Dopamine reuptake transporter (DAT) “inverse agonism” – A novel hypothesis to explain the enigmatic pharmacology of cocaine

Heal, David J.; Gosden, Jane; Smith, Sharon L.

doi:10.1016/j.neuropharm.2014.06.012

Cited by 45 publications

(46 citation statements)

References 173 publications

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“…Otherwise, a reduction in the mood response would have been expected. Methylphenidate, which inhibits the DA transporter more potently than bupropion (Simmler et al, 2013b;Heal et al, 2014), did not attenuate the subjective effects of MDMA . In contrast, several studies showed that the subjective effects of MDMA in humans are significantly reduced by 5-HT Farre et al, 2007;Tancer and Johanson, 2007) and NE (Hysek et al, 2011) transporter inhibition and almost completely blocked by dual 5-HT and NE transporter inhibition (Hysek et al, 2012d).…”

Section: Discussionmentioning

confidence: 78%

“…In contrast to methylphenidate, bupropion is a more potent DA transporter inhibitor than NE transporter inhibitor (Stahl et al, 2004) and is more selective for DA compared with methylphenidate, which blocks the DA and NE transporters with equal potency . Additionally, bupropion has been proposed to bind to the substrate recognition site on the DA transporter similarly to MDMA, whereas psychoactive DA transporter ligands, such as methylphenidate and cocaine, may interact with a different binding site on the DA transporter (Heal et al, 2014). Bupropion reaches a high brain-to-plasma ratio and brain concentrations above its IC 50 value for DA transporter inhibition (Stahl et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Interactions between Bupropion and 3,4-Methylenedioxymethamphetamine in Healthy Subjects

Schmid

Rickli

Schaffner

et al. 2015

J Pharmacol Exp Ther

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3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a popular recreational drug. The aim of the present study was to explore the role of dopamine in the psychotropic effects of MDMA using bupropion to inhibit the dopamine and norepinephrine transporters through which MDMA releases dopamine and norepinephrine. The pharmacodynamic and pharmacokinetic interactions between bupropion and MDMA in 16 healthy subjects were investigated using a double-blind, placebo-controlled, crossover design. Bupropion reduced the MDMA-induced elevations in plasma norepinephrine concentrations and the heart rate response to MDMA. In contrast, bupropion increased plasma MDMA concentrations and prolonged its subjective effects. Conversely, MDMA increased plasma bupropion concentrations. These results indicate a role for the transporter-mediated release of norepinephrine in the cardiostimulant effects of MDMA but do not support a modulatory role for dopamine in the mood effects of MDMA. These results also indicate that the use of MDMA during therapy with bupropion may result in higher plasma concentrations of both MDMA and bupropion and enhanced mood effects but also result in lower cardiac stimulation.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Interactions between Bupropion and 3,4-Methylenedioxymethamphetamine in Healthy Subjects

Schmid

Rickli

Schaffner

et al. 2015

J Pharmacol Exp Ther

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“…In a similar manner, atomoxetine only ameliorates ADHD symptoms after weeks of treatment, whereas methylphenidate can produce beneficial effects after a single dose (231). The acute effects seen with methylphenidate are also seen with the structurally similar phenethylamine, amphetamine (232), which is also used to treat ADHD via acute dosing regimes (231). Besides being able to reliably affect core ADHD symptoms after acute dosing, psychostimulants also produce euphoric effects that do not occur with atomoxetine (232).…”

Section: Action Restraintmentioning

confidence: 99%

“…The acute effects seen with methylphenidate are also seen with the structurally similar phenethylamine, amphetamine (232), which is also used to treat ADHD via acute dosing regimes (231). Besides being able to reliably affect core ADHD symptoms after acute dosing, psychostimulants also produce euphoric effects that do not occur with atomoxetine (232). Noting that acute administration of psychostimulants can induce both improvements in executive control and euphoria, albeit at different doses with high doses producing euphoria and lower does favouring cognitive effects (232), we conjectured that a common neurobiological mechanism might underlie these phenomena and would differentiate them from atomoxetine and other catecholamine reuptake inhibitors.…”

Section: Action Restraintmentioning

confidence: 99%

“…For example, acute doses of a range of highly specific dopamine reuptake inhibitors (DRIs), including bupropion, vanoxerine and silbutramine, do not produce euphoric effects in healthy volunteers (232)(233)(234). Additionally, Volkow et al showed that although a first dose of methylphenidate was still occupying >80% of striatal DAT, a second methylphenidate infusion 60 minutes later produced an additional wave of euphoric feelings, suggesting that another mechanism beyond DAT blockade was operating (235).…”

Section: Action Restraintmentioning

confidence: 99%

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Neurochemical and neurophysiological bases of executive control

Nandam¹

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The aim of this work is to further understanding into the biological bases of human executive control through an integration of neuropsychology, psychopharmacology and functional imaging. Executive control includes the prototypical executive functions of response inhibition and error awareness.Response inhibition can be further divided into action cancellation and action restraint, which were assayed with the stop signal (SST) and Error Awareness (EAT) tasks, respectively. The EAT, which is a modified go-no go paradigm, was also used to measure error awareness behaviour. Monoamine neurotransmitters, specifically dopamine, noradrenaline and serotonin, were modulated during task performance with acute doses of methylphenidate (a dopamine and noradrenaline reuptake inhibitor), atomoxetine (a noradrenaline reuptake inhibitor), citalopram (a serotonin reuptake inhibitor) and cabergoline (a D 2 agonist). The pharmacoimaging correlates of task performance were also examined with functional magnetic resonance imaging (fMRI). All experiments adhered to a randomised, double blind, placebo-controlled, crossover design and were limited to 18-35 year old healthy right-handed male participants.In Chapter 1, twenty-four (24) participants received acute doses of methylphenidate (30mg), atomoxetine (60mg), citalopram (30mg) and placebo and performed the SST. Methylphenidate, but not atomoxetine or citalopram, led to a reduction in response time variability and stop-signal reaction time indicating enhanced action cancellation compared with the other drug conditions. This enhancement occurred without change to overall response speed suggesting that methylphenidate was modulating core response inhibition processes rather than simply augmenting overall processing speed.This result argued for the prominence of dopaminergic, rather than adrenergic or serotonergic, mechanisms in action cancellation.In Chapter 2, the pharmacoimaging correlates of action restraint aspect were explored. Twenty-seven (27) males received acute doses of methylphenidate (30mg), atomoxetine (60mg), citalopram (30mg) and placebo whilst undertaking the EAT during fMRI. No-go related BOLD activations were then correlated for each of the drug conditions. Although Inhibitory performance under methylphenidate was numerically superior to the other drug conditions, this difference did not achieve statistical significance. On fMRI, methylphenidate activated, versus placebo, the anterior cingulate cortex, right inferior frontal, left middle frontal, left angular and right superior temporal gyri and right caudate. Atomoxetine activated a broad network of cortical regions.Both methylphenidate and atomoxetine, but not citalopram, activated superior temporal, right inferior frontal and left middle frontal clusters. Citalopram only activated the left inferior occipital lobe. Taking each condition's activations as functionally defined regions of interest, the specificity of no-go related activity was compared across the four conditions. Only methylphenidate demonstrat...

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