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PubMed1980

Chemical lesions of both dorsal and median raphe nuclei and changes in social and aggressive behaviour in rats.

Microinjections of 5,7-dihydroxytryptamine into both the dorsal and median raphe nuclei resulted in 90% depletions of striatal and hippocampal 5-HT concentrations. Compared with vehicle-injected controls the lesioned rats showed reduced active social interaction scores in all four of the test conditions and also reduced levels of locomotor activity. The lesioned rats did not differ from the controls in their latency to start drinking in a novel environment; or in their response to intruder rats placed in their home cages, or in their behaviour as intruders when they were placed in the home-cages of unoperated rats. The difficulties of interpreting the behavioural effects of a lesion when the lesion produces hypoactivity, and the differences between the effects of these joint lesions of both dorsal and median raphe nuclei amd the effects of separate lesions of each nucleus are discussed.

5,7-Dihydroxytryptamine↗

PubMed1980

Effects of 5-hydroxytryptamine on defecation in open-field behavior in rats.

An attempt was made to elucidate the role of the serotonergic nervous sytem in defecation resulting from environmental stimulation in rats. The open-field (OF) test and shuttle box method were used to study the defecation. 5-Hydroxytryptophan (5-HTP) significantly decreased the number of fecal boluses excreted in both emotional situations, namely, in both OF and shuttle box. The fecal excretion was significantly reduced compared with the controls after intraventricular injection of 5-hydroxytryptamine (5-HT). Animals pretreated with p-chlorophenylalanine (pCPA) and 5,6-dihydroxytryptamine (5,6-DHT) tended to show a slight increase in the OF defecation. 5-HTP was equally effective in diminishing the OF performance of pCPA-treated rats. The inhibitory effects of 5-HTP on the defecation were also observed after depletion of biogenic amines by reserpine treatment. Home cage defecation was increased after 5-HTP administration, decreased under pretreatment with pCPA and not influenced by intraventricular injection of 5-HTP. These results suggested that the defecation after environmental stimuli was due to a change in 5-HT levels in the brain.

5,6-Dihydroxytryptamine↗

PubMed1982

Age-dependent reduction in maximum electroshock convulsive threshold associated with decreased concentrations of brain monoamines.

This study investigated modification of the tonic convulsive threshold to maximum electroshock in 15- and 30 day old rats treated with drugs which reduce steady-state concentrations of monoamines. On postnatal day 15, reduction of central catecholamine concentrations by 6-hydroxydopamine or of central serotonin concentrations by 5,7-dihydroxytryptamine or p-chloroamphetamine did not alter the tonic convulsive threshold. However, simultaneous depletion of catecholamines and serotonin by tetrabenazine was associated with a significant decrease in the tonic threshold. This effect could be reversed partially by simultaneous administration of the catecholamine and serotonin precursors, L-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively. On postnatal day 30, reduction of brain serotonin concentration, but not catecholamine concentrations, was associated with a significant decrease of the tonic convulsive threshold. In a previous study, in which 7-8 day old rats were used, a tetrabenazine-induced decrease in the tonic convulsive threshold prevented by L-dihydroxyphenylalanine but not 5-hydroxytryptophan. Furthermore, intracisternal 6-hydroxydopamine, but not 5,7-dihydroxyhyptamine, decreased the threshold on postnatal day 8. Therefore, the results of the present day study involving 15- and 30 day old rats, together with the earlier findings in 7-8 day old rats, [28] suggest an apparent developmental transition from catecholaminergic to serotonergic dominance in regulation of the tonic convulsive threshold during the first postnatal month.

5,7-Dihydroxytryptamine↗

PubMed1983

The involvement of nigral serotonin innervation in the control of punishment-induced behavioral inhibition in rats.

