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PubMed1987

Paraventricular nucleus serotonin mediates neurally stimulated adrenocortical secretion.

The purpose of this study was to further elucidate the role of serotonin (5-HT) in adrenocortical regulation. The effects of stimulating the frontal cortex and extrahypothalamic limbic structures, on plasma corticosterone (CS) responses, were studied in rats with vehicle or 5,7-dihydroxytryptamine (5,7-DHT) injection into the midbrain raphe nuclei. In another group of rats the neurotoxin was injected locally into the paraventricular nucleus (PVN) in view of its importance in adrenocortical regulation, and the effects of photic and dorsal hippocampal stimulation on plasma CS were studied. 5,7-DHT caused a significant depletion of hypothalamic 5-HT and blocked the rise in plasma CS following the stimulation of the above neural modalities. These studies suggest that the PVN 5-HT mediates the adrenocortical responses following afferent neural stimuli.

5,7-Dihydroxytryptamine↗

PubMed1988

Supranormal levels of serotonin and its metabolite after raphe cell transplantation in serotonin-denervated rat hippocampus.

Transplantation of fetal raphe cells (14 days of gestation) into the adult rat hippocampus, 2 weeks following serotonin (5-HT)-denervation with intracisternal injection of 5,7-dihydroxytryptamine, can restore 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in the hippocampus to far beyond normal values. Transplantation into the unilateral hippocampus produces asymmetrical turning behavior after administration of the 5-HT releasor, p-chloroamphetamine (IP), comparable to the behavior reported for rats with 5-HT denervation of the unilateral hippocampus. The effect is blocked by prior depletion of 5-HT with p-chlorophenylalanine (IP). The asymmetry in 5-HT levels are correlated with the behavioral change. These data indicate that a large amount of 5-HT is released from nerve terminals of transplanted raphe cells, and suggest that the supranormal levels of 5-HT and 5-HIAA after raphe cell transplantation are neurochemical correlates of 5-HT hyper-innervation of the hippocampus which has been reported previously.

5,7-Dihydroxytryptamine↗

PubMed1989

Monoamine depletion does not alter angiotensin II binding sites in the rat brain.

6-Hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT) was administered in the lateral cerebral ventricles of rats. These respective treatments caused reductions in norepinephrine (NE) and 5-hydroxytryptamine (5-HT) levels in the hypothalamus-thalamus-septum-midbrain (HTSM; 62% and 44%) and brainstem (57% and 26%), respectively. Catecholamine depletion in 6-OHDA-treated rats resulted in a 55% decrease in the pressor response to ICV Ang II which was not associated with any significant change in the binding of 125I-sarcosine1, isoleucine8 Ang II to Ang II binding sites in the HTSM or brainstem. The radioligand binding was not significantly affected by the 5,7-DHT treatment. These results indicate that brain Ang II binding sites are not predominantly localized on NE- or 5-HT-containing nerve terminals. They do not, however, preclude the existence of a small proportion of Ang II binding sites on these neuronal populations.

5,7-Dihydroxytryptamine↗

PubMed1989

Serotonin involvement during in vitro conditioning of Hermissenda.

To determine if serotonin may be involved in associative conditioning-produced changes in the excitability and photoresponses of Type B photoreceptors, isolated nervous systems were exposed to an in vitro conditioning procedure in the presence or absence of drugs that alter normal serotonergic neurotransmission. Pairings of light and intracellular depolarization of a caudal hair cell (in vitro conditioning) produced a pairing-specific depolarization of Type B photoreceptors that was accompanied by an increase in resting input resistance. Treatment of nervous systems with pharmacological agents which disrupt 5-HT neurotransmission attenuated membrane potential and input resistance changes of Type B photoreceptors. These drugs included serotonin uptake inhibitors (imipramine, fluoxetine), a receptor antagonist (bufotenine), and a neurotoxin (5,7-dihydroxytryptamine; 5, 7-DHT). Yohimbine, an alpha 2-receptor antagonist, was without effect. These results, and those in the accompanying papers, suggest that serotonin modulates Type B photoreceptor excitability during associative conditioning.

