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PubMed1986

5,7-Dihydroxytryptamine modifies excitability of rat dorsal raphe serotonergic neurons in vitro.

Activity of serotonergic dorsal raphe neurons was recorded intracellularly in a brainstem slice preparation from rats before and after local microperfusion of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). The initial effect of the drug consisted of a transient hyperpolarization. Over 1-2 h after drug application there was a gradual decrease in efficacy of a hyperpolarizing current pulse to evoke a transient rectification. Also, action potentials in some cells failed to evoke a spike after-hyperpolarization. These effects are related to the neurodegenerative action of 5,7-DHT.

5,7-Dihydroxytryptamine↗
PubMed1989

Alterations in serotonin binding sites after 5,7-dihydroxytryptamine treatment in the rat spinal cord.

The 5-HT1B subtype of serotonin (5-HT) receptor regulates the release of 5-HT in the rat spinal cord. In an attempt to confirm the presynaptic location of the 5-HT1B receptor, serotonergic nerves were destroyed neurochemically with 5,7-dihydroxytryptamine (5,7-DHT) administered intrathecally. At 3, 7 and 14 days post 5,7-DHT, competitive radioligand binding assays were performed using 2 nM [3H]5-HT and varying concentrations of trifluoromethylphenylpiperazine (TFMPP), a drug which interacts with 5-HT1B and 5-HT1A binding sites (affinity of 5-HT1B site greater than 5-HT1A site for TFMPP). The decrease in 5-HT1B sites that was expected was not observed at any time following the lesion. However, the binding capacity of the 5-HT1B site, as well as the 5-HT1A site, increased significantly by 7 and 14 days postlesion, respectively. Thus, it appears that an up-regulation of 5-HT1B sites occurred that may have obscured the ability to observe a reduction in a small population of sites located on the serotonergic nerve terminals.

5,7-Dihydroxytryptamine↗
PubMed1983

Effects of 5,7-dihydroxytryptamine on HRP retrograde transport from hippocampus to midbrain raphe nuclei in the rat.

The combination of horseradish peroxidase (HRP) retrograde tracing and specific lesioning using 5,7-dihydroxytryptamine (5,7-DHT) was applied to the midbrain raphe-hippocampal system. Serotonergic fibers from the median raphe nucleus (MRN) of the rat reach the dorsal hippocampus (HIPP) through the cingulum bundle (CB) and the fornix-fimbria (FF). Intracerebral microinjections of 5,7-DHT in these two bundles were made at various times before HRP injections into the dorsal HIPP. After both CB and FF lesion, the number of labeled cells in MRN is reduced to 49.6% at zero time (HRP injected immediately after 5,7-DHT) and to 6.5% after 2 days. There was no significant effect on the number of labeled cells in the locus ceruleus. Selective lesioning of 5-HT fibers in the CB or the FF revealed that raphe-CB-HIPP neurons and raphe-FF-HIPP neurons have a similar distribution pattern in the MRN, but that a dorsal group of neurons at the junction of MRN and dorsal raphe nucleus took the CB route exclusively to innervate the HIPP. The CB pathway was used by more neurons (55% of total number of labeled neurons) than was the FF (21%). An appreciable number of fibers (23%) appear to have branches in both pathways. Our findings are discussed with regard to the recovery of HIPP function seen after long term destruction of 5-HT fibers in the CB.

5,7-Dihydroxytryptamine↗
PubMed1990

The functional significance of neonatal 5,7-dihydroxytryptamine lesions in the rat: response to selective 5-HT1A and 5-HT2,1C agonists.

To study the involvement of serotonin (5-HT) receptor subtypes in behavioral supersensitivity following neonatal 5,7-dihydroxytryptamine (5,7-DHT) lesions, we measured acute behavioral responses to a single dose of selective 5-HT1A (8-OH-DPAT) or 5-HT2,1C (DOI) agonist compared to 5-hydroxytryptophan (5-HTP) in rats injected with 5,7-DHT intraperitoneally or intracisternally 14 weeks earlier. Only intraperitoneal 5,7-DHT injection resulted in brainstem 5-HT hyperinnervation, but cortical 5-HT depletions were also less. Effects of DOI, such as shaking behavior and forepaw myoclonus, were enhanced by 5,7-DHT lesions made intracisternally not intraperitoneally, whereas 8-OH-DPAT-evoked behaviors, such as forepaw myoclonus and head weaving, were enhanced more by the intraperitoneal route. The main consequence of intraperitoneal compared to intracisternal 5,7-DHT injection on supersensitivity to 5-HT agonists was increased presynaptic 5-HT1A responses and decreased 5-HT2,1C responses. In contrast, 5-HTP evoked more shaking behavior and less of the serotonin syndrome with the intraperitoneal compared to the intracisternal route of 5,7-DHT injection. Behavioral supersensitivity to 5-HTP, which was attributable to 5-HT1A, 5-HT2,1C, and possibly to other 5-HT receptors, was orders of magnitude greater than that elicited by direct receptor agonists and more clearly differentiated between rats with 5,7-DHT lesions and their controls, and between routes of 5,7-DHT injections, than responses to 5-HT agonists at the dose studied. 5,7-DHT induced dysregulation of 5-HT receptors, including both presynaptic and postsynaptic changes and altered interactions between receptor subtypes, better explains these data than postsynaptic changes alone.

