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Journal ArticleDOI

Effects of sertraline and citalopram given repeatedly on the responsiveness of 5-HT receptor subpopulations

01 Jan 1992-Journal of Neural Transmission (J Neural Transm Gen Sect)-Vol. 88, Iss: 2, pp 143-156
TL;DR: The results indicate that sertraline and citalopram given repeatedly decrease the responsiveness of 5-HT1A (presynaptic) and5-HT2 receptors but increase the responsivenessof 5- HT1B receptors to respective agonists.
Abstract: The effect of repeated treatment (5 and 10 mg/kg, po, twice daily, 14 days) with sertraline and citalopram (antidepressants which selectively inhibit the reuptake of 5-hydroxytryptamine (5-HT)) on the responsiveness of different 5-HT receptors to their agonists, was examined in rats and mice. Sertraline and citalopram (both at a dose 5 and 10 mg/kg) antagonized (the first one more potently) the hypothermia induced in mice by 8-OH-DPAT (a 5-HT1A agonist), but not the behavioural syndrome induced in rats by this substance. The m-chlorophenylpiperazine-induced hypothermia in mice (a 5-HT1B effect) was increased by sertraline and citalopram (only in a dose of 10 mg/kg). Both antidepressants, given repeatedly (as well acutely) attenuated exploratory hypoactivity induced in rats by m-chlorophenylpiperazine (a 5-HT1C effect). L-5-HTP-induced head twitches in mice (5-HT2 effect) were antagonized dose-dependently by both repeated sertraline and citalopram. Both antidepressants (citalopram only in higher dose) reduced the fenfluramine-induced hyperthermia in rats (5-HT2 effect). The results indicate that sertraline and citalopram given repeatedly decrease the responsiveness of 5-HT1A (presynaptic) and 5-HT2 receptors but increase the responsiveness of 5-HT1B receptors to respective agonists.
Citations
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Journal ArticleDOI
29 Nov 1996-Science
TL;DR: The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5HTT expression and 5HT uptake in lymphoblasts as discussed by the authors, which is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs.
Abstract: Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.

5,072 citations

Journal Article
TL;DR: The results strongly implicate a role for 5-HT(2C) receptors in the behavioral effects of antidepressant drugs and exemplify the benefits of using the modified rat forced swim test, which was sensitive to serotonergic compounds and distinguished behavioral changes associated with serotoneric and noradrenergic effects.
Abstract: The role of the 5-HT(2C) receptor in mediating active behaviors in the modified rat forced swim test was examined. Three novel selective 5-HT(2C) receptor agonists, WAY 161503 (0.1-3.0 mg/kg), RO 60-0175 (2-20 mg/kg), and RO 60-0332 (20 mg/kg), all decreased immobility and increased swimming, a pattern of behavior similar to that which occurs with the selective serotonin reuptake inhibitor fluoxetine (5-20 mg/kg). However, the prototypical but nonselective 5-HT(2C) receptor agonist m-chlorophenylpiperazine (1-10 mg/kg) increased immobility scores in the forced swim test. The selective 5-HT(2C) receptor antagonist SB 206533 was inactive when given alone (1-20 mg/kg). However, SB 206533 (20 mg/kg) blocked the antidepressant-like effects of both WAY 161503 (1 mg/kg) and fluoxetine (20 mg/kg). The atypical antidepressant (noradrenergic alpha(2) and 5-HT(2C) receptor antagonist) mianserin reduced immobility and increased climbing at 30 mg/kg. At a behaviorally subactive dose (10 mg/kg), mianserin abolished the effects of WAY 161503 (1 mg/kg) on both swimming and immobility scores. Mianserin blocked the effects of fluoxetine (20 mg/kg) on swimming only; mianserin plus fluoxetine reduced immobility and induced a switch to climbing behavior, suggesting activation of noradrenergic transmission. These data exemplify the benefits of using the modified rat forced swim test, which was sensitive to serotonergic compounds and distinguished behavioral changes associated with serotonergic and noradrenergic effects. Taken together, the results strongly implicate a role for 5-HT(2C) receptors in the behavioral effects of antidepressant drugs.

315 citations

Journal ArticleDOI
TL;DR: The role of 5-HT(2C) receptors in the control of brain DA function will be reviewed, and the search for new therapies for neuropsychiatric disorders, such as depression, schizophrenia and drug addiction, based on these findings will be discussed.