5,7-Dihydroxytryptamine↗

PubMedDate not supplied

Involvement of serotonin in mediation of inhibition of substantia nigra neurons by noxious stimuli.

Neuronal activities of the substantia nigra pars compacta (SNC) are known to be inhibited by noxious stimuli. Extracellular recording of spontaneous firing of SNC neurons were made to investigate how such inhibition would be influenced by treatment with 5,7-dihydroxytryptamine (5,7-DHT) or p-chlorophenylalanine (PCPA) or by IV injection of the serotonin antagonist, cyproheptadine. Noxious stimuli were produced by tail pinching (TP) and tail heating (HW). In 5,7-DHT-treated experiment, the inhibition indices were 62.8 +/- 4.4 (TP) and 63.4 +/- 4.6 (HW)% for vehicle-treated control, then the inhibition indices were 26.3 +/- 2.6 (TP) and 27.8 +/- 2.9 (HW)% for 5,7-DHT-treated animals. As to the PCPA-treated experiment, the inhibition indices were 63.1 +/- 2.6 (TP) and 64.8 +/- 2.5 (HW)% for saline control rats, while the inhibition indices were 30.3 +/- 1.6 (TP) and 30.1 +/- 1.6 (HW)% for the PCPA-treated ones. Furthermore, in another observation, the firing rates of SNC neurons were reduced from the saline (control) level by 53.2 +/- 2.12 and 52.1 +/- 2.07% during the application of stimulation of TP and HW, respectively. Following the intravenous injection of cyproheptadine, the firing rates of those were reduced by only 6.71 +/- 1.38 and 4.38 +/- 1.79% for TP and HW, respectively. That is, the TP- and HW-induced inhibition were attenuated about 47% by the injection of cyproheptadine. The results strongly suggested that the serotonergic mechanism would be involved in the mediation of the inhibition of SNC neurons by noxious stimuli.

5,7-Dihydroxytryptamine↗

PubMed1993

The role of serotonergic neurons in intravenous hypertonic saline-induced secretion of vasopressin, oxytocin, and ACTH.

This study tested the effect of brain serotonin (5-HT) depletion on the secretion of oxytocin (OT), vasopressin (VP), and adrenocorticotropin (ACTH) due to an osmotic load. The 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) was used to deplete brain 5-HT. The OT, VP, and ACTH osmotic sensitivity (slope of delta[OT]/delta[Osm]) and the osmotic threshold (X intercept of delta[OT]/delta[Osm]) were evaluated. Depletion of brain 5-HT decreased the OT osmotic sensitivity by > 80% (p < 0.001) without changing the OT osmotic threshold. Brain 5-HT depletion had no effect on the VP osmotic sensitivity and increased the VP osmotic threshold from 287.8 +/- 1.5 to 293.1 +/- 2.0 mOsm/kg (p < 0.05). The plasma ACTH increase due to infusion of hypertonic saline was not affected by brain 5-HT depletion. Brain 5-HT depletion significantly (p < 0.01) decreased the pituitary content of OT and VP by 38 and 32%, respectively, without changing ACTH content. These results provide evidence for a functional role of serotonergic neurons in osmoregulation of plasma and pituitary concentration of OT and VP, but not ACTH.

5,7-Dihydroxytryptamine↗

PubMed1995

Anxiolytic effect of the 5-HT1A compounds 8-hydroxy-2-(di-n-propylamino) tetralin and ipsapirone in the social interaction paradigm: evidence of a presynaptic action.