5,7-Dihydroxytryptamine↗
PubMed1990

Regional central serotonin-2 receptor binding and phosphoinositide turnover in rats with 5,7-dihydroxytryptamine lesions.

"Denervation supersensitivity" of serotonin (5-HT) receptors has been proposed to explain the behavioral supersensitivity to 5-hydroxytryptophan (5-HTP) which develops after lesions of indoleamine neurons with 5,7-dihydroxytryptamine (5,7-DHT). To examine the possible role of receptor recognition sites and second messenger activity in supersensitivity, we measured regional 5-HT2 receptor ligand binding and 5-HT-stimulated phosphoinositide turnover in adult rats with 5,7-DHT lesions made by intracisternal injection and their saline-treated controls. In [3H]ketanserin binding studies of fresh brain tissue two weeks after 5,7-DHT injection, there were no significant changes in frontal cortex, brainstem, or spinal cord in Bmax, Kd, or nH of 5-HT2 receptors, 5,7-DHT lesions did not affect basal levels of [3H]inositol phosphate (IP) accumulation but significantly increased 5-HT-stimulated [3H]IP accumulation in the brainstem (+27%) and cortex (+23%). Because brainstem rather than cortex is involved in 5-HTP-evoked myoclonus, increased 5-HT-stimulated phosphoinositide hydrolysis in brainstem following 5,7-DHT lesions in the rat may be relevant to serotonergic behavioral supersensitivity.

5,7-Dihydroxytryptamine↗
PubMed1990

Autoxidation of the serotonergic neurotoxin 5,7-dihydroxytryptamine.

The indolic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) has been widely speculated to express its neurodegenerative effects as a result of intraneuronol autoxidation. Until recently, it was believed that autoxidation led to reactive electrophilic quinone imine species which alkylated neuronal membrane proteins and that byproducts of the autoxidation reaction were cytotoxic reduced-oxygen species. This study reveals that at physiological pH carbanions of 5,7-DHT act as the primary electron-donor species to yield C(4)- and C(6)-centered free radical superoxide complexes in a 1:2 ratio. The C(4)-centered complex reacts to yield, ultimately, 5-hydroxytryptamine-4,7-dione which has been shown to be a significantly more powerful neurotoxin than 5,7-DHT. The C(6)-centered radical superoxide complexes react to give 6,6'-bis(5-hydroxytryptamine-4,7-dione). It is likely that the latter reaction yields O2.- as a cytotoxic byproduct.

5,7-Dihydroxytryptamine↗
PubMed1988

5,7-Dihydroxytryptamine identifies living dopaminergic neurons in mesencephalic cultures.

The autofluorescent serotonin analogue 5,7-dihydroxytryptamine (5,7-DHT) was used to identify living catecholaminergic neurons in monolayer cultures derived from the embryonic rat mesencephalon. A high correlation between 5,7-DHT accumulation and aldehyde-induced catecholamine fluorescence as well as tyrosine hydroxylase but not dopamine-beta-hydroxylase or phenylethanolamine-N-methyltransferase immunoreactivity was found. This indicates that these cells were dopamine-containing neurons. Whole-cell patch recordings showed that all mesencephalic neurons had resting membrane potentials of -50 mV or greater and input resistances ranging between 200 and 700 M omega and exhibited spontaneous action potentials and postsynaptic potentials. The duration of the action potential of the dopamine-containing neurons was characteristically longer than that of the non-dopamine-containing mesencephalic cells. In some dopamine-containing neurons, repolarization of the action potential was clearly biphasic, and the slow phase of repolarization was reversibly blocked by local application of Cd2+ or Co2+. This "shoulder" in the action potential was never observed in non-dopamine-containing neurons, where Cd2+ or Co2+ application was always without effect. It is concluded that 5,7-DHT can be used to identify living dopamine-containing neurons in dissociated mesencephalic cultures and these neurons express distinct electrical properties.

