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PubMed1994

Thyrotropin-releasing hormone reverses the supersensitively depressed monosynaptic transmission by serotonin in 5,7-dihydroxytryptamine-treated neonatal rats in vitro.

The interaction of serotonin and thyrotropin-releasing hormone (TRH) on monosynaptic reflex (MSR) in isolated neonatal spinal cords was examined. Superfusion of serotonin (1-30 microM) in untreated cords, depressed the MSR in a dose-dependent manner. The depression was about 25% at 10 microM of serotonin, in either control or vehicle-treated groups. While for the same concentration of serotonin, the depression was 97 +/- 2.1% of the control in cords from 5,7 dihydroxytryptamine (5,7-DHT)-treated animals. The inhibition of the reflex seen in cords obtained from 5,7-DHT-treated animals could not be reversed by washing with normal physiological solution (> 60 min) or in presence of serotonin antagonists. TRH (0.03-1.0 microM) reversed the depression in a concentration-dependent manner and complete reversal could be seen with 1 microM of TRH. These observations indicate that, serotonin and TRH act dissimilarly on the spinal synaptic transmission though they are known to coexist in the descending bulbospinal tracts.

5,7-Dihydroxytryptamine↗
PubMed1995

Effects of combined or separate 5,7-dihydroxytryptamine lesions of the dorsal and median raphe nuclei on responding maintained by a DRL 20s schedule of food reinforcement.

Previous studies have shown that long-term 5-hydroxytryptamine (5-HT) depletion induced by combined dorsal and median raphe injections of 5,7-dihydroxytryptamine (5,7-DHT) leads to impairments in the acquisition and performance of behaviour maintained under a differential-reinforcement-of-low-rate (DRL) schedule of reinforcement. The present studies examined the relative importance of dorsal versus median raphe 5-HT projections in mediating these effects by investigating the impact of separate versus combined infusions of 5,7-DHT into these sites on DRL responding. Adult male rats received injections of 3 micrograms 5,7-DHT into both dorsal raphe and median raphe, dorsal raphe only, or median raphe only. Sham-operated controls received vehicle injections. Animals were then trained to respond on a DRL 20s schedule for 36 days. Combined dorsal raphe and median raphe 5,7-DHT infusions depleted striatal and hippocampal 5-HT by > 90%, increased responding, decreased the number of reinforcers earned, lowered the mean inter-response time (IRT), and shifted the frequency distribution of IRTs to the left. Median raphe 5,7-DHT infusions induced similar behavioural effects and reduced hippocampal 5-HT by 64%. Dorsal raphe 5,7-DHT lesions, that depleted striatal 5-HT by 56%, and hippocampal 5-HT by 30%, had no effect on behaviour. In a final experiment it was shown that providing an external cue light to signal food availability, and that removed the need to rely on internal timing processes, resulted in rapid acquisition of responding, and prevented the behavioural deficits in 5,7-DHT-lesioned rats. Following removal of this cue, responding deteriorated, and the 5,7-DHT treated animals performed worse than controls. These results suggest that destruction of 5-HT neurons arising from the median raphe is sufficient to disrupt behaviour maintained by a DRL 20s schedule, and that the behavioural changes observed may involve a deficit in timing.

5,7-Dihydroxytryptamine↗
PubMed1984

Effect of local 5,6-dihydroxytryptamine on the rat olfactory bulb responsiveness during wakefulness and sleep.

This study investigated a possible participation of the centrifugal serotonergic (5-HT) innervation of the olfactory bulb (OB) in the control of the multiunit mitral cell responsiveness in behaving rats. A bilateral injection of 5,6-dihydroxytryptamine solution (5,6-DHT) into the OB induced in this structure an average 70% reduction in the level of endogenous serotonin. Control and treated animals were habituated to eat a single 2 h daily meal. Recording sessions were performed either after a 22 h fasting period or just after the meal. The summated multiunit mitral cell activity and vigilance state parameters were recorded in the absence of and during repeated stimulation by puffs of food odour and isoamyl acetate. The results showed that the 5,6-DHT treatment did not modify significantly previously established centrifugal controls exerted at the OB level: (1) the selective enhancement of the mitral cell responsiveness to food odour occurring in waking food-deprived animals; (2) the inhibition of the olfactory input during slow wave sleep. However, the considered 5-HT projections could mediate some inhibitory influence on mitral cell activity during wakefulness only. Finally, the 5-HT innervation of the OB did not seem to be involved in basic mechanisms of olfactory recognition.

