular pretreatment with 5,7-dihydroxytryptamine (150 microg/rat) did not affect attenuation of ethanol intake induced by HPE2, but reduced its effect in the forced swimming test (FST). Intraperitoneal pretreatment with the sigma-1 receptor antagonist NE-100 (0.25 mg/kg) did not affect inhibition of ethanol intake induced by HPE1 (250 mg/kg) or HPE2 (125 mg/kg), but abolished the effect of both extracts in the FST. In conclusion, the present results indicate that HPE2 inhibits ethanol intake more potently than HPE1; the higher potency of HPE2 parallels the hyperforin content, suggesting that hyperforin may have an important role in reducing ethanol intake. Moreover, different neurochemical mechanisms are apparently responsible for the reduction of ethanol intake and for the antidepressant-like effect of HPE.

5,7-Dihydroxytryptamine↗

PubMed2003

Effects of 5,7-dihydroxytriptamine (5,7-DHT) on circadian locomotor activity of the blow fly, Calliphora vicina.

The biogenic amine serotonin (5-HT) is a neuromodulator in both vertebrates and invertebrates. It has been shown that serotonin, apart from its distinct effects on behavior, also plays a morphoregulatory role during the ontogeny of the insect's nervous system. The role of serotonin in modulating circadian locomotor activity of the blow fly, Calliphora vicina was explored. Injection of a specific neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the hemolymph appeared to significantly reduced the level of locomotor activity and lengthened the period (tau) of circadian rhythmicity. After drug injection in constant darkness flies continued with their free-running rhythm of a locomotor activity, depending on the time of 5,7-DHT injection. This compound causes phase delay when administered in the early subjective day, and phase advance in the late subjective day. This effect is the opposite of the phase response curve obtained for 5-HT injections. This suggests that 5-HT might act as an entraining agent via the output pathway by feedback to clock neurons in the brain. Some of the injected insects regained their normal level of activity after a few days. These findings suggest a potential role for serotonin as modulator of circadian rhythms in insect including regulation of the level of locomotor activity.

5,7-Dihydroxytryptamine↗

PubMed1998

Alteration of central serotonin modifies onset and severity of adjuvant-induced arthritis in the rat.

OBJECTIVE: Previous studies have determined that depletion of serotonin reduces the severity of hind-paw inflammation in adjuvant-induced arthritis (AA) in the rat. We wished to (i) test the hypothesis that this effect may be mediated, at least in part, through a central mechanism and (ii) to investigate further the pro-inflammatory role of serotonin we determined whether increasing serotonin using a selective serotonin reuptake inhibitor (SSRI), to increase serotonin availability at the active site of release, would increase inflammation. METHODS: (i) Serotonin was depleted in the brain of rats with the selective neurotoxin 5'7'-dihydroxytryptamine. (ii) Rats were treated with an SSRI on days 10, 11 and 12 following adjuvant injection. Hind-paw inflammation was determined with plethysmometry as an index of severity of inflammation, and brain, pituitaries and blood were collected for assessment of changes in the hypothalamo -pituitary adrenal (HPA) axis. RESULTS: (i) Serotonin depletion significantly reduced hind-paw inflammation. (ii) SSRI-treated animals developed hind-paw inflammation sooner, and the severity was increased compared to vehicle-treated AA rats. The changes in the HPA axis associated with inflammation were partly reversed by this treatment. CONCLUSION: These data suggest a pro-inflammatory role for central serotonin in this disease model and indicate that treatment with SSRIs may exacerbate the development of inflammation.

5,7-Dihydroxytryptamine↗

PubMed2001

Modulations of spinal serotonin activity affect the development of morphine tolerance.

