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PubMed1983

Cholinergic-dopaminergic interactions and the mechanisms of action of antidepressants.

A series of experiments was performed to evaluate the mechanism(s) by which chronic administration of desipramine (DMI) facilitates the locomotor stimulant action of d-amphetamine, a response thought to be dependent on the mesolimbic dopaminergic system. Prior lesions of central noradrenergic or serotonergic neurons, induced by neonatal treatment with 6-hydroxydopamine (6-OHDA) or intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) respectively, failed to block DMI-induced facilitation of amphetamine hypermotility. Chronic administration of DMI did not significantly influence specific [3H]spiperone binding in the striatum or the nucleus accumbens. In other experiments it was found that chronic administration of some (amitryptyline, imipramine, mianserin, iprindole) but not all (zimelidine, nomifensine, fluoxetine) antidepressants enhanced the locomotor response to d-amphetamine. The weak anticholinergic effects of the latter compounds suggest that the positive results obtained with the former drugs may be related to their anticholinergic properties. This hypothesis is consistent with the observation that chronic administration of scopolamine also increased the locomotor response to d-amphetamine. The results suggest that the facilitation by chronic DMI of amphetamine-induced locomotor activity is not mediated by primary actions of this tricyclic antidepressant on central noradrenergic or serotonergic systems. In addition, the results argue against an effect of DMI on dopamine receptors as measured by [3H]spiperone binding. Instead, the facilitation of the amphetamine response by some of these antidepressant compounds may be related to their anticholinergic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗

PubMed1983

Monoamine involvement in the overeating caused by muscimol injection in the rat nucleus raphe dorsalis and the effects of d-fenfluramine and d-amphetamine.

Injections of 5,7-dihydroxytryptamine in the nucleus raphe dorsalis did not significantly modify the eating caused by muscimol (100 ng) injected in the same area of freely fed rats 11 days later. Eating caused by muscimol, like food intake in starved rats, was significantly reduced by phenoxybenzamine (5, 10 and 20 mg/kg i.p.). Penfluridol (2.5 and 5 mg/kg p.o.), a dopamine receptor blocker, markedly reduced muscimol-induced eating, but had no effect on the food intake of starved rats. d-Fenfluramine (2.5 mg/kg i.p.), a releaser of serotonin from nerve terminals, significantly reduced eating in muscimol-injected and starved animals whereas d-amphetamine 1.25 and 2.5 mg/kg i.p. only inhibited the food intake of starved rats. Eating elicited by muscimol injected in the nucleus raphe dorsalis appears to constitute a catecholamine-mediated model of hyperphagia selectively inhibited by agents which increase serotonin transmission.

5,7-Dihydroxytryptamine↗

PubMed1983

Codepletion of serotonin and TRH induces apparent supersensitivity of spinal TRH receptors.

Thyrotropin-releasing hormone (TRH), substance P (SP) and serotonin (5-HT) coexist in raphe efferents to the spinal cord. Lesions of these serotonergic projections by intracisternal injection of 5,7-dihydroxytryptamine (50 micrograms) in rat pups resulted in 93% and 65% decreases in 5-HT and TRH content of adult rat spinal cords, respectively. This codepletion induced a 30-40% increase in binding of [3H][3-Me-His2]TRH [( 3H]MeTRH) to TRH receptors. The affinity and pharmacological specificity of [3H]MeTRH binding to control and DHT-lesioned cords appeared closely similar.

5,7-Dihydroxytryptamine↗

PubMed1984

A reduction of the tone of 5-hydroxytryptamine neurons decreases utilization rates of striatal and hypothalamic enkephalins.

The administration of drugs such as fenfluramine, p-chlorophenylalanine or 5,7-dihydroxytryptamine, which lower brain 5-hydroxytryptamine content, increases the enkephalin content of hypothalamus and striatum. None of these treatments changes proenkephalin mRNA content. On the basis of these results, we propose that 5-hydroxytryptamine does not increase the biosynthesis of enkephalin, but might increase the content of the neuropeptide by reducing peptide utilization.

5,7-Dihydroxytryptamine↗

PubMed1985

The analgesic activity of calcitonin and the central serotonergic system.

The effect of peripherally administered cyproheptadine or reserpine and the administration of 5,7-dihydroxytryptamine (5,7-DHT) in the nucleus raphe dorsalis on the analgesic activity of salmon calcitonin (sCT) injected into the lateral ventricle were investigated in male rats. Cyproheptadine or reserpine, given respectively 30 min or 24 h before the peptide, completely abolished the analgesic activity at all the times studied. However, when reserpine was given before the peptide it increased the effect of sCT at 30 (P less than 0.01), 60 (P less than 0.001), 120 (P less than 0.01) and 180 (P less than 0.01) min. 5,7-DHT injected in the nucleus raphe dorsalis 15 days before the peptide led to complete abolition of the analgesic activity. If neurotoxin was injected 4 days before sCT, the effect of the peptide was significant (P less than 0.05) only at 60 min. The results obtained confirm that the analgesic activity of sCT may involve central serotonergic pathway(s), and that the midbrain raphe nuclei 5-HT content is an important focus for this activity.