5,6-Dihydroxytryptamine↗
PubMed1979

Correlation between the increase in tyrosine hydroxylase activity and the decrease in serotonin content in the rat locus coeruleus after 5,6-dihydroxytryptamine.

A correlation is demonstrated between the increase in tyrosine hydroxylase activity and the decrease in serotonin concentration in the rat locus coeruleus after various doses of 5,6-dihydroxytryptamine and gradual protection of serotonin neurons by pretreatment with two serotonin uptake inhibitors: fluoxetine or citalopram.

5,6-Dihydroxytryptamine↗
PubMed1987

Sensitivity of spinal reflexes to TRH and 5-HT in 5,6-dihydroxytryptamine-treated rats.

Destruction of descending serotonergic nerve terminals containing thyrotropin-releasing hormone (TRH) was affected in rats by the intracisternal injection of 5,6-dihydroxytryptamine (5,6-DHT) two weeks before subsequent experiments. Although the level of TRH in the lumbar enlargement was significantly reduced in 5,6-DHT-treated rats, the effects of TRH on the monosynaptic reflex (MSR) and the polysynaptic reflex (PSR) in these rats were no different from those in control rats. MSR inhibition by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) was attenuated by 5,6-DHT treatment although there was no obvious difference in the effects of 5-MeODMT on the PSR between 5,6-DHT-treated and control rats. In 5,6-DHT-treated rats, L-5-hydroxytryptophan (5-HTP) markedly decreased the MSR and increased the PSR although the same doses of 5-HTP did not produce any effects on either the MSR or the PSR in control rats. In control rats, after administration of imipramine or clorgyline, 5-HTP produced effects similar to those observed in 5,6-DHT-treated rats. These results suggest that the supersensitivity to 5-HTP in 5,6-DHT-treated rats is due to a lack of 5-hydroxytryptamine (5-HT) uptake into 5-HT-containing nerve terminals rather than to a change in 5-HT receptors.

5,6-Dihydroxytryptamine↗
PubMed1994

Spinal supersensitivity to 5-HT1, 5-HT2 and 5-HT3 receptor agonists following 5,7-dihydroxytryptamine.

The present study examined functional supersensitivity to 5-hydroxytryptamine (5-HT) and 5-HT ligands selective for 5-HT1, 5-HT2 and 5-HT3 receptors in two tests for nociception following the spinal administration of 5,7-dihydroxytryptamine (5,7-DHT). Intrathecal pretreatment with 5,7-DHT 30-100 micrograms (following desipramine) produced a selective depletion of spinal cord 5-HT levels of > 80% and augmented the antinociceptive action of 5-HT in the tail flick and hot plate tests. The tail flick test was the more sensitive test for expression of this action. Supersensitivity was observed with the 5-HT1 receptor ligands CGS 12066B (7-trifluoromethyl-4-(4-methyl-1-piperazinyl-pyrrolo[1,2-a] quinoxalinedimaleate), RU 24969 (5-methoxy-3-(1,2,4,6-tetrahydro-4-pyridinyl)1H indole succinate), TFMPP (m-trifluoromethylphenyl-piperazine HCl), mCPP (1-(3-chlorophenyl)piperazine dihydrochloride) and 5-Me-ODMT (5-methoxy-N,N-dimethyltryptamine hydrogen oxalate) but not with the 5-HT2 receptor ligand DOI ((+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane HCl) or the 5-HT3 receptor ligand 2-Me-5-HT (2-methyl-5-hydroxytryptamine maleate) in the tail flick test. In the hot plate test, supersensitivity was observed only with 5-Me-ODMT. Intrathecal pretreatment with fluoxetine, a 5-HT uptake inhibitor, potentiated the action of 5-HT but not any of the other 5-HT1 receptor ligands examined. These results indicate that supersensitivity occurs with 5-HT and 5-HT1 receptor ligands but not with 5-HT2 or 5-HT3 receptor ligands. Both the loss of uptake sites and receptor upregulation may contribute to enhanced activity of 5-HT, but for other ligands, only the latter mechanism appears to occur.