258 citations

Journal ArticleDOI
TL;DR: It is concluded that fluoxetine inhibits dopaminergic function in the VTA by enhancing the synaptic levels of 5‐HT, which possibly acts through the 5‐ HT2C/2B receptor subtype.
Abstract: 1. Electrophysiological techniques were used to study the effects of fluoxetine and citalopram on the basal activity of dopaminergic neurones in the ventral tegmental area (VTA) and substantia nigra, pars compacta (SNc) of rats. 2. Acute i.v. injection of fluoxetine (20-1280 micrograms kg-1) caused a dose-dependent inhibition of the firing rate of VTA dopaminergic neurones, but did not affect the activity of dopaminergic cells in the SNc. Citalopram (20-1280 micrograms kg-1, i.v.) inhibited the firing rate of dopaminergic neurones in the VTA, but its effect (maximal inhibition: 14 +/- 7%) was less pronounced than that of fluoxetine (maximal inhibition: 34 +/- 7%). 3. Pretreatment with mesulergine (80 micrograms kg-1, i.v.), a 5-hydroxytryptamine2C/2B (5-HT2C/2B) receptor antagonist, blocked the inhibitory effect of fluoxetine on VTA dopaminergic cells. Selective lesions of 5-hydroxytryptaminergic neurones by the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), abolished the fluoxetine-induced reduction of VTA dopaminergic activity. 4. In a series of experiments, fluoxetine (10 mg kg-1, i.p.) was administered once daily for 21 consecutive days. Acute i.v. administration of fluoxetine (20-1280 micrograms kg-1, 72 h after the last i.p. injection) did not cause any change in the basal firing rate of VTA dopaminergic neurones in treated rats, whereas it induced the typical inhibitory effect in control animals. A group of rats chronically treated with fluoxetine, received i.v. m-chlorophenylpiperazine (mCPP; 10-320 micrograms kg-1), a 5-HT2C/2B receptor agonist. This drug significantly inhibited VTA dopaminergic function in control rats, but did not modify the basal activity of dopaminergic cells in animals given chronic fluoxetine. 5 It is concluded that fluoxetine inhibits dopaminergic function in the VTA by enhancing the synaptic levels of 5-HT, which possibly acts through the 5-HT2C/2B receptor subtype. Repeated treatment with fluoxetine induces tolerance to its inhibitory effect on dopaminergic activity, possibly as a consequence of down-regulation of 5-HT2C/2B receptors. The effects of fluoxetine on VTA dopaminergic cell activity might be relevant for its therapeutic actions and may explain the origin of the reported cases of akathisia.

185 citations

Journal ArticleDOI
TL;DR: It is argued that there is a neurobiological cause of impaired neuropsychological function in depression and this relationship may be a result of interactions between the serotonergic system and the HPA axis, particularly in the hippocampus with involvement ofserotonergic 5-HT1A and glucocorticoid receptors.
Abstract: Background. Depressed patients show deficits on neuropsychological tests. However, the basis of these impairments and their relationship with mood disturbance remains unclear. Methods. This paper reviews the literature regarding the relationship between mood disturbance and neuropsychological impairment in depression and the evidence for serotonergic and hypothalamic‐pituitary‐adrenal (HPA) axis involvement in these two domains. Results. Mood disturbance and neuropsychological impairment both occur in depression, but have no clear relationship in time or degree. Impairment of post-synaptic 5-HT "A receptor function may result in the symptom of low mood in depression. Depressed patients demonstrate abnormalities in the functional control of the HPA axis with a resultant hypercortisolaemia, which may impair neuropsychological function. These processes may be related given the extensive interactions between the serotonergic system and the HPA axis. Conclusions. We argue that there is a neurobiological cause of impaired neuropsychological function in depression. The complex relationship between neuropsychological function and mood may be a result of interactions between the serotonergic system and the HPA axis, particularly in the hippocampus with involvement of serotonergic 5-HT "A and glucocorticoid receptors. A primary dysfunction in these receptors will produce a lowering of mood and neuropsychological impairment respectively. Either dysfunction will result in a secondary impairment of the alternate system. Thus, the aective and psychological changes of depressive illness are likely to have complex relationships in time and severity to one another and the illness as a whole may result from a range of primary aetio-pathologies.

171 citations

References
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Journal ArticleDOI
TL;DR: This classification of 5-HT receptors into three main groups is based largely, but not exclusively, on data from studies in isolated peripheral tissues where definitive classification is possible, and is believed that this working classification will be relevant to functional responses to 5- HT in the central nervous system.

1,259 citations

Journal ArticleDOI

862 citations


"Effects of sertraline and citalopra..." refers background in this paper

  • ...8 -OH-DPAT, a selective agonist o f 5-HT1A receptors, i n d u c e s - v i a postsynaptic s t i m u l a t i o n - a characteristic syndrome which is antagonized by 5HT~A receptor blockers (Hjorth etal. , 1982; Middlemiss and Fozard, 1983; Tricklebank et al., 1985; Yamada et al., 1988)....

    [...]

Journal ArticleDOI
TL;DR: The residual behavioural effects of 8-OH-DPAT in reserpinised rats may, therefore, reflect the consequences of stimulation of the putative 5-HT1A receptor.