In rats, serotonergic innervation of the substantia nigra plays a role in the control of experimentally-elicited anxiety: punishment-induced inhibition is lessened following bilateral intra-nigral infusion of 5,7-dihydroxytryptamine (2 micrograms; 0.5 microliter). A significant correlation (0.62) is found between the loss of nigral, but not hippocampal, tryptophan hydroxylase activity and the release of behavior in two situations of shock-induced suppression of responding. Likewise, infusion of this neurotoxin (1 microgram; 0.4 microliter) into the nucleus raphé dorsalis causes an attenuation of punishment-induced suppression. These findings suggest an involvement of serotonergic raphé-nigral neurons in experimentally-elicited anxiety.

5,7-Dihydroxytryptamine↗

PubMed1984

Anorexia and brain serotonin: development of tolerance to the effects of fenfluramine and quipazine in rats with serotonin-depleting lesions.

The acute and chronic effects of the "serotonergic anorectics" quipazine and dl-fenfluramine were examined in rats with substantial and specific depletions of brain 5-hydroxytryptamine (5-HT) induced by 5,7-dihydroxytryptamine (5,7-DHT). A "dessert" test which did not involve food deprivation was used to assess anorexia. Markedly increased sensitivity to the L-5-HTP-induced behavioral syndrome in 5,7-DHT-lesioned rats indicated postsynaptic 5-HT receptor supersensitivity. We found low (2 mg/kg) and intermediate (5 mg/kg) doses of fenfluramine, a putative presynaptic agent, were more effective in producing anorexia in lesion rats versus controls. A higher dose of fenfluramine (10 mg/kg) was less effective in lesion rats, suggesting that high dose and low dose fenfluramine anorexia are mediated by different mechanisms. We found quipazine, a putative 5-HT postsynaptic agonist, in a dose range of 2-10 mg/kg, to be no more effective in producing anorexia in lesion rats compared to controls. The development of tolerance to both fenfluramine and quipazine anorexia was similar for lesion and control rats showing that an intact brain 5-HT system is not necessary for tolerance. Tolerance to the "behavioral syndrome" induced by high doses of these agents developed rapidly in controls but not at all in lesion rats. This suggests that the behavioral syndrome and anorexia are independent effects of fenfluramine and quipazine. These results also challenge the popular notion that the primary anorectic action of fenfluramine is via brain serotonin.

5,7-Dihydroxytryptamine↗

PubMed1986

Nicotine-induced convulsions in cats and central nicotinic receptors.

The effects were investigated of intracerebroventricular (ICV) injections in the cat of ganglionic blocking agents, antimuscarinic drugs, alpha and beta adrenergic blocking substances, dopamine antagonists, an antihistamine, reserpine and a 5-hydroxytryptamine antagonist as well as the inhibitors of catecholamines, 5-hydroxytryptamine and acetylcholine synthesis upon convulsions produced by nicotine, which was similarly injected. Mecamylamine and hexamethonium but not atropine, scopolamine, yohimbine, phenoxybenzamine, tolazoline, propranolol, practolol, chlorpromazine, haloperidol, antazoline and methysergide abolished the convulsions evoked by nicotine. Furthermore, reserpine, but not 6-hydroxydopamine, as well as 5,6-dihydroxytryptamine and hemicholinium blocked the convulsions caused by nicotine. It appears, therefore, that the convulsions produced by nicotine are mediated through central nicotinic receptors. However, the depressed catecholaminergic, 5-hydroxytryptaminergic and histaminergic mechanisms induced by reserpine can also suppress the convulsions evoked by nicotine.

5,6-Dihydroxytryptamine↗

PubMed1986

Comparison of motor depressant effects of caerulein and N-propylnorapomorphine in mice.