This study analyses at which site, pre- or postsynaptic, the 5-HT1A ligands--8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ipsapirone--induce their anxiolytic action. The experimental anxiety was assessed in the social interaction test. An anxiolytic action was observed after the systemic administration of 8-OH-DPAT (0.25 and 0.5 mg/kg) and ipsapirone (5 but not 10 mg/kg). In 5,7-dihydroxytryptamine (5,7-DHT, 150 micrograms/10 microliters) lesioned rats the anxiolytic effect of 8-OH-DPAT and ipsapirone was not observed, suggesting a presynaptic action of these drugs. When directly injected into the dorsal raphe nucleus 8-OH-DPAT (0.1 microgram/microliter) and ipsapirone (0.2 microgram/microliter), both compounds produce anxiolytic effects. At same doses, these drugs lacked an effect after their intrahippocampal infusion. All data strongly suggest that both drugs act presynaptically to reduce the anxiety levels in the social interaction paradigm.

5,7-Dihydroxytryptamine↗

PubMed1994

Proposed animal model of attention deficit hyperactivity disorder.

Dopamine (DA) neurons are implicated in the hyperlocomotion of neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of attention deficit hyperactivity disorder (ADHD). Because serotonin (5-HT) neurons mediate some DA agonist effects, we investigated the possible role of 5-HT neurons on locomotor activity. Rats were treated at 3 days after birth with vehicle or 6-OHDA (134 micrograms ICV; desipramine pretreatment, 20 mg/kg IP, 1 h), and at 10 weeks with vehicle or 5,7-dihydroxytryptamine (5,7-DHT; 75 micrograms ICV; pretreatment with desipramine and pargyline, 75 mg/kg IP, 30 min), to destroy DA and/or 5-HT fibers. Intense spontaneous hyperlocomotor activity was produced in rats lesioned with both 6-OHDA and 5,7-DHT. Locomotor time in this group was 550 +/- 17 s in a 600 s session, vs. 127 +/- 13 s in the 6-OHDA group and < 75 s in 5,7-DHT and intact control groups (p < 0.001). Oral activity dose-effect curves established that 5,7-DHT attenuated DA D1 receptor supersensitivity and further sensitized 5-HT2c receptors. Acute treatment with dextroamphetamine (0.25 mg/kg SC) reduced locomotor time in 6-OHDA + 5,7-DHT-lesioned rats to 76 +/- 37 s (p < 0.001). Striatal DA was reduced by 99% and 5-HT was reduced by 30% (vs. 6-OHDA group). Because combined 6-OHDA (to neonates) and 5,7-DHT (to adults) lesions produce intense hyperlocomotion that is attenuated by amphetamine, we propose this as a new animal model of ADHD. The findings suggest that hyperactivity in ADHD may be due to injury or impairment of both DA and 5-HT neurons.

5,7-Dihydroxytryptamine↗

PubMed1994

Does GFAP mRNA and mitochondrial benzodiazepine receptor binding detect serotonergic neuronal degeneration in rat?

Intracerebroventricularly (ICV) injected 5,7-dihydroxytryptamine (5,7-DHT), which reduced by 70-90% forebrain serotonin levels, significantly raised glial fibrillary acidic protein (GFAP) mRNA levels in the hippocampus and nucleus raphe dorsalis 5 days but not 15 days after the lesion. A significant increase of mitochondrial benzodiazepine receptors (MBR), measured by binding autoradiography of 3H-PK 11195, was found in the nucleus raphe dorsalis 5 and 15 days after the ICV 5,7-DHT and also in the hippocampus, ventral tegmental area, and substantia nigra at 15 days. No significant effect was observed in the striatum and cortex for either GFAP mRNA or MBR binding. Unlike the ICV route, bilateral injection of 5,7-DHT into the medial forebrain bundle, which caused a 65-90% reduction of serotonin levels in different forebrain regions, significantly raised GFAP mRNA and MBR binding only at the site of injection with no effect in hippocampus, striatum, and cortex. MBR binding slightly increased in the nucleus raphe dorsalis 15 days after the lesion. High doses of d-fenfluramine (10 mg/kg intraperitoneally twice daily for 4 days) caused 80-90% reduction of serotonin levels 5 days after the last injection but did not change the GFAP mRNA or the MBR binding in any of the brain regions considered. These findings suggest that the effect of 5,7-DHT on microglial and glial markers is probably related to a nonspecific interaction with other neuronal systems besides the serotonin or to direct interaction with glial cells; the use of these parameters for detecting selective degeneration of serotonin axons presents some obvious limitations.