689 citations


"Effects of sertraline and citalopra..." refers background in this paper

  • ...8 -OH-DPAT, a selective agonist o f 5-HT1A receptors, i n d u c e s - v i a postsynaptic s t i m u l a t i o n - a characteristic syndrome which is antagonized by 5HT~A receptor blockers (Hjorth etal. , 1982; Middlemiss and Fozard, 1983; Tricklebank et al., 1985; Yamada et al., 1988)....

    [...]

  • ...Each score was summed up over 5 observation periods (Tricklebank et al., 1985)....

    [...]

  • ...To this end we examined the effect of sertraline on the responsiveness to agonists of these receptors, having taken into consideration the effects characteristic of them: -- 5-HT1A receptors-behavioural syndrome in rats and hypothermia in mice both induced by 8-OH-DPAT (Tricklebank et al., 1985; Goodwin and Green, 1985) - 5-HT1B receptors - hypothermia induced by m-CPP in mice (Maj et al....

    [...]

Journal ArticleDOI
John Hyttel1
TL;DR: Citalopram has no antagonistic activity towards DA, NA, 5-HT, histamine, gamma aminobutyric acid (GABA), acetylcholine, and morphine receptors, which makes it a most promising antidepressant drug.
Abstract: 1 Citalopram (Lu 10-171), a new bicyclic phthalane derivative, is an extremely potent inhibitor of neuronal serotonin (5-HT) uptake but has no effect on the uptake of noradrenaline (NA) and dopamine (DA) 2 Citalopram has no antagonistic activity towards DA, NA, 5-HT, histamine, gamma aminobutyric acid (GABA), acetylcholine, and morphine receptors In this way it clearly deviates from many old and new antidepressant drugs which have antagonistic effects towards some of these transmitters 3 In contrast to many tricyclic antidepressants citalopram is devoid of cardiotoxic effects, even when animals are exposed to concentrations far above the therapeutic level 4 In man citalopram is metabolized to compounds which are also potent 5-HT-uptake inhibitors without effect of NA uptake and which are found in lower concentrations than citalopram itself 5 In account of its extreme specificity as a 5-HT-uptake inhibitor citalopram should be considered as an experimental tool of the utmost importance In preliminary clinical experiments citalopram has shown a clear antidepressant effect This property together with the absence of troublesome anticholinergic adverse effects and cardiotoxic effects also make citalopram a most promising antidepressant drug

581 citations

Journal ArticleDOI
TL;DR: It was demonstrated that the simplified ergot congener 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, is able to elicit pronounced biochemical and behavioural alterations indicative of central serotoninomimetic activity, and may be regarded the most potent, selective centrally acting 5-HT agonist described to date.
Abstract: It was demonstrated that the simplified ergot congener 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, is able to elicit pronounced biochemical and behavioural alterations indicative of central serotoninomimetic activity. Since these effects are resistant to prior monoamine depletion and/or synthesis inhibition by means of reserpine andα-propyldopacetamide (H22/54), respectively, they are most likely to be attributable to direct serotonin-receptor agonism by 8-OH-DPAT. With regard to central 5-HT neurotransmission the effects of 8-OH-DPAT-increased 5-HT levels, decreased 5-HIAA levels, 5-HT-synthesis rate and 5-HT utilization and inhibited 5-HT neuronal firing-are virtually identical, and comparable in potency, to those reported to result from the administration of lisuride or LSD. In contrast, however, to lisuride and LSD (included for comparative purposes in this study) as well as to several differently N-substituted, 5,6-dihydroxy, 6,7-dihydroxy and 5-, 6- and 7-monohydroxy 2-aminotetralins, 8-OH-DPAT lacks appreciable effects on central catecholamine receptors. The compound may thus be regarded the most potent, selective centrally acting 5-HT agonist described to date. accordance with this it was shown that the full-blown 5-HT-like behaviour syndrome induced by 8-OH-DPAT cannot be antagonized by reserpin phenoxybenzamine, propranolol and haloperidol. In addition, of the truputative 5-HT-receptor blockers cyproheptadine, methergoline and methrothepin only the latter was able to counteract the 8-OH-DPAT-induce syndrome. The results are discussed in relation to the recent subclassification of central 5-HT receptor sites. A comparison between the chemical structures and biological activities for different fragments of the ergot nucleus was also made. The data suggest, in that while the role of the A ring in the ergot structure for dopaminer activity at present is unclear, this ring may be important for the 5-HT-receptor activity like in e.g. lisuride and LSD. Moreover, based on the present results and literature reports, it is speculated that a selective 5-HT-receptor agonist such as 8-OH-DPAT would be liable to induce hallucinations in man.

505 citations