The motor depressant effects of caerulein and N-propylnorapomorphine (NPA) were compared in male mice. Caerulein (1-50 micrograms/kg SC) in a dose dependent manner depressed the exploratory activity, whereas NPA in lower doses (0.5-10 micrograms/kg SC) decreased the motor activity, but in higher doses (over 50 micrograms/kg) had stimulating effect on the exploratory behavior. In mice selected according to their motor response after administration of 100 micrograms/kg NPA to weak and strong responders, the low dose of NPA (1 microgram/kg) similarly suppressed motor activity in both selected groups, while the effect of caerulein (2 micrograms/kg) was apparently higher in weak responders. Destruction of catecholaminergic terminals by 6-hydroxydopamine (60 micrograms ICV) reversed completely the motor depressant effect of NPA, whereas degeneration of serotoninergic terminals (5,7-dihydroxytryptamine 60 micrograms ICV or p-chloroamphetamine 2 X 15 mg/kg IP) enhanced the sedative effect of NPA. The motor depressant effect of caerulein remained unchanged after lesions of monoaminergic terminals in forebrain. Subchronic haloperidol (0.25 mg/kg IP, twice daily during 14 days) treatment, reducing significantly the density of high-affinity dopamine2- and serotonin2-receptors, decreased the motor depressant action of caerulein. It is possible that motor depressant effect of caerulein, differently from the action of NPA, is mediated through the high-affinity dopamine2-receptors and in lesser extent through the high-affinity serotonin2-receptors.

5,7-Dihydroxytryptamine↗

PubMed1987

Effects of 5-HT receptor subtype-selective drugs on locomotor activity and motor habituation in the DHT adult rat model.

5-Hydroxytryptophan (5-HTP) induces biphasic time and dose dependent effects on locomotor activity (LMA) and motor habituation in rats with 5,7-dihydroxytryptamine (DHT) lesions. To identify the role of serotonin (5-HT) receptors in these responses, we studied the effects of 5-HT2 receptor antagonists on LMA occurring spontaneously and evoked by 5-HTP or putative selective 5-HT agonists in rats injected intracisternally with DHT or vehicle. Motor habituation was assessed by analysis of computer-tabulated 10 minute "bins" during hour long recording. Neuroleptic 5-HT2 antagonists prevented 5-HTP stimulation of LMA in DHT-lesioned rats in the rank order of potency pirenperone greater than pipamperone greater than ketanserin = cinanserin. The non-neuroleptic ritanserin, however, did not reduce LMA stimulated by the 5-HT1B agonist RU24969 but did reverse transient suppression of LMA induced by high dose 5-HTP and by the putative 5-HT2 agonist DOI. RU24969, like 5-HTP, induced a failure of motor habituation which differed from DOI-evoked alteration. 8-OH-DPAT did not affect motor habituation at the dose tested. These data suggest that the 5-HT1B site mediates 5-HTP-evoked locomotor hyperactivity in the DHT model, that the 5-HT2 site participates in the transient hypoactivity seen with high doses of 5-HTP, and that 5-HT1 and 5-HT2 sites may be functionally linked. Both sites differentially influence motor habituation, which appears to be under complex regulation. Bin analysis is a sensitive index of these habituation effects.

5,7-Dihydroxytryptamine↗

PubMed1987

Evidence against serotonin involvement in the hyperactivity produced by injections of muscimol into the median raphe nucleus.

Microinjections of muscimol into the median raphe nucleus were found to result in pronounced hyperactivity which could not be attenuated by the serotonin depletion produced either by systemic treatment with p-chlorophenylalanine or by intra-raphe injections of 5,7-dihydroxytryptamine. Furthermore, hyperactivity could not be produced by intra-median raphe injections of serotonin or of fenfluramine, compounds which would be expected to inhibit serotonergic raphe cells. These results argue strongly against an essential involvement of serotonin in mediating the effects of intra-median raphe muscimol injections. Muscimol failed to produce hyperactivity, however, when injected into rats who had previously received an electrolytic median raphe lesion. This finding suggests that muscimol injected into the median raphe produces hyperactivity as a result of an action on local cell bodies, rather than by diffusion to a distant site. The simplest explanation of the current results is that muscimol injected into the median raphe produces hyperactivity as a result of an inhibition of nonserotonergic cells within the median raphe nucleus.

5,7-Dihydroxytryptamine↗

PubMed1988

The relative contribution of ascending and descending serotonergic pathways in p-chloroamphetamine-induced antinociception.