To test whether modulations of spinal serotonin (5-HT) levels would affect the development of morphine tolerance, we treated rats with either intrathecal 5-HT or 5,7-dihydroxytryptamine (5,7-DHT; a 5-HT neurotoxin) in addition to systemic infusion with morphine (2 mg x kg(-1) x h(-1)). Continuous infusion of 5-HT (10 microg x 6 microL(-1) x h(-1)) into the lumbar subarachnoid space of rats for 9 h accelerated the development of morphine tolerance. The area under the curve for the tail-flick latency test was 454.1 +/- 35.1 in the Sham Control group vs 327.6 +/- 41.0 in the 5-HT-Infused group. mu-opioid receptor binding in the lumbar spinal cord showed a decrease in the Bmax (maximal binding -46.5%), but not the binding affinity (Kd), in 5-HT-infused rats. However, intrathecal injection of 5,7-DHT (50 microg), which resulted in a 48% reduction in 5-HT and 51% reduction in 5-hydroxyindoleacetic acid concentrations, led to an attenuation of morphine tolerance (the area under the curve was 613.0 +/- 24.7 in the 5,7-DHT-Lesioned group). The binding study indicated that the affinity of lumbar micro-opioid receptors decreased 196% in 5-HT-depleted rats, whereas there was no effect on apparent binding. The infusion of 5-HT (10 microg x 6 microL(-1) x h(-1)) was not analgesic and the 5,7-DHT-induced lesion did not affect acute morphine-induced analgesia. We conclude that activity of spinal 5-HT-containing neurons plays a crucial role during the development of morphine tolerance.

5,7-Dihydroxytryptamine↗

PubMed1992

5,7-DHT facilitated lordosis: effects of 5-HT agonists.

The role of 5-HT (serotonin) in regulating lordosis was investigated by combining peripheral administration of the 5-HT agonists 8-OH-DPAT (8-hydroxy-2-[di-N-propylamino]tetralin) or TFMPP (1-[m-trifluoromethylphenyl]piperazine), with intrahypothalamic application of the 5-HT neurotoxin 5,7-DHT (5,7-dihydroxytryptamine). The 5-HT1A agonist, 8-OH-DPAT, significantly inhibited lordosis in 5,7-DHT-treated and non-treated rats. TFMPP, an agonist at 5-HT1B and 5-HT1C receptors, significantly facilitated lordosis in 5,7-DHT-treated and non-treated rats. Our results show that both inhibitory and facilitatory influences of hypothalamic 5-HT on lordosis, are modulated via postsynaptic receptors.

5,7-Dihydroxytryptamine↗

PubMed1992

Effects of paroxetine on 5-HT-induced head twitches and phosphatidylinositol hydrolysis in mice.

Head-twitch response and phosphatidylinositol (PIP) hydrolysis in cortex and spinal cord were measured after single or chronic (21 days) administration of paroxetine to normal mice or to mice neonatally treated with 5,7-dihydroxytryptamine, a serotonergic neurotoxin. In normal animals, a down-regulation of 5-HT-receptor numbers after chronic paroxetine was suggested by the attenuation of head-twitch responses compared with a single dose. There was a concomitant decrease in PIP hydrolysis. In DHT-treated animals, although changes in behavioural responses were comparable to those in normals, PIP hydrolysis in cortex and spinal cord after chronic paroxetine increased significantly. These results demonstrate that head-twitch responses and PIP hydrolysis may not be mediated by the same receptor and that the effects of chronic administration of paroxetine depend on the functional state of the serotonergic pathways.

5,7-Dihydroxytryptamine↗

PubMed1996

Fetal raphe transplants reduce seizure severity in serotonin-depleted GEPRs.

This study investigated whether transplantation of fetal raphe tissue into genetically epilepsy-prone rats (GEPR-3s) would reduce the severity of seizures previously exacerbated by depletion of brain serotonin. Mild-seizure GEPR-3s were depleted of brain serotonin by 5,7-dihydroxytryptamine (DHT) and evaluated for seizure severity. Rats then received 15-day fetal raphe tissue, fetal neocortical tissue or were sham grafted. GEPR-3s treated with 5,7-DHT showed increased seizure severity following depletion of serotonin and subsequent reductions in severity as a result of fetal raphe transplantation. Sham- or neocortex-grafted rats maintained elevated seizure severity scores throughout the study. Prominent raphe or cortical grafts were observed within the third ventricle of GEPRs at autopsy. These findings show that transplantation of fetal raphe tissue promotes lasting reductions in increased seizure severity resulting from depletion of serotonin in the GEPR brain.