5,7-Dihydroxytryptamine↗

PubMed1985

Short-term lithium administration enhances serotonergic neurotransmission: electrophysiological evidence in the rat CNS.

Rats received lithium-containing chow for 48 h. Brain and plasma lithium concentrations ranged from 0.4 to 1.0 mEq/l. A first series of experiments served to assess the responsiveness of CA3 hippocampal pyramidal neurons to microiontophoretically applied serotonin (5-HT) and norepinephrine (NE). The response of the same neurons to electrical stimulation of the ventro-medial 5-HT pathway was measured after lithium treatment. The responsiveness to 5-HT and NE was not modified whereas the effect of activation of the ascending 5-HT pathway was increased two-fold by the lithium treatment. These neurons were activated to their physiological firing rate by means of small ejection currents of acetylcholine. A pretreatment with the 5-HT neurotoxin 5,7-dihydroxytryptamine abolished the response to the electrical stimulation in lithium-treated rats. In a second series of experiments, unitary recordings of 5-HT neurons were obtained from the dorsal raphe nucleus. The lithium treatment modified neither the number of spontaneously active 5-HT neurons nor their mean firing rate. These results provide direct electrophysiological evidence for the enhancement of 5-HT neurotransmission by short-term lithium treatment through its presynaptic action on 5-HT terminals.

5,7-Dihydroxytryptamine↗

PubMed1985

Effect of substances influencing brain serotonergic transmission on plasma vasopressin levels in the rat.

Studies were carried out in the rat to investigate whether serotonin (5-HT) is involved in the regulation of vasopressin (ADH) release. For this purpose plasma ADH levels were measured in rats treated with drugs enhancing 5-HT transmission, such as d-fenfluramine and quipazine and with 5-HT depleting drugs, p-chlorophenylalanine (PCPA) and 5,7-dihydroxytryptamine (5,7-DHT). Forebrain 5HT, noradrenaline (NA) and dopamine (DA) were also measured. d-Fenfluramine and quipazine induced dose-related increases in plasma ADH levels in normohydrated rats. The effects of quipazine and d-fenfluramine were prevented by PCPA, indicating that 5-HT transmission was required for the biologic response. 5,7-DHT and PCPA pretreatment decreased forebrain 5-HT content and prevented ADH increases involved by water deprivation, suggesting that 5HT is necessary for the hormonal response to osmotic stimuli. The results summarized imply that serotonin may have a role in the physiological release of ADH from neurohypophysis.

5,7-Dihydroxytryptamine↗

PubMed1985

Characterization of [3H]5-hydroxytryptamine uptake within rat cerebrovascular tree.

The in vitro uptake of tritiated serotonin ([3H]5HT) was studied in a preparation of rat extracerebral arteries. The uptake of [3H]5HT was time- and temperature-dependent and of high affinity; linear regression analysis gave a Km value of 6.48 X 10(-7) M for the specific uptake. Bilateral superior cervical ganglionectomy was without effect on [3H]5HT uptake while it significantly reduced the uptake of tritiated norepinephrine by the preparation of rat extracerebral arteries. The serotonergic neurotoxin 5,7-dihydroxytryptamine and lesions to both the medial and the dorsal raphe nuclei caused a marked loss of [3H]5HT uptake but did not change the uptake of tritiated norepinephrine. Competition studies with norepinephrine, desimipramine (a noradrenergic uptake blocker), nomifensine (a dopaminergic uptake blocker) and fluoxetine (a 5HT uptake blocker) confirmed the specificity of the [3H]5HT uptake mechanism. Histoautoradiographic studies showed the highest density of silver grains at the level of the adventitial-medial border of the basilar artery. Fluoxetine inhibited the accumulation of silver grains within the adventitial-medial border in the blood vessel studied. The present data further support the view that a neuronal serotonergic system may play a role in the control of blood flow in the cerebrovascular tree.

5,7-Dihydroxytryptamine↗

PubMed1985

The effects of surgical and chemical lesions on striatal [3H]threo-(+/-)-methylphenidate binding: correlation with [3H]dopamine uptake.