5,7-Dihydroxytryptamine↗
PubMed1982

Biochemical evidence for alteration of neostriatal dopaminergic function by 5,7-dihydroxytryptamine.

Unilateral injection of 5,7-dihydroxytryptamine (DHT) into the rat neostriatum markedly reduced not only striatal tryptophan hydroxylase (TPH) activity but also striatal tyrosine hydroxylase (TH) activity and dopamine (DA) concentration measured 10--15 days later. The decrease in striatal TH activity was dose related over the range of 8--32 micrograms of DHT; a dose of 16 micrograms reduced striatal TH activity to 40--50% of control, DA concentration to 38% of control, and TPH activity to 5--20% of control. Intrastriatal injection of 16 micrograms of DHT reduced TH activity in the ipsilateral substantia nigra to 51% of control. Pretreatment with amfonelic acid, a potent DA uptake inhibitor, significantly reduced the effect of DHT on striatal and nigral TH activity and striatal DA concentration without affecting the DHT-induced decrease in striatal TPH activity. Desmethylimipramine (5 and 25 mg/kg) had no effect on the DHT-induced decrease in striatal TH activity. Striatal choline acetyltransferase and glutamic acid decarboxylase activities were not decreased by 16 micrograms of DHT. The results indicate that DHT can alter dopaminergic function in the rat neostriatum through a direct effect of the drug on DA neurons.

5,7-Dihydroxytryptamine↗
PubMed1985

Intraventricular 5,7-dihydroxytryptamine increases thyrotropin-releasing hormone content in regions of rat brain.

Rats received intraventricular (i.v.t.) injections of 5,7-dihydroxytryptamine (5,7-DHT) (100-600 micrograms). Some animals also received intraperitoneal injections of the 5-hydroxytryptamine uptake blocker fluoxetine (FX) (20 mg/kg) or the norepinephrine uptake blocker desmethylimipramine (DMI) (48 mg/kg) 30-90 min prior to i.v.t. 5,7-DHT. Rats were killed between 2 and 35 days following i.v.t. 5,7-DHT, brains were dissected, and regions were assayed for thyrotropin-releasing hormone (TRH) by radioimmunoassay. Dose-dependent increases in TRH content following i.v.t. 5,7-DHT were noted in the brainstem and hippocampus. DMI pretreatment blocked the increase in hippocampal TRH, but not in brainstem TRH. FX pretreatment was ineffective in blocking any increases in TRH content. These results suggest differential regulation of regional TRH content by interactions with specific neurotransmitter systems.

5,7-Dihydroxytryptamine↗
PubMed1981

Effect of intracisternal 5,-7-dihydroxytryptamine on the acute antihypertensive action of propranolol in the sino-aortic denervated anaesthetized dog.

1 The anti-hypertensive effects of intravenously and intracisternally administered (+/-)-propranolol were studied in anaesthetized dogs with acute neurogenic (sino-aortic denervation) hypertension. The animals were pretreated 7 days earlier with intracisternally administered 5,7-dihydroxytryptamine (5,7-DHT 200 microgram/kg plus desipramine 5 mg/kg i.v.). 2 5,7-DHT (plus desipramine) failed to decrease both basic blood pressure and heart rate measured before sino-aortic denervation. After 5,7-DHT (plus desipramine) pretreatment, acute sino-aortic denervation induced a rise in blood pressure and stimulated the heart rate, these effects being similar (in intensity and duration) to those observed in control (saline-pre-treated) debuffered dogs during the first hour following the deafferentation. 3 In debuffered dogs, (+/-)-propranolol given by intracisternal (50 microgram/kg) or intravenous (300 microgram/kg) routes decreased both blood pressure and heart rate. 4 5,-DHT (plus desipramine) pretreatment abolished the antihypertensive effect of intracisternal propranolol whereas the action of intravenous propranolol was only delayed. In contrast, this pretreatment failed to reduce and even sometimes enhanced the negative chronotropic response induced by propranolol. 5 These results suggest that central 5-hydroxytryptaminergic pathways play an important role in the acute hypotension elicited by intracisternal (+/-)-propranolol in debuffered hypertensive anaesthetized dogs, but little, if any in propranolol-induced bradycardia.

5,7-Dihydroxytryptamine↗
PubMed1988

Increased behavioural response to intrathecal substance P after intracerebroventricular 5,7-dihydroxytryptamine but not after p-chlorophenylalanine administration.