5,7-Dihydroxytryptamine↗

PubMed1997

Neonatal serotonin depletion modifies development but not plasticity in rat barrel cortex.

Effects of serotonin depletion (induced by neonatal injection of 5,7-dihydroxytryptamine) upon dimensions of cortical barrels and their metabolic activation, and upon effects of neonatal vibrissectomy sparing row C, were examined in 1-month-old rats. Dimensions of row C barrels, and of [14C]2-deoxyglucose (2-DG) labelling in the cortex obtained after stimulation of the row C vibrissae, were measured. Serotonin depletion did not change dimensions of barrels, but reduced the extent of 2-DG labelling of cortical representation of the row C whiskers by 30%. Vibrissectomy sparing this row resulted in an expansion of the row C barrels and of 2-DG labelling in the barrel cortex that were similar in both control and serotonin-depleted rats.

5,7-Dihydroxytryptamine↗

PubMed1998

Role of serotonin in the amygdala in hypothalamo-pituitary-adrenocortical responses.

In view of the fact that the amygdala (AMG) and hypothalamic serotonin (5-HT) have an excitatory effect on the hypothalamo-pituitary-adrenal (HPA) axis, we have investigated the role of 5-HT in the AMG on this response. In intact freely moving rats, a mildly stressing short photic stimulation caused depletion of median eminence CRH-41, due to its release into the portal circulation and a rise in serum ACTH and corticosterone levels. This effect was significantly inhibited in rats in which 5-HT was depleted in the AMG following local 5,7-dihydroxytryptamine administration, which did not affect hypothalamic 5-HT content. Also, local pretreatment with ketanserin (a 5-HT2 receptor antagonist) in the AMG had the same inhibitory effect on the HPA axis response. These results indicate that AMG 5-HT has an important role in the activation of the HPA axis following neural stimulation and that 5-HT2 receptors are involved.

5,7-Dihydroxytryptamine↗

PubMed1999

Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats.

The effect of L-dihydroxyphenylalanine (L-DOPA) on extracellular dopamine (DA) in the striatum was determined by microdialysis in 6-hydroxydopamine (6-OHDA)-lesioned rats treated with and without the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At the same time the intensity of L-DOPA-induced rotational behavior was assessed. In 6-OHDA-lesioned rats treated with 5,7-DHT, L-DOPA (50 mg/kg, i.p.) increased extracellular DA only to 20% of that measured in animals not treated with 5,7-DHT. Likewise, 6-OHDA-lesioned rats treated with 5,7-DHT exhibited a significantly lower number of L-DOPA-induced rotations. These results suggest that serotonergic terminals in the striatum can convert exogenously administered L-DOPA into DA that can be released into the extracellular space.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

The central hypotensive effect induced by methionin-enkephalin involves a serotonergic pathway.

Both endogenous opiate peptides and serotonin are known to be involved in blood pressure control. In this work we present results obtained in anaesthetized normotensive rats in which we studied the possible interaction between the central blood pressure effects induced by methionin (met)-enkephalin and serotonergic pathways. Met-enkephalin administered intracerebroventricularly produced a dose-dependent hypotensive action that was prevented by pretreating the animals with naloxone (opioid antagonist), or with methiothepin (serotonergic S1 and S2 receptor antagonist) or 5,7-dihydroxytryptamine (a serotonergic neurotoxin). In contrast, ritanserin, a serotonergic S2 receptor antagonist, failed to alter the hypotensive action of met-enkephalin. These data suggest that the central activation of opiate receptors induces a hypotensive action in which a serotonergic pathway is required. In this case the serotonergic receptor involved seems to belong to the S1 subtype.

5,7-Dihydroxytryptamine↗