The specific binding of [3H]threo-(+/-)-methylphenidate to membranes prepared from rat striatum was significantly reduced following either surgical lesions of the medial forebrain bundle or intracerebroventricular administration of 6-hydroxydopamine. The decrease in the density of [3H]threo-(+/-)-methylphenidate binding sites in striatum following chemical or surgical denervation was highly correlated with the decrease in [3H]dopamine uptake. In contrast, intracerebroventricular administration of 5,7-dihydroxytryptamine, AF64A, or chronic parenteral administration of reserpine did not alter either the number of apparent affinity of [3H]threo-(+/-)-methylphenidate binding sites. These data suggest that the specific binding sites for [3H]-threo-(+/-)-methylphenidate in striatum are localized to dopaminergic nerve terminals, and may be associated with the dopamine transport complex.

5,7-Dihydroxytryptamine↗

PubMed1986

8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) elicits eating in free-feeding rats by acting on central serotonin neurons.

A subcutaneous injection of 0.5 mg/kg 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a drug with high affinity for 5-hydroxytryptamine (5-HT1A) binding sites, substantially increased eating in non-deprived rats. Intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT), a neurotoxin for 5-HT neurons, also significantly increased eating in rats and antagonized the effect of 8-OH-DPAT. Microinjections of 8-OH-DPAT (0.5 and 1 microgram) in the nuclei dorsalis and medianus raphe also significantly increased eating in rats. 8-OH-DPAT appears to stimulate eating by acting on 5-HT-containing neurons. These results are compatible with the hypothesis that a decrease in central 5-HT function disinhibits feeding.

5,7-Dihydroxytryptamine↗

PubMed1986

Noradrenergic-serotonergic interactions and nociception in the rat.

Spinal noradrenaline (NA) depletion in rats, via either systemic N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4) or intrathecal 6-hydroxydopamine (6-OHDA), reversed and/or abolished the analgesic effects of the 5-hydroxytryptamine (5-HT) agonists, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and p-chloroamphetamine (PCA), in shock titration, hot-plate and tail-flick measures of pain sensitivity. Spinal NA depletion also abolished the analgesic effects of 5-HT itself, administered intrathecally, in all three nociception tests and potentiated the analgesic effects of intrathecal NA, a demonstration of receptor supersensitivity. Spinal 5-HT depletion, via intrathecal 5,7-dihydroxytryptamine (5,7-DHT), only attenuated 5-MeODMT-induced analgesia in the tail-flick test but potentiated the 5-MeODMT effect in the hot-plate test. Intrathecal 5,7-DHT treatment caused a drastic potentiation of NA-induced analgesia in the shock titration and tail-flick tests but not in the hot-plate test. Biochemical analyses confirmed the NA and 5-HT depletion. The spinal noradrenergic system appears to be an important tonic factor modulating the function of the descending 5-hydroxytryptaminergic pathway.

5,7-Dihydroxytryptamine↗

PubMed1986

Evidence of the involvement of dopamine in the analgesic effect of nefopam.

The involvement of brain monoamines in the mechanism of action of nefopam, a new analgesic, was investigated in rats. The study was designed to evaluate the effect of various means of impairing monoaminergic transmission on nefopam analgesia as measured with the hot plate method. Pretreatment with reserpine (2 mg/kg) significantly reduced the antinociceptive action of nefopam (40 mg/kg), indicating that the interaction of this drug with the monoaminergic systems is important for its effects. A role for serotonin (5-HT) or norepinephrine (NE) was ruled out by the fact that selective depletion of 5-HT (using 5,7-dihydroxytryptamine) or NE (using DSP-4 or FLA-63) did not affect nefopam analgesia. A significant reduction of the effect of nefopam was found in rats pretreated with 6-hydroxydopamine (6-OHDA). Also 6-OHDA plus desipramine, which selectively depleted brain DA, markedly reduced the antinociceptive effect of nefopam. The data strongly suggest that a critical dopaminergic synapse is involved in the mechanism by which nefopam inhibits nociceptive responses in rats.

5,7-Dihydroxytryptamine↗

PubMed1987

Amygdaloid catecholaminergic mechanisms involved in suppressive effects of electroconvulsive shock on duration of immobility in rats forced to swim.

Chronic but not acute treatment with electroconvulsive shock (ECS) significantly reduced the duration of immobility in rats forced to swim. The immobility-reducing effect of chronic treatment with ECS was strongly antagonized by 6-hydroxydopamine but not by 5,7-dihydroxytryptamine given into the medial amygdaloid nucleus. These results indicate that ECS, like the tricyclic antidepressants, reduces the duration of immobility in rats forced to swim and that catecholaminergic mechanisms in the medial amygdaloid nucleus are involved in the suppressive effect of ECS on the duration of immobility, as are the tricyclic antidepressants.

5,7-Dihydroxytryptamine↗

PubMed1988

Electroconvulsive shock decreases beta-adrenoceptors despite serotonin lesions.

