Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats

Koch, Susanne; Hemrick‐Luecke, Susan K.; Thompson, Linda; Evans, David C.; Threlkeld, Penny G.; Nelson, David L.; Perry, Kenneth W.; Bymaster, Frank P.

doi:10.1016/s0028-3908(03)00268-5

Cited by 108 publications

(105 citation statements)

References 35 publications

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“…Imipramine and clomipramine did not affect the duration of freezing in the elevated open-platform test. In microdialysis studies, imipramine and clomipramine increased equally the extracellular levels of both 5-HT and noradrenaline (28,29). Therefore, the absence of anti-freezing effects for tricyclic antidepressants may be due to their dual effects on the serotonergic and noradrenergic neurotransmissions.…”

Section: Resultsmentioning

confidence: 98%

Effects of Serotonergic Anxiolytics on the Freezing Behavior in the Elevated Open-Platform Test in Mice

et al. 2007

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Abstract. Freezing behavior is thought to be a sign of fear in animals. We examined whether the freezing behavior during the elevated open-platform stress, which is a psychological stressor without painful stimulus, is modulated by serotonergic neurotransmission and would be a useful marker for screening anxiolytic and / or antidepressant. Male ICR mice (6 -8-week-old) were individually placed on an elevated open-platform and the duration of freezing behavior of mouse was measured for 10 min. Fluoxetine and citalopram, selective serotonin (5-HT) reuptake inhibitors, markedly decreased the duration of freezing. Fenfluramine, a 5-HT releaser, and 8-OH-DPAT, a potent 5-HT 1A -receptor agonist, also significantly decreased the duration of freezing. In contrast, the 5-HT-synthesis inhibitor p-chlorophenylalanine significantly increased the duration of freezing. Diazepam, a benzodiazepine anxiolytic, had no effect on the duration of freezing at doses having no effect on locomotor activity. Imipramine and clomipramine, tricyclic antidepressants, also did not affect the duration of freezing. Reboxetine, a selective noradrenaline reuptake inhibitor, significantly increased the duration of freezing. These results indicate that the activation of serotonergic neurotransmission attenuates the fear-related behavior in the elevated open-platform test, while the activation of noradrenergic neurotransmission increases the fearrelated behavior. In addition, this test is convenient for assaying anxiolytic drugs that affect serotonergic neurotransmission.

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Section: Resultsmentioning

confidence: 98%

Effects of Serotonergic Anxiolytics on the Freezing Behavior in the Elevated Open-Platform Test in Mice

et al. 2007

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“…Male SD rats (180 -230 g; Harlan, Indianapolis, IN) were used for these experiments. Inhibition of the transporters in vivo was determined for 5-HT transporters by blockade of p-CA (10 mg/kg)-induced depletion of serotonin in rat brain and for NE transporters by ␣-methyl-m-tyrosine (␣-MMT; 6.25 mg/kg)-induced depletion of norepinephrine in rat cerebral cortex as described previously (Koch et al, 2003). Monoamine concentrations were determined by high-performance liquid chromatography/electrochemical techniques (Koch et al, 2003).…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Duloxetine, a Potent and Balanced Serotonin-Norepinephrine Reuptake Inhibitor in Persistent Pain Models in Rats