5,7-Dihydroxytryptamine↗

PubMed1996

Hypothalamic serotonin release and raised blood pressure after raphe nuclei stimulation in rats.

Electrical stimulation of dorsal raphe (DR) nuclei, in addition to enhancing serotonin (5-HT) release in the hypothalamus, elicited proportional hypertension and tachycardia in anesthetized rats. This could be mimicked by microinjection of two excitatory amino acids, kainic acid and glutamate, into the DR of rat brain. Intrahypothalamic administration of DOI (a 5-HT2 agonist), but not 8-OH DPAT (a 5-HT1 agonist) or 2-methyl-serotonin (a 5-HT3 agonist), also produced both hypertension and tachycardia in rats. The DR stimulation-induced hypertension, tachycardia, or increased hypothalamic 5-HT release were attenuated by prior destruction of the ascending serotonergic system produced by ICV injection of 5,7-dihydroxytryptamine and by prior blockade of postsynaptic serotonergic receptors produced by intrahypothalamic injection of 5-HT2 antagonists, cyproheptadine and ketanserin. The DOI-induced hypertension and tachycardia were also reduced by prior blockade of 5-HT2 receptors with cyproheptadine or ketanserin. Thus, it appears that DR stimulation activates the 5-HT release in the hypothalamus, then activates the hypothalamic 5-HT2 receptors and results in both hypertension and tachycardia in rats.

5,7-Dihydroxytryptamine↗

PubMed1976

Central serotonergic mechanisms and development of morphine dependence.

The effects of different manipulations of brain serotonin (5-HT) content on the development of morphine dependence were investigated in rats, which were implanted with morphine pellets for 40 days. Serotonin content was decreased by (a) short or long term inhibition of tryptophan hydroxylase with para-chlorophenylalanine (PCPA), (b) by short or long term degeneration of 5-HT containing nerve terminals with 5,6-dihydroxytryptamine or (c) by degeneration of 5-HT containing nerve terminals by lesioning of midbrain raphe nuclei. With all methods used, the frequency of withdrawal jumping was significantly reduced, while other withdrawal signs remained more or less unchanged. Additional administration of 5-HTP to chronically PCPA treated rats did not reverse the PCPA effect. Since chronic reduction of 5-HT level during the whole time of morphine exposure changed withdrawal symptomatology in nearly the same way as did a decrease in 5-HT level during the time of withdrawal only, it is suggested that serotonergic mechanisms are not linked to the basic processes underlying dependence development but that they are only involved in the nervous pathways mediating the expression of some withdrawal signs.

5,6-Dihydroxytryptamine↗

PubMed1991

Activity of hippocampal extract on development of [3H]5-HT high-affinity uptake in dissociated microcultures.

Specific and localized lesions of the 5-HT fibers in the hippocampus induce homotypic collateral sprouting and enhance serotonergic fiber outgrowth from adult neurons and transplanted fetal tissue. In this study, hippocampal extracts were prepared and applied to primary cultures of fetal serotonergic neurons. The effects of plating density and serum additives were examined. The growth of the serotonergic neurons in the rostral brainstem dissociated cultures were estimated by measuring the specific uptake of [3H]5-HT. The results indicate the presence of a trypsin-sensitive factor which is active when prepared fresh at dilutions up to 1/10,000. The factor is higher in hippocampus than cerebellum. Young male tissue contained more activity than either female or aged hippocampus. Although both positive and negative effects are described, higher dilutions of factor (1/1,000) were generally stimulatory in high density cultures while lower dilutions (1/10) were inhibitory in low density cultures. Specific removal of 5-HT hippocampal afferents with fornix-fimbria microinjections of 5,7-dihydroxytryptamine resulted in an initial loss of activity (2 days and 2 weeks) followed by an enhanced activity (2 months) compared to normal hippocampal extract. Several possibilities are discussed as to the identity of the serotonergic growth factor from hippocampal supernatant.