We have measured the effect of electroconvulsive shock (ECS) on high- and low-affinity [3H]dihydroalprenolol binding in cerebral cortex of control rats and rats with lesions of serotonin neurons. Eleven days of treatment with ECS (once daily) resulted in a decrease in the number of beta-adrenoceptor binding sites for which isoproterenol has high-affinity. Following lesions with 5,7-dihydroxytryptamine, ECS still resulted in a decrease in these receptors. Hence, ECS does not require intact serotonin neurons to decrease the number of high-affinity beta-adrenoceptors.

5,7-Dihydroxytryptamine↗

PubMed1991

Antinociceptive effect of paracetamol in rats is partly dependent on spinal serotonergic systems.

The possible involvement of bulbo-spinal monoaminergic pathways in the antinociceptive effect of paracetamol was investigated in rats. Serotonergic pathways were lesioned with intrathecal 5,6-dihydroxytryptamine (5,6-DHT), and noradrenergic pathways with 6-hydroxydopamine (6-OHDA). Intact and lesioned rats were tested in the formalin test after i.p. paracetamol (400 mg/kg) or vehicle. Behaviour was scored for 1 h after the dorsal injection of 100 microliters of 5% formalin into one hind paw. Behavioural variables were evaluated with a multivariate statistical procedure, as well as an analysis of variance. Paracetamol itself reduced pain-related behaviour and increased normal motor activity. This antinociceptive effect was reduced in rats lesioned with 5,6-DHT. In lesioned rats paracetamol caused a change in nociceptive behaviour from active, focused behaviour towards passive, protective and non-focused behaviour in the early phase of the formalin test. No significant effect of lesioning with 6-OHDA upon the paracetamol effect was found. These results show that activation of spinal serotonergic systems is involved in the antinociceptive effect of paracetamol. The relative importance of this mechanism in the central effect of paracetamol and the mechanisms that cause the activation remain to be determined.

5,6-Dihydroxytryptamine↗

PubMed1993

Effect of fluoxetine on the spontaneous electrical activity of fronto-cortical neurons.

The effect of fluoxetine on spontaneous extracellular activity of fronto-cortical neurons of chloral hydrate-anesthetized rats was investigated. Fluoxetine significantly increased the basal firing rate of cortical neurons in a dose-dependent manner (0.1-1000 micrograms kg-1 i.v.), with a maximum excitatory effect of 53% at 1000 micrograms kg-1. Selective destruction of ascending serotoninergic pathways induced by intracerebroventricular injections of 150 micrograms 5,7-dihydroxytryptamine, in desipramine-pretreated rats, antagonized the excitatory effect of fluoxetine. The present results suggest that fluoxetine significantly increases the electrical activity of the fronto-cortical neurons acting on serotoninergic uptake mechanisms localized at the level of raphe nuclei.

5,7-Dihydroxytryptamine↗

PubMed1993

Quantitative autoradiography of 5-HT1E binding sites in rodent brains: effect of lesion of serotonergic neurones.

Binding sites corresponding to 5-HT1E receptors were labelled in mouse, rat, and guinea-pig brains by using [3H]5-hydroxytryptamine ([3H]5-HT) in the presence of 5-carboxamidotryptamine (5-CT) (0.1 microM), and their distribution within the brain was studied by quantitative autoradiography. The results obtained with mouse brain show that 5-HT1E binding sites are particularly present in the cortex, caudate-putamen and claustrum, where they showed the highest density. Lower densities were measured in other regions. Saturation experiments showed that the affinity of [3H]5-HT for 5-HT1E binding sites (nanomolar range) was very similar in the different structures. The distribution of 5-HT1E binding sites was similar in rat and guinea-pig brains. In rat brain, selective lesioning of serotonergic fibres by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), a specific 5-HT neurotoxin, did not affect the density of 5-HT1E binding, indicating that these receptors are mainly localized on non-serotonergic neurones.

5,7-Dihydroxytryptamine↗

PubMed1995

Modafinil and cortical gamma-aminobutyric acid outflow. Modulation by 5-hydroxytryptamine neurotoxins.

The acute or chronic administration of modafinil, (diphenyl-methyl-sulfinyl-2-acetamide, 30 mg/kg s.c.) decreased gamma-amino-butyric acid (GABA) outflow from the cerebral cortex of freely moving guinea pigs and rats. In 5,7-dihydroxytryptamine intracerebroventricularly pretreated guinea pigs, the effect of modafinil on GABA outflow was reversed and the noradrenaline cortical levels increased. Prazosin (35.8 ng/kg i.p.) blocked the drug-induced increase in GABA efflux. In vitro experiments, performed in rat cortical slices, showed that modafinil failed to affect [3H]GABA release and uptake as well as glutamic acid decarboxylase activity. In conclusion, our results suggest that the balance between central noradrenaline and 5-hydroxytryptamine transmission is important for the regulation by modafinil of the GABAergic release in the cerebral cortex.

5,7-Dihydroxytryptamine↗