5,7-Dihydroxytryptamine↗
PubMed1996

Neither intranigral fluoxetine nor 5,7-dihydroxytryptamine alter audiogenic seizures in genetically epilepsy-prone rats.

Previous studies have shown that widespread depletion of brain 5-hydroxytryptamine (5-HT, serotonin) exacerbates audiogenic seizures in genetically epilepsy-prone rats (GEPRs), while elevations in brain 5-HT attenuate these seizures. However, the location of the central nervous system site(s) at which 5-HT exerts its anticonvulsant action on audiogenic seizures, remains unknown. The substantia nigra has been shown to exert modulatory actions over both brainstem and forebrain driven seizures in normal rats, and receives a rich serotonergic innervation. The present study was designed to determine if 5-HT exerts its modulatory effect on audiogenic seizures by an action in the substantia nigra. Microinfusion of 5,7-dihydroxytryptamine (4 micrograms/0.25 microliter bilateral) into the substantia nigra of GEPRs which display a moderate seizure (GEPR-3s) failed to alter the audiogenic seizure. Consistent with these findings, microinfusions of fluoxetine-HCl into the substantia nigra of severe seizure GEPRs (GEPR-9s) failed to alter any aspect of the audiogenic seizure. This effect was observed when fluoxetine was infused alone, or in combination with systemic administration of 5-hydroxytryptophan (75 mg/kg, i.p.). The present findings argue against a modulatory role of nigral 5-HT on audiogenic seizures in GEPRs.

5,7-Dihydroxytryptamine↗
PubMed1996

Effect of 5,7-dihydroxytryptamine on audiogenic seizures in genetically epilepsy-prone rats.

To further assess the role of 5-HT in the modulation of audiogenic seizures (AGS) in the Genetically Epilepsy-Prone Rat (GEPR), changes in AGS severity after widespread chronic depletion of brain 5-HT by intracerebroventricular administration of 5,7-dihydroxytryptamine (5,7-DHT) were examined in moderate seizure GEPRs (GEPR-3s). Following treatment with 5,7-DHT (150 micrograms/30 microliters), a significant increase in seizure severity was observed at 2, 3 and 4 weeks as compared to vehicle-injected controls. The increase in seizure severity was evidenced by a significant increase in the incidence of tonic convulsions in 5,7-DHT treated animals (53% in treated animals compared to 0% in vehicle treated controls) over the testing period. Interestingly, the latency to wild running was increased in 5,7-DHT treated GEPRs, suggesting that depletion of brain 5-HT may slow initiation of AGS. Neurochemical analysis revealed marked depletion of 5-HT in the cortex (-96%), hippocampus (-94%), thalamus (-80%), hypothalamus (-62%), midbrain (-51%) and pons-medulla (-52%) in animals that received 5,7-DHT. However, no significant reductions in brain norepinephrine content were observed in any of the regions assayed due to the pretreatment of all animals with protriptyline. The present findings lend further support for an inhibitory action of brain 5-HT on audiogenic seizures in GEPRs.

5,7-Dihydroxytryptamine↗
PubMed1983

Changes in nociception after intrathecal administration of 5,6-dihydroxytryptamine in mice.

