Third‐generation antidepressants

Pinder, Roger M.; Wieringa, Joop H.

doi:10.1002/med.2610130304

Cited by 79 publications

(65 citation statements)

References 384 publications

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“…Interestingly, the effects of fluoxetine were unaltered in heterozygous 5-HTT knockout mice, indicating that a 50% loss of 5-HTT is sufficient to retain the anti-immobility effects of fluoxetine. These data also show that fluoxetine's direct actions on 5-HT 2C receptors (Jenck et al 1993;Pinder and Wieringa 1993;Pälvimäki et al 1996) do not mediate the anti-immmobility effects of the drug (Borsini et al 1991;Bourin et al 1996;Redrobe and Bourin 1997;Cryan and Lucki 2000;Clenet et al 2001). However, although the loss of fluoxetine's anti-immobility effects in 5-HTT Ϫ/Ϫ mice was clear and unequivocal at the single dose tested, it will be important to conduct a full dose-response curve to determine whether 5-HTT KO mice are differentially sensitive to other doses of this compound.…”

supporting

confidence: 57%

Evaluation of Antidepressant-related Behavioral Responses in Mice Lacking the Serotonin Transporter

Holmes

Yang

Murphy

et al. 2002

Neuropsychopharmacology

263

181

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Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT 5-HTT Ϫ / Ϫ mice on the C57BL/6J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL/6J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT Ϫ / Ϫ mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT Ϫ / Ϫ mice retained sensitivity to the anti-immobility effects of the norepinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg Antidepressants are thought to normalize the disturbances in monoamine function that occur in affective disorders (Feighner and Boyer 1996;Frazer 1997; Montgomery and Den Boer 2001). While dysfunctions in noradrenergic and dopaminergic systems are putative etiological factors in depression, there is considerable evidence indicating that perturbation of central serotonergic activity is a major etiological component of depression (Willner 1985;Murphy 1990;Maes and Meltzer 1995;Charney 1998 NO . 6 Antidepressant Responses in 5-HTT KO Mice 915 (for reviews see Brown and Linnoila 1990;Owens and Nemeroff 1998;Mann 1999). The serotonin transporter (5-HTT) acts as a key regulator of serotonin signaling. By regulating reuptake of released serotonin, the 5-HTT controls the duration and intensity of serotoninergic activity at the synapse. The 5-HTT has been directly implicated in depression by the finding that brain 5-HTT binding density is reduced in brains and platelets of depressed patients (e.g., Nemeroff et al. 1994;Malison et al. 1998;Mann et al. 2000). Moreover, a number of studies have found an association between genetic variation in the regulatory region of the 5-HTT gene and depression (e.g., Battersby et al. 1996; Collier et al. 1996a,b;Furlong et al. 1998;Rees et al. 1997;Menza et al. 1999; but see Seretti et al. 1999). The 5-HTT is also a major target for many antidepressant drug treatments (Blakely et al. 1991;Ramamoorthy et al. 1993). It is well known that the serotonin reuptake inhibitor (SRI) class of antidepressants increase concentrations of serotonin in the synapse by blocking the serotonin transporter (5-HTT) (Blakely et al. 1991;Ramamoorthy et al. 1993). However, given the time lag between the initial inhibitory effects of antidepressants on the 5-HTT and an observable improvement in sympt...

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supporting

confidence: 57%

Evaluation of Antidepressant-related Behavioral Responses in Mice Lacking the Serotonin Transporter

Holmes

Yang

Murphy

et al. 2002

Neuropsychopharmacology

263

181

View full text Add to dashboard Cite

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“…These NA projections to the 5-HT neurons in the raphe are mediated by 1 receptors on the 5-HT cell bodies (which are not blocked by mirtazapine) and the whole system is regulated by inhibitory 2 receptors, as is the release of both NA and 5-HT in forebrain areas. Mirtazapine blocks these 2 autoreceptors and therefore decouples the negative feedback system and permits increased NA drive of the 5-HT neurons (as well as increasing NA and 5-HT release in forebrain areas) (Pinder and Wieringa, 1993). There are also believed to be additional, 2 mediated interactions between 5-HT neurons and the NA cell bodies (probably mediated by GABA-releasing inter-neurons) that further facilitate activity in NA neurons (Haddjeri et al, 2000).…”

Section: Onset Of Response and Serotonergic Cell Firingmentioning

confidence: 98%

Pharmacological principles of antidepressant efficacy

Schatzberg

2002

Hum. Psychopharmacol. Clin. Exp.

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Both noradrenaline (NA) and serotonin (5-HT) appear to be involved in depression. Evidence suggests that dual-acting antidepressants, i.e. those that affect both monoamine systems, such as tricyclic antidepressants and the noradrenergic and specific serotonergic antidepressant mirtazapine, may have greater efficacy and a faster onset of action than drugs that act on a single monoamine system only, such as the selective serotonin reuptake inhibitors (SSRIs). Cell firing is reduced by SSRIs in the short-term, but is increased by mirtazapine, probably due to its actions on both NA (via alpha(2) antagonism) and 5-HT (via alpha(1)-stimulation by NA). This may help to explain clinical evidence suggesting that mirtazapine has a faster onset of action than the more selective antidepressants.

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“…Tomoxetine and Viloxazine), have been developed. 31 Structural examination of such compounds revealed that several of them contain the γ-amino ether functionality in their structures, Figure 3. Based on some previous studies, we planned the synthesis of the 2-benzazepine 22 via a one-pot threecomponent Mannich-type reaction.…”

Section: An Efficient Catalyst-free Four-component Synthesis Of Novelmentioning

confidence: 99%

Recent contributions to the Diversity-Oriented Synthesis (DOS) mediated by iminium ions through multicomponent Mannich-type reactions

Abonı́a¹,

Castillo²,

Kotali³

2017

Arkivoc

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This short account summarizes the most recent contributions of the author and his collaborators to the Diversity Oriented Synthesis (DOS) mediated, at least in a step of the process, by Mannich-type reactions (MTR) and using formaldehyde as common starting material in all cases. Through this strategy, diverse nitrogen-containing acyclic and heterocyclic systems were synthesized, whether in straightforward or multicomponent approaches.

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Third‐generation antidepressants

Cited by 79 publications

References 384 publications

Evaluation of Antidepressant-related Behavioral Responses in Mice Lacking the Serotonin Transporter

Evaluation of Antidepressant-related Behavioral Responses in Mice Lacking the Serotonin Transporter

Pharmacological principles of antidepressant efficacy

Recent contributions to the Diversity-Oriented Synthesis (DOS) mediated by iminium ions through multicomponent Mannich-type reactions

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