5,7-Dihydroxytryptamine↗

PubMed1996

Effects of the selective 5-HT2A receptor antagonist MDL 100,907 on MDMA-induced locomotor stimulation in rats.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) releases dopamine and serotonin in vivo and stimulates locomotor activity. Previous work demonstrated that MDMA-stimulated dopamine release could be reduced by the selective 5-HT2A receptor antagonist [R-(+)-a- (2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinem ethanol] (MDL 100,907). In the present study MDL 100,907 significantly reduced MDMA-stimulated locomotion without affecting basal levels of locomotion. Other agents with 5-HT2A antagonist activity (ritanserin, clozapine, MDL 28,133A, or methiothepin), as well as agents that block 5-HT1A-(propranolol), D2-(haloperidol), or D1 receptors (SCH 23390) also reduced MDMA-stimulated locomotion. Intraventricularly administered 5,7-dihydroxytryptamine decreased regional 5-HT levels and attenuated MDMA-stimulated locomotion. These data support the conclusion that serotonin released onto 5-HT2A receptors contributes to MDMA-stimulated locomotion and suggest that MDMA-stimulated locomotion may be useful as an in vivo behavioral measure of 5-HT2A antagonism. The data also support previous reports of contributions of 5-HT1A, D1 and D2 receptors to MDMA-stimulated locomotion. A preliminary time-course analysis indicating time-dependent contributions of different receptors to MDMA-stimulated locomotion suggests the potential utility of this model for characterizing potential atypical antipsychotic compounds.

5,7-Dihydroxytryptamine↗

PubMed1993

A fast activating presynaptic reuptake current during serotonergic transmission in identified neurons of Hirudo.

An electrogenic serotonin (5-HT) uptake process was characterized in the serotonergic Retzius-P cell synapse of the leech, and the simultaneous activation of this presynaptic reuptake and the postsynaptic response was monitored during evoked transmitter release. A presynaptic, Na(+)-dependent inward current upon application of 5-HT was isolated at membrane potentials between -80 and +60 mV. Its identification as a transmitter uptake current was confirmed by monitoring accumulation of the autofluorescent 5-HT analog 5,7-dihydroxytryptamine during activation of this current. To study the kinetics of 5-HT reuptake in functional synapses, transmitter release was stimulated by flash photolysis of the Ca(2+)-caging DM-nitrophen. The results demonstrate that reuptake activates with a minimal delay of less than a millisecond during synaptic transmission. It acts as a rapid transmitter removal system to determine the time course of the postsynaptic response and monitors the kinetics of transmitter clearance at the synaptic site.

5,7-Dihydroxytryptamine↗

PubMed1991

Use of in situ hybridization to investigate the regulation of hippocampal corticosteroid receptors by monoamines.

The hippocampus receives major noradrenergic and serotoninergic (5-HT) innervations which interact with corticosteroid-sensitive cells. However, the subregional localization of these actions and the corticosteroid receptor types involved have not been defined and current ligand binding techniques for estimating corticosteroid receptors are hampered by several methodological limitations. We have developed in situ hybridization histochemical techniques to allow specific and sensitive estimation of glucocorticoid (GR) and mineralocorticoid receptor (MR) mRNA expression in rat hippocampus. Investigation of the effects of 5,7-dihydroxytryptamine lesions of 5-HT neurons showed significantly reduced GR and MR mRNA expression in some hippocampal subregions. Both abnormal 5-HT neurotransmission and excessive corticosteroid secretion are associated with major affective disorder, particularly depression. The crucial interaction between these two systems may occur, at least in part, at the level of regulation of hippocampal corticosteroid receptor expression.

5,7-Dihydroxytryptamine↗

PubMed2005

Differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not in psychotomimetic drug-induced hyperlocomotion.