Systemic administration in rats of p-chloroamphetamine (PCA; 2 x 10 mg/kg) reduced the in vitro uptake of 14C-5-hydroxytryptamine (14C-5-HT) in cortical synaptosomes by 76% and in spinal cord synaptosomes by 35%. Intrathecal injection of 5,6-dihydroxytryptamine (20 micrograms/rat) selectively lesioned the descending serotonergic pathways (83% reduction in uptake of 14C-5-HT in spinal synaptosomes, no significant change in uptake in cortical synaptosomes). Administration of PCA or 5,6-DHT did not significantly alter the uptake of 3H-noradrenalin into cortical or spinal synaptosomes. The response thresholds of the rats in the increasing temperature hot plate test (1 to 7 days after administration) were unaffected by either type of lesion. Interference with the antinociceptive effect of PCA (2.5 mg/kg) was evaluated 7 days after administration of the neurotoxins. PCA pretreatment strongly reduced the peak of the PCA-induced antinociception while 5,6-DHT reduced its duration. Thus, both ascending and descending serotonergic pathways contribute to PCA-induced antinociception.

5,6-Dihydroxytryptamine↗

PubMed1990

Behavioral reactivity following 5-MeODMT administration in 5,7-DHT-pretreated killer rats.

Grouped, nonkiller and killer animals were centrally injected either with vehicle or with 5,7-dihydroxytryptamine. After a period of 7-10 days, forepaw treading and hindlimb abduction were induced by 5-MeODMT administration in all sham and lesioned rats. As expected, behavioral supersensitivity was observed in grouped and nonkiller lesioned rats. A reduced increase in 5-MeODMT-induced behaviors was obtained in killer lesioned animals. 5-HT uptake studies showed a comparable reduction of 5-HT uptake within all the lesioned rats. This evidence suggests an altered capacity to promote adaptive changes on 5-HT sites in killer rats following the destruction of central serotonergic fibers.

5,7-Dihydroxytryptamine↗

PubMed1991

Alcohol drinking attenuated by sertraline in rats with 6-OHDA or 5,7-DHT lesions of N. accumbens: a caloric response?

The purpose of this study was to elucidate further the role of serotonin (5-HT) in the preference for ethyl alcohol induced in the Sprague-Dawley rat by lesions of the N. accumbens. Following a standard preference test for 3-30% alcohol, dopaminergic or serotonergic neurons in the N. accumbens of the rat were lesioned bilaterally by 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT), respectively. After recovery postoperatively, each rat was offered water and its maximally preferred concentration of alcohol, which ranged from 7% to 11%. Following a 4-day pretest, either the saline control vehicle or the 5-HT reuptake inhibitor, sertraline, was injected subcutaneously in a dose of either 3.0 or 10 mg/kg b.i.d. at 0800 and 2000 h over the next 3 days. Alcohol preference during the injection sequence and for 4 days thereafter was significantly reduced by sertraline in terms of both absolute g/kg and proportion of alcohol to water intakes. Saline was without effect on alcohol drinking. Comparisons of the drinking profiles of serotonergic versus dopaminergic lesioned rats revealed a dose dependent response to sertraline only in the 5,7-DHT lesioned animals. Although sertraline did not alter water drinking, the consumption of food declined significantly during and after its administration with a decline in body weight also observed at the higher dose. These results suggest that in addition to dopaminergic neurons in the N. accumbens, the synaptic activity of 5-HT in this structure contributes to the aberrant drinking of alcohol. However, this interpretation is tempered by the fact that caloric intake was suppressed concomitantly by the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Naphthylamine↗

PubMed1991

Muscimol injections into the median raphe nucleus increase serum ACTH and corticosterone concentrations via a nonserotonergic mechanism.