Intrathecal administration of 5,6-dihydroxytryptamine (5,6-DHT) (5 micrograms) to mice selectively lesioned descending serotonergic pathways, reducing spinal levels of 5-hydroxytryptamine (5-HT) by 80%, without significantly changing the levels of noradrenaline. Increased sensitivity to noxious stimulation, as measured by the tail-flick and hot-plate tests, was observed 2 days after injection of 5,6-DHT. The tail-flick latencies returned to normal on day 6, but were again reduced by administration of the 5-HT receptor blocker metergoline, suggesting that the normalization process involved compensatory mechanisms in the remaining 5-HT system. In the hot-plate test, the latencies both to shaking or kicking of a hindpaw (kick) and to hindpaw lick were recorded, but the time course for the changes of these two responses was found to be different. The latencies to hindpaw lick were normalized within 2 weeks, whereas the hindpaw kick latencies remained reduced throughout the 21 day observation period.

5,6-Dihydroxytryptamine↗
PubMed1984

The effects of lesions produced by 5,7-dihydroxytryptamine on 5-hydroxytryptamine-mediated behaviour induced by amphetamine in large doses in the rat.

The role of 5-hydroxytryptamine (5-HT)-containing terminals in the spinal cord and basal ganglia in behavioural responses induced by amphetamine in large doses have been investigated using the neurotoxin for 5-HT, 5,7-dihydroxytryptamine (5,7-DHT). The effects of pretreatment with 5,7-DHT were also examined using the 5-HT agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). d-Amphetamine (25 mg/kg) induced several classical 5-HT-dependent behavioural responses (head weaving , forepaw treading, hind limb abduction, "wet dog" shakes, Straub tail), together with some classical dopamine (DA)-dependent behaviour and backward locomotion which requires both transmitters. Pretreatment with 5,7-DHT, given into the striatum significantly decreased "wet dog" shakes and virtually abolished backward walking. Pretreatment with 5,7-DHT in the nucleus accumbens or substantia nigra did not significantly alter behaviour. Pretreatment with 5,7-DHT intraspinally did not significantly alter behaviour induced by amphetamine, although a decrease of Straub tail just failed to reach significance (P = 0.056). Similar pretreatment in rats given 5-MeODMT (8 mg/kg) significantly enhanced both Straub tail and tremor but did not alter the other behavioural responses induced by this drug (limb abduction, forepaw treading, head weaving ). The results in general suggest that behavioural responses induced by 5-HT can be classified into 3 groups (a) those requiring striatal 5-HT ("wet dog" shakes and backward locomotion), (b) those requiring spinal 5-HT (Straub tail, tremor) and (c) those requiring neither spinal nor striatal 5-HT (hind limb abduction, head weaving and forepaw treading).

5,7-Dihydroxytryptamine↗
PubMed1985

Changes in nociception after lesions of descending serotonergic pathways induced with 5,6-dihydroxytryptamine. Different effects in the formalin and tail-flick tests.

Intrathecal administration of 5,6-dihydroxytryptamine (5,6-DHT) in mice selectively lesioned descending serotonergic pathways. Nociception was evaluated 3 days after injection of 5,6-DHT using the tail-flick and formalin tests. In the tail-flick test shortened latencies were found in the lesioned animals. In contrast, the initial behavioural response (0-15 min) to formalin was reduced, while the late response (15-40 min) was not altered. Fourteen days after intrathecal administration of 5,6-DHT the changes in nociception, both in the tail-flick and in the formalin test, had returned to the control level. These findings support the contention that the raphe-spinal serotonergic system participates in the tonic regulation of nociception in the spinal cord. Apparently this system tonically inhibits spinal nociceptive reflexes, but tonically enhances the initial behavioural responses to noxious chemical stimulation, as measured with the formalin test.

5,6-Dihydroxytryptamine↗
PubMed1981

The effect of d-lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), pentobarbital and methaqualone on punished responding in control and 5,7-dihydroxytryptamine-treated rats.