The behavioural response to intrathecally injected substance P (SP, 1.25 ng) was investigated in mice after lesioning of serotonergic (5-HT) pathways by intracerebroventricular 5,7-dihydroxytryptamine (5,7-DHT, 80 micrograms base/mouse) and after 5-HT synthesis inhibition by p-chlorophenylalanine (PCPA, 400 mg kg-1 for 6 consecutive days). Pretreatment with 5,7-DHT and PCPA reduced the 5-HT level in the spinal cord to 6 and 7% of controls and the noradenaline (NA) level to 69 and 84% of controls, respectively. Intrathecally injected SP produced a response consisting of vigorous biting, licking and scratching of the caudal part of the body. The response to SP was significantly increased 5 days after injection of 5,7-DHT, but only a non-significant tendency towards enhancement of the response was found after 24 h. There was no change in the response to SP 24 h after the last injection of PCPA. It is suggested that 5,7-DHT but not PCPA induces receptor supersensitivity to SP, and that reduction in spinal SP by 5,7-DHT may be a factor in this change in receptor sensitivity.

5,7-Dihydroxytryptamine↗
PubMed1988

Increased behavioural response to intrathecal serotonin after lesion of serotonergic pathways with 5,7-dihydroxytryptamine seems not to be due to depletion of serotonin.

The behavioural response to intrathecal i.th. serotonin (5-HT) was examined in mice pretreated with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) which produce similar extensive depletion of central 5-HT levels. Intrathecal 5-HT (0.4 micrograms) elicited a behavioural response consisting of reciprocal hindlimb scratching and biting or licking of the hindquarters indicative of nociceptive stimulation. The response to i.th. 5-HT was markedly increased 5 days after intracerebroventricular (i.c.v.) injection of 5,7-DHT (80 micrograms base per mouse). On the other hand, 24 h after the last pretreatment injection of PCPA (400 mg kg-1 for 6 consecutive days), the response to i.th. 5-HT was unaltered. These results indicate that i.c.v. 5,7-DHT produces supersensitivity to 5-HT. Since PCPA failed to alter the effect of 5-HT, the supersensitivity seems not to be due to depletion of 5-HT levels after the lesion.

5,7-Dihydroxytryptamine↗
PubMed1989

Intracisternal 5,7-dihydroxytryptamine lesions in neonatal and adult rats: comparison of response to 5-hydroxytryptophan.

There have been few previous studies of the functional significance of 5,7-dihydroxytryptamine (5,7-DHT) lesions made in neonatal rats. To study the role of serotonin (5-HT) in recovery of function, rat pups and adult rats were injected intracisternally with 5,7-DHT or saline and challenged acutely with the 5-HT precursor 5-hydroxytryptophan (5-HTP) 4 weeks later as a test of behavioral supersensitivity. Compared to 5,7-DHT lesions in adults, neonatal lesions induced significantly greater 5-HT depletions in brainstem, but 5-HT depletions in other regions were not significantly different in the two groups. Rats with early 5,7-DHT lesions displayed supersensitive behavioral responses to 5-HTP, consisting of all the component myoclonic-serotonergic behaviors seen in rats with 5,7-DHT lesions made as adults. However, there was significantly less 5-HTP-evoked head weaving, truncal myoclonus and shaking behavior in rats treated with 5,7-DHT as neonates. Body weight was reduced both in rats with early and late 5,7-DHT lesions, but reduction persisted in rats with early lesions. These data indicate overall similarity with some differences between neurochemical and behavioral effects of early and late 5,7-DHT lesions made by the intracisternal route. They suggest that recovery mechanisms did not occur or failed to reverse the neurochemical or behavioral consequences of early 5,7-DHT lesions.

5,7-Dihydroxytryptamine↗
PubMed1982

Developmental changes in serotonin and 5-hydroxyindoleacetic acid concentrations and opiate receptor binding in rat spinal cord following neonatal 5,7-dihydroxytryptamine treatment.

Normal levels of serotonin and 5-hydroxyindoleacetic (5-HIAA) were measured in the developing rat spinal cord and brain stem using HPLC. Serotonin, 5-HIAA and 3H-naloxone binding were monitored following neonatal 5,7-dihydroxytryptamine (5,7-DHT) treatment. Serotonin in the spinal cord develops biphasically with peaks at gestation day 21 (E21) and postnatal day 8 (P8) while 5-HIAA peaks at P3 and between P8 and P11. In the brain stem, serotonin gradually rises from E15 to adult levels which are reached by P32 while 5-HIAA rises sharply to P15 and thereafter decreases to adult levels by P32. 5,7-DHT treatment neonatally causes greater than 50% reduction of serotonin and 5-HIAA in the spinal cord through P32. Opiate receptor binding in the spinal cord is reduced acutely by about 22% and remains slightly depressed into adulthood.