Midbrain raphe serotonin (5-HT) neurons can influence the pituitary-adrenal axis. The midbrain raphe nuclei also contain a number of non-5-HT neurons, including gamma-aminobutyric acid (GABA) interneurons which can modulate 5-HT neuronal activity. We investigated the effects of intraraphe injections of the GABAA agonist, muscimol, on serum adrenocorticotropin hormone (ACTH) and corticosterone concentrations. Rats were infused with muscimol (0, 25, 50, and 100 ng in 0.5 microliters saline) into the median raphe nucleus (MR). The animals were killed 30 min later, and trunk blood was collected for measurement of serum concentrations of ACTH and corticosterone by radioimmunoassay. Muscimol dose dependently increased plasma concentrations of these two pituitary-adrenal hormones. In order to determine the role of MR 5-HT neurons in these effects, separate groups of implanted animals were infused with either the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) or ascorbic acid vehicle into the MR. Two weeks later, the animals were infused with muscimol (100 ng in 0.5 microliters) and sacrificed as above. Treatment with 5,7-DHT, which markedly reduced hippocampal concentrations of 5-HT (-83%) and 5-HIAA (-73%), did not block intra-MR muscimol-induced elevations in ACTH and corticosterone. Thus, 5-HT neurons within the MR apparently do not mediate the increased activity of the pituitary-adrenal axis produced by stimulation of MR GABAA receptors.

5,7-Dihydroxytryptamine↗

PubMed1991

Differential role of serotonin and noradrenaline on anxiety reduction after ejaculation in the rat.

As previously reported, a reduction in anxiety after ejaculation was observed. In a previous report it was demonstrated that the GABA-benzodiazepine system is involved in the mediation of this reduction in anxiety. The anxiety levels were measured using a defensive burying model. This work was performed to elucidate the serotonin and noradrenaline participation in the mediation of this phenomenon. Two experiments were made. In the first experiment the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT, 10 micrograms/10 microliters) was intracerebroventricularly injected. Five days after its administration the behavioral tests were performed. In the second experiment, the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4, 50 mg/kg X 2) was IP administered. The neurochemical data reveal a drastic reduction in various brain areas respective monoamine levels after these treatments. The lesion produced by 5,7-DHT was able to reverse the reduction in anxiety in copulating males, but produced no changes in noncopulating animals. This finding supports the idea that the serotonergic system is involved in the reduction of anxiety observed after ejaculation. The results of the DSP4 experiment suggest that there is not a direct participation of the noradrenergic system in the anxiety reduction observed after ejaculation.

5,7-Dihydroxytryptamine↗

PubMed1991

Postsynaptic 5-HT1 receptors and offensive aggression in rats: a combined behavioural and autoradiographic study with eltoprazine.

The present study was designed to assess whether the antiaggressive effects of eltoprazine are mediated via presynaptic and/or postsynaptic 5-HT1 receptors. We describe the effects of central 5-HT depletion 1) on the behaviour of resident TMD-S3 rats in a territorial situation, 2) on the efficacy of eltoprazine to inhibit offensive aggression, and 3) on the 5-HT1A, 5-HT1B and 5-HT1C receptor binding in brains of rats previously used in behavioural studies. Male resident rats were given combined 5,7-dihydroxytryptamine (5,7-DHT) injections into the dorsal and median raphe nuclei. Two to four weeks after the lesions, rats were confronted with an intruder Wiser rat in their home cage for a 10-min period. The 5,7-DHT treatment resulted in a modest reduction of offensive behaviour, while having no effects on other social and nonsocial behaviours. Oral administration of eltoprazine (1 mg/kg) specifically reduced offensive aggression in both sham- and 5,7-DHT-lesioned animals, leaving social interest and exploration intact or even increasing it. A low dose (0.3 mg/kg) of eltoprazine did not affect the behavioural repertoire of sham-operated rats, whereas this dose significantly reduced offense behaviours in the 5,7-DHT-lesioned residents. Quantitative autoradiographic studies 5 weeks after 5,7-DHT treatment revealed a significant increase in radioligand binding to 5-HT1A, 5-HT1B and 5-HT1C sites in many brain regions studied, except for the raphe nuclei where [3H]8-OH-DPAT binding to 5-HT1A sites was markedly reduced. The concentrations of 5-HT and 5-HIAA in frontal cortex were reduced to approximately 10% of controls. The results indicate that serotonin has a stimulatory rather than an inhibitory influence on offensive aggressive behaviour. Central 5-HT depletion does not prevent the antiaggressive effects of eltoprazine, indicating a role for postsynaptic 5-HT1 receptors in the modulation of offensive aggression. The 5,7-DHT-induced overall upregulation of 5-HT1A, 5-HT1B and 5-HT1C binding sites suggests that these three receptor subtypes receive a tonic serotonergic influence. It is conceivable that this postsynaptic 5-HT1 receptor supersensitivity is reflected by the increased efficacy of eltoprazine to inhibit offensive aggression.