While there is abundant evidence for a role of 5-HT and the amygdala in anxiety and depression, the role of 5-HT in this brain region in schizophrenia is less well understood. We therefore examined the effects of local 5-HT depletion in the amygdala on psychotomimetic drug-induced locomotor hyperactivity and prepulse inhibition, two animal model of aspects of schizophrenia. Pentobarbital-anaesthetized (60 mg/kg, i.p.) male Sprague-Dawley rats were stereotaxically micro-injected with 0.5 microl of a 5 microg/mul solution of the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into either the basolateral (BLA) or central nucleus of amygdala (CeN). Two weeks after the surgery, rats with BLA lesions did not show changes in either psychotomimetic drug-induced locomotor hyperactivity or prepulse inhibition. In contrast, rats with CeN lesions showed significant disruption of prepulse inhibition, but no changes in psychotomimetic drug-induced locomotor hyperactivity. Neurochemical analysis and autoradiographic labelling of 5-HT transporter sites showed that a good degree of anatomical selectivity was obtained. Following administration of 5,7-DHT into the amygdala, the concentration of 5-HT was significantly reduced. Similarly, 5-HT transporter autoradiographs showed differential and selective lesions of 5-HT innervation in targeted subregions of the amygdala. These results provide evidence for differential involvement of 5-HT projections within the amygdala in prepulse inhibition but not locomotor hyperactivity. Thus, the present study supports the view that 5-HT in the amygdala may be involved in aspects of schizophrenia and a target for antipsychotic drug action.

5,7-Dihydroxytryptamine↗

PubMed2005

5,7-DHT lesion of the dorsal raphe nuclei impairs object recognition but not affective behavior and corticosterone response to stressor in the rat.

Previous studies with acute tryptophan depletion, leading to transient central 5-HT reductions, showed no effects on affective behavior but impaired object memory. In the present study, the behavioral effects of a 5,7-dihydroxytryptamine (5,7-DHT) lesion in the dorsal raphe were evaluated in animal models of anxiety (open field test), depression (forced swimming test), behavioral inhibition (discrete fixed interval test) and cognition (object recognition task). The corticosterone response to a stress condition was examined at several intervals after 5,7-DHT treatment. The substantial reduction in neuronal 5-HT markers in the dorsal raphe did not affect anxiety-related, depressive-like or impulsive behavior. Compared to the SHAM group, the lesioned rats showed a lower response latency to obtain a reward, indicating a quick and accurate reaction to a stimulus. No differences were found in the progressive ratio test for food motivation. A marked impairment in object recognition was found. The 5,7-DHT treatment did not affect the corticosterone response to a stressful situation. Overall, these results corroborate studies with acute tryptophan depletion suggesting a role of 5-HT in object memory, but not affective behavior.

5,7-Dihydroxytryptamine↗

PubMed2004

Serotonergic modulation of psychological stress-induced alteration in synaptic plasticity in the rat hippocampal CA1 field.

In order to elucidate possible involvement of the serotonergic neuronal system in the stress-induced alteration in synaptic plasticity, the effects of contextual fear conditioning (CFC) on long-term potentiation (LTP) in the hippocampal CA1 field were examined in 5-HT-depleted rats by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, 200 microg/rat, i.c.v.). LTP induction was suppressed by footshock (FS) stimulation in 5-HT-lesioned rats and vehicle-treated controls. When rats were exposed to CFC, which was received 24 h after FS stimulation, LTP was also blocked in both-treated groups. CFC-induced impairment of LTP, however, significantly attenuated in 5-HT-lesioned rats when compared with that in controls. Fear-related freezing behavior after FS stimulation occurred similarly in both treated groups, whereas the behavior observed during exposure to CFC significantly reduced in 5-HT-lesioned rats. These results suggest that the serotonergic mechanism is involved in the psychological stress-induced alteration in synaptic plasticity, which appears to be associated with fear-related behavior.

5,7-Dihydroxytryptamine↗