Pharmacological profile of antidepressants and related compounds at human monoamine transporters

1,022

790

Section: Discussionsupporting

confidence: 92%

“…Furthermore, atomoxetine is a potent inhibitor of the presynaptic NE transporter and has minimal affinity for other neurotransmitter transporters and neuronal receptors (Gehlert et al 1995;Tatsumi et al 1997;Wong et al 1982). In this study, we have further investigated the pharmacology of atomoxetine to understand its therapeutic actions in ADHD.…”

mentioning

confidence: 99%

Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder

Bymaster

Katner

Nelson

et al. 2002

1,022

790

“…Duloxetine and venlafaxine inhibited binding to the rat 5-HT and NE transporters with similar affinities to that of human transporters. The K i values of duloxetine for inhibition of 5-HT and NE transporters are in agreement with previously reported values in rat tissue (Béïque et al 1998;Wong et al 1993) and for venlafaxine in human and rodent tissue (Tatsumi et al 1997;Béïque et al 1998). The selectivity ratios of duloxetine and venlafaxine for NE/ 5-HT blockade of human transporters were 9.4 and 30, respectively.…”

Section: Discussionsupporting

confidence: 90%

“…However, venlafaxine has been shown to display relatively low affinity for NE uptake into rat synaptosomes compared to 5-HT uptake and for the human NE transporter versus the 5-HT transporter (Bolden-Watson and Richelson 1993;Béïque et al 1998;Tatsumi et al 1997). In vivo , intravenously administered venlafaxine was about 10 times more potent at prolonging recovery of firing activity of dorsal hippocampal neurons after microiontophoretically applied 5-HT than NE (Béïque et al 1998).…”

mentioning

confidence: 99%

Comparative Affinity of Duloxetine and Venlafaxine for Serotonin and Norepinephrine Transporters in vitro and in vivo, Human Serotonin Receptor Subtypes, and Other Neuronal Receptors

Bymaster

Dreshfield-Ahmad

Threlkeld

et al. 2001

658

305

“…Finally, we assessed the role of the 5-HTT in the pharmacological actions of three antidepressants with differing affinity for the 5-HTT, fluoxetine, desipramine and imipramine. Fluoxetine has high affinity for the 5-HTT, desipramine has high affinity for the norepinephrine transporter, while imipramine has high affinity for both sites (Frazer 1997;Tatsumi et al 1997;Stahl 1998). …”

mentioning

confidence: 99%

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

Holmes

Yang

Murphy

et al. 2002

263

181

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...