5,7-Dihydroxytryptamine↗

PubMed1992

Cocaine-induced suppression of renin secretion is partially mediated by serotonergic mechanisms.

Acute cocaine reduces renin secretion. To determine whether serotonergic neurons mediate this effect, male Sprague-Dawley rats received the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (75 micrograms/side, ICV) 2 weeks prior to cocaine injections (3.75-15 mg/kg, IP). 5-HT lesions attenuated the cocaine-induced reduction of plasma renin concentration (PRC), suggesting a partial 5-HT role. To determine which receptors mediate this response, rats were pretreated with the partial 5-HT1A agonist 8-[2-[4-(2-methoxyphenyl)-l-piperazinyl]ethyl]-8-azaspirol-[4,5]- decane-7,9-dione (BMY 7378) (1 mg/kg, SC), the 5-HT1C/5-HT2 antagonist ritanserin (0.1 mg/kg, SC), or the alpha 2/5-HT1A antagonist yohimbine (1 mg/kg, SC) prior to cocaine. None of the antagonists altered the cocaine-induced suppression of PRC, although BMY 7378 and yohimbine elevated PRC. The data suggest that cocaine's effect is partially mediated by a serotonergic mechanism, but do not support a role for 5-HT1A receptors, 5-HT2/5-HT1C receptors, or alpha 2-adrenoceptors in mediating the suppressive effect of cocaine on renin secretion.

5,7-Dihydroxytryptamine↗

PubMed1992

Role of the central serotonergic system in the anticonflict effect of d-AP159.

d-AP159 is a d-optical isomer, and in rats it has a high affinity for 5-hydroxytryptamine1A (5-HT1A) receptors and potent anticonflict activity, equal to that of buspirone. The anticonflict effects of d-AP159 and buspirone were investigated in animals in which lesions of the serotonergic neurons were caused by intradorsal raphe (d-RA) injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). The anticonflict effect of buspirone, but not that of d-AP159, was attenuated in 5-HT neuron-lesioned rats. The anticonflict effect of d-AP159 injected into various brain sites was also studied. d-AP159 and buspirone microinjected into the d-RA caused significant anticonflict activity in rats. There was a significant anticonflict effect of d-AP159 injected into the amygdala centralis (ACE), but not the dorsal hippocampus (d-HC). The anticonflict effect of d-AP159 injected into the d-RA was antagonized by systemic administration of (-)propranolol but not Ro 15-1788. This effect of d-AP159 injected into the ACE was antagonized by systematic administration of Ro 15-1788 but not (-)propranolol. These results suggest that the d-RA and the ACE play important roles in the anticonflict effects of d-AP159 but that the mechanisms by which this drug acts at these sites are different.

5,7-Dihydroxytryptamine↗

PubMed1992

Serotonin depletion causes long-term reduction of exploration in the rat.

This study assessed the effects of central serotonergic depletion on exploratory activity at baseline, as well as after administration of d-amphetamine or the anxiogenic beta-carboline FG-7142. Intraventricular 5,7-dihydroxytryptamine (5,7-DHT) induced an almost complete depletion of serotonin [5-hydroxytryptamine (5-HT)] in the medial prefrontal cortex, nucleus accumbens, medial corpus striatum, and hippocampus with no changes in norepinephrine, dopamine or dihydroxyphenylacetic acid concentrations. 5-HT-depleted rats demonstrated reduced spontaneous and d-amphetamine-augmented exploration 3-10 weeks postoperatively. An effect on FG-7142-induced inhibition of exploratory activity was not apparent. These data implicate 5-HT systems in the expression of different aspects of exploratory and amphetamine-augmented motor behaviors.

5,7-Dihydroxytryptamine↗