Iyengar

Webster²,

Hemrick‐Luecke³

et al. 2004

J Pharmacol Exp Ther

271

176

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5-Hydroxytryptamine (serotonin) (5-HT) and norepinephrine (NE) are implicated in modulating descending inhibitory pain pathways in the central nervous system. Duloxetine is a selective and potent dual 5-HT and NE reuptake inhibitor (SNRI). The ability of duloxetine to antagonize 5-HT depletion in para-chloramphetamine-treated rats was comparable with that of paroxetine, a selective serotonin reuptake inhibitor (SSRI), whereas its ability to antagonize NE depletion in ␣-methyl-m-tyrosinetreated rats was similar to norepinephrine reuptake inhibitors (NRIs), thionisoxetine or desipramine. In this paradigm, duloxetine was also more potent than other SNRIs, including venlafaxine or milnacipran and amitriptyline. Low doses of the SSRI paroxetine or the NRI thionisoxetine alone did not have an effect on late phase paw-licking pain behavior in the formalin model of persistent pain; however, when combined, significantly attenuated this pain behavior. Duloxetine (3-15 mg/kg intraperitoneal) significantly attenuated late phase paw-licking behavior in a dose-dependent manner in the formalin model and was more potent than venlafaxine, milnacipran, and amitriptyline. These effects of duloxetine were evident at doses that did not cause neurologic deficits in the rotorod test. Duloxetine (5-30 mg/kg oral) was also more potent and efficacious than venlafaxine and milnacipran in reversing mechanical allodynia behavior in the L5/L6 spinal nerve ligation model of neuropathic pain. Duloxetine (3-30 mg/kg oral) was minimally efficacious in the tail-flick model of acute nociceptive pain. These data suggest that inhibition of both 5-HT and NE uptake may account for attenuation of persistent pain mechanisms. Thus, duloxetine may have utility in treatment of human persistent and neuropathic pain states.

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“…However, inhibition of NA uptake or ligand binding at NET has been demonstrated in vitro for a range of antidepressants and their metabolites (Pristupa et al, 1994;Owens et al, 1997;Tatsumi et al, 1997;Bymaster et al, 2001;Millan et al, 2001;Bymaster et al, 2002;Koch et al, 2003;Kuo et al, 2004;Vaishnavi et al, 2004), and maprotiline, desipramine, reboxetine, and to a lesser extent nortriptyline are highly selective for NET (above SERT and DAT). Paroxetine and venlafaxine act as NET antagonists in vivo at clinical doses (Gilmor et al, 2002;Davidson et al, 2005;Owens et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Monoamine Transporter Occupancy of a Novel Triple Reuptake Inhibitor in Baboons and Humans Using Positron Emission Tomography

Comley

Salinas

Slifstein

et al. 2013

J Pharmacol Exp Ther

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The selection of a therapeutically meaningful dose of a novel pharmaceutical is a crucial step in drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between the plasma concentration of a drug and its target occupancy, optimizing dose selection and reducing the time and cost of early development. Triple reuptake inhibitors (TRIs), also referred to as serotonin-norepinephrine-dopamine reuptake inhibitors, enhance monoaminergic neurotransmission by blocking the action of the monoamine transporters, raising extracellular concentrations of those neurotransmitters. GSK1360707 [(1R,6S)-1-(3,4-dichlorophenyl)-6-(methoxymethyl)-4-azabicyclo[4.1.0]heptane] is a novel TRI that until recently was under development for the treatment of major depressive disorder; its development was put on hold for strategic reasons. We present the results of an in vivo assessment of the relationship between plasma exposure and transporter blockade (occupancy). Studies were performed in baboons (Papio anubis) to determine the relationship between plasma concentration and occupancy of brain serotonin reuptake transporter (SERT), dopamine reuptake transporter (DAT), and norepinephrine uptake transporter (NET) using the radioligands [ 11 C]DASB and [ 11 C]PE2I. In P. anubis, plasma concentrations resulting in half-maximal occupancy at SERT, DAT, and NET were 15.16, 15.56, and 0.97 ng/ml, respectively. In humans, the corresponding values for SERT and DAT were 6.80 and 18.00 ng/ml. GSK1360707 dose-dependently blocked the signal of SERT-, DAT-, and NET-selective PET ligands, confirming its penetration across the blood-brain barrier and blockade of all three monoamine transporters in vivo.

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Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats

Cited by 108 publications

References 35 publications

Effects of Serotonergic Anxiolytics on the Freezing Behavior in the Elevated Open-Platform Test in Mice

Effects of Serotonergic Anxiolytics on the Freezing Behavior in the Elevated Open-Platform Test in Mice

Efficacy of Duloxetine, a Potent and Balanced Serotonin-Norepinephrine Reuptake Inhibitor in Persistent Pain Models in Rats

Monoamine Transporter Occupancy of a Novel Triple Reuptake Inhibitor in Baboons and Humans Using Positron Emission Tomography

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