5,7-Dihydroxytryptamine↗
PubMed1981

Reduction of ECS-induced retrograde amnesia of passive avoidance conditioning after 5,7-dihydroxytryptamine median raphe nucleus lesion in the rat.

5,7-Dihydroxytryptamine (5,7-DHT), median raphe nucleus (MRN)-lesioned and sham-lesioned rats were submitted to one-trial passive avoidance conditioning followed by electroconvulsive shock (ECS) or sham-ECS. On test session (24 h later) MRN-lesioned rats presented a longer conditioned response and, chiefly, a remarkable reduction of ECS-induced retrograde amnesia in comparison to sham-lesioned animals. This effect appeared unrelated to major changes in spontaneous behavior: on training session MRN-lesioned rats exhibited a faster stepping-down from the platform; their exploratory activity into a novel cage was characterized by a slightly higher initial response; moreover MRN lesion did not significantly effect pain threshold. A reduced brain 5-HT functional activity following MRN lesion was suggested by the study of the hyperactivity syndrome induced by tranylcypromine plus L-tryptophan. Lastly, MRN-lesioned rats showed a significantly lower brain 5-HT steady level without differing from the sham-lesioned ones with respect to turnover rate. The reduction of ECS-induced retrograde amnesia observed in 5,7-DHT, MRN-lesioned rats was considered as due to a lower synaptic availability of 5-HT at the time of ECS administration.

5,7-Dihydroxytryptamine↗
PubMed1983

Effects of microinjections of 5,7-dihydroxytryptamine in the suprachiasmatic nuclei of the rat on serotonin reuptake and the circadian variation of corticosterone levels.

The role of the 5-hydroxytryptamine (5-HT) terminals in the suprachiasmatic nucleus (SCN) in the production of the circadian variation of corticosterone secretion was investigated by lesioning the 5-HT inputs to the SCN with 5,7-dihydroxytryptamine (5,7-DHT). Vehicle-injected animals showed a normal circadian variation of corticosterone levels. In contrast, the mean corticosterone levels of the 5,7-DHT-lesioned group were intermediate between control peak and trough values, and although the individual rats showed fluctuations, no significant circadian variation was present in the group as a whole. 3H-5-HT reuptake in the SCN was reduced to 38% of the mean control level in the 5,7-DHT-lesioned group, but ventromedial hypothalamic 3H-5-HT reuptake was only decreased to 82% of control. These results indicated that the SCN 5-HT terminals may play an important role in the synchronization of the circadian variation of corticosterone secretion.

5,7-Dihydroxytryptamine↗
PubMed1986

Pre- and postsynaptic localization of 3H-imipramine binding sites: action of 5-7 dihydroxytryptamine and triton X-100 on subcellular fractions of rat brain.

In rats injected intraventricularly with 5-7 dihydroxytryptamine there was a considerable reduction of 5-hydroxytryptamine and 5-hydroxyindol acetic acid content in cerebral cortex and hippocampus. After cell fractionation of these structures, a 37% reduction of 3H-imipramine binding was observed in the crude mitochondrial fraction of the treated rats, that contains the synaptosomes. In purified synaptosomal membranes the reduction was about 20%. Dissolution of the presynaptic membrane with 0.1 and 0.2% Triton X-100 on the treated membranes further reduced 3H-imipramine binding respectively by 25% and 40%, values similar to those obtained on control synaptosomal membranes. These findings were further substantiated using saturation experiments for the high affinity site of 3H-imipramine. The results obtained are discussed in relation to the possible mechanism of action of antidepressant drugs at the synaptic region, and the possible postsynaptic effect is emphasized.

5,7-Dihydroxytryptamine↗
PubMed1999

Melanogenesis from 5-hydroxytryptamine, 5,6- and 5,7-dihydroxytryptamines. An in vitro study using MALDI-TOF.

The role of tyrosinase and peroxidase in melanogenesis of 5-hydroxytryptamine, 5,6- and 5,7-dihydroxytryptamines was investigated by matrix-assisted laser desorption/ionization mass spectrometry. Each enzyme was incubated with the tryptamine derivatives and samples were drawn at various times, ultrafiltered and immediately lyophilized. The results indicated that peroxidase promotes oligomerization of 5-HT with fast kinetics but with yields lower than those achieved by tyrosinase. 5,6- and 5,7-DHT formed low molecular mass oligomers in the presence of peroxidase alone. The addition of hydrogen peroxide evidences different reactivity of the two isomers: 5,6-DHT formed immediately a black precipitate while oligomers of the molecule itself and of its oxidation products were detectable for 5,7-DHT.

5,6-Dihydroxytryptamine↗