The purpose of the present study was to determine the role of central 5-hydroxytryptamine (5-HT) neuronal systems in the effects of d-lysergic acid diethylamide (LSD), 2,5-methoxy-4-methylamphetamine (DOM), pentobarbital (PB) and methaqualone (MQ) on punished responding in rats. Water-deprived rats were trained to drink from a tube that was electrified at intervals (variable interval 21 sec; 0.03 mA current intensity), electrification being signalled by a tone. In daily 10-min control sessions, these animals accepted a relatively constant number of shocks; water consumption was also quite stable. At maximally effective doses PB, and to a lesser extent MQ, produced large (400-600 percent of control) increases in punished responding with little decrease in water intake. Higher doses of these agents produced a significant depression of unpunished responding (water intake). The hallucinogens, on the other hand, produced only moderate (125-175 percent of control) increases in the number of shock received, yet a similar depression of unpunished responding. Selective destruction of 5-HT neurons by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine per se produced little change in the number of shocks received or water consumed in controls sessions. This destruction of 5-HT neurons failed to alter the effects of PB or MQ on punished or unpunished responding. The increase in punished responding produced by the hallucinogens, however, was blocked by this destruction of 5-HT neurons. Furthermore, the capacity of the hallucinogens to decrease water intake was significantly potentiated by the neurotoxin pretreatment. These data demonstrate that the effects of the hallucinogens LSD and DOM on conditioned suppression are quite different from those of PB and MQ, and that this difference may be due to the extent of 5-HT involvement in the effects of these agents.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1983

Time course of changes in nociception after 5,6-dihydroxytryptamine lesions of descending 5-HT pathways.

Intrathecal injection of 5,6-dihydroxytryptamine (5,6-DHT) in rats produced selective lesions of the descending 5-HT pathways. Spinal 5-HT levels gradually fell to less than 10% of controls within 10 days of 5,6-DHT administration with no recovery evident within 4 weeks. The uptake of 14C-5-HT into crude spinal synaptosomes was similarly reduced. The uptake of 3H-NA into spinal synaptosomes was unaffected, as was the uptake of 14C-5-HT and 3H-NA into cortical synaptosomes. Following 5,6-DHT, tail-flick latencies were reduced by 20-30% during the first post-injection week, but returned to control levels during the second week. Intrathecal or systemic administration of the 5-HT receptor antagonist metergoline significantly reduced latencies of normal rats and of 5,6-DHT treated rats tested after the second week when the response was normalized. Metergoline did not, however, further reduce the latencies of lesioned rats during the first post-injection week. It is concluded that functional adaptation involving 5-HT neurotransmission compensated for the selective lesion of descending 5-HT pathways induced by 5,6-DHT.

5,6-Dihydroxytryptamine↗
PubMed1995

Enhanced quinpirole response in rats lesioned neonatally with 5,7-dihydroxytryptamine.

The ontogenic destruction of dopamine (DA) neurons in rat brain is associated with supersensitization of DA D1 receptors. This effect is attenuated when rats are cotreated in ontogeny with the serotonin (5-HT) neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). In an attempt to determine whether 5-HT fibers might have a similar modulatory role on the sensitivity of the DA D2 receptor complex, we pretreated rats with desipramine HCl (20 mg/kg, IP, base), 1 h before the DA neurotoxin, 6-hydroxydopamine (6-OHDA; 134 micrograms ICV, base) and/or 5,7-DHT (75 micrograms ICV) and/or vehicle. At about 3 months after birth dose-effect curves for quinpirole-induced oral activity were constructed for each group of rats. We found that quinpirole, an agonist for the DA D2 receptor complex, produced a dose-related increase in oral activity in all groups of rats. After a 200 micrograms/kg dose of quinpirole HCl, however, neonatal 5,7-DHT-lesioned rats had a peak oral response of 54.4 +/- 5.1 (mean and SEM) vs. 22.6 +/- 4.8 for control rats (p < 0.01). In neonatal 6-OHDA-lesioned rats this dose of quinpirole increased oral activity to 36.8 +/- 5.8 oral movements (p < 0.05 vs. control). In rats lesioned with both 5,7-DHT and 6-OHDA, the oral response was not different from control. The enhanced oral response to quinpirole in 5,7-DHT-lesioned rats was attenuated by spiperone, an antagonist for the DA D2 receptor complex.(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗
PubMed1993

5,7-Dihydroxytryptamine lesions in the fornix-fimbria attenuate latent inhibition.

When animals are preexposed to a stimulus without consequence they are subsequently slower to associate this stimulus with an important event, such as footshock. This retarding effect of stimulus preexposure is called latent inhibition and can be demonstrated in a variety of classical and instrumental paradigms and in a wide range of species, including man. Latent inhibition is disrupted in acute schizophrenics and by amphetamine treatment in both rat and man. The present study investigated the role of hippocampal 5HT terminals in latent inhibition using a conditioned suppression procedure with male Sprague-Dawley rats. Microinjections of 5,7-dihydroxytryptamine in the fornix-fimbria significantly reduced hippocampal indoleamine levels and attenuated latent inhibition of conditioned suppression. This finding supports the hypothesis that the destruction of mesolimbic 5-hydroxytryptamine terminals reduces latent inhibition. This result is discussed in terms of the possible involvement of reduced serotonergic function in schizophrenic attentional disorder. In addition to the predicted lesion effect, biochemical analyses indicated that experimental treatments in the latent inhibition procedure altered neurotransmitter turnover: utilization ratios for 5-hydroxytryptamine and/or dopamine were increased in preexposed relative to nonpreexposed animals in four of the six brain regions sampled.

5,7-Dihydroxytryptamine↗
PubMed1979

5,7-dihydroxytryptamine lesions of dorsal and median raphé nuclei and performance in the social interaction test of anxiety and in a home-cage aggression test.

Micro-injections of the neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus produced a behavioural profile in the social interaction test of anxiety similar to that seen in rats treated chronically with benzodiazepines. Neurotoxin injections into the median raphé nucleus did not produce a profile significantly different from that of the controls. In the control rats and in the rats with lesions of the median raphé nucleus, ACTH1-24 (corticotrophin) significantly reduced active social interactions, whereas it was without effect on the rats with lesions of the dorsal raphé nucleus. In the home-cage intruder test, the median raphé-lesioned rats submitted less to the intruder and stood and jumped on him more often than did the controls. The dorsal raphé-lesioned rats showed significantly fewer interactions of all kinds, compared with control rats when an intruder was placed in their home cages.

5,7-Dihydroxytryptamine↗
PubMed1992

Plasticity and ontogeny of the central 5-HT transporter: effect of neonatal 5,7-dihydroxytryptamine lesions in the rat.

5,7-Dihydroxytryptamine (5,7-DHT) is unique as a serotonin (5-HT) neurotoxin in that i.p. injection of neonatal rats increases concentrations of 5-HT in brainstem while depleting 5-HT in cortex, hippocampus and spinal cord. To study the mechanism of this effect we measured the 5-HT transporter or uptake site, a presynaptic marker, using [3H]paroxetine binding. There were significant regional differences in Bmax of vehicle-injected rats: brainstem, diencephalon > striatum, cortex, spinal cord > hippocampus, cerebellum. There were also regional differences in the ontogeny of bindings sites: at postnatal day 7, [3H]paroxetine sites were 39% of adult levels in cortex compared to 63% in brainstem. Thirty days after 100 mg/kg 5,7-DHT i.p., Bmax of [3H]paroxetine binding was significantly increased in brainstem (+67%) and diencephalon (+136%), whereas it decreased in cortex (-59%), hippocampus (-94%) and spinal cord (-99%), striatum (-41%) and cerebellum (-37%). KD remained unaltered. In dose-response studies (0-200 mg/kg), 50 mg/kg was the threshold dose for Bmax effects and 200 mg/kg was lethal. In weekly time-course studies, changes were apparent 1 week after 5,7-DHT lesions. Binding site increases in diencephalon and brainstem were not maximal until 3 weeks after injection, whereas percent decreases in cortical sites remained unchanged at each week studied. Lesion effects on the ontogeny of [3H]paroxetine binding sites were region-dependent: cortical sites continued to increase with age but spinal sites did not. There was no significant recovery in spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