Individual differences in impulsive action and dopamine transporter function in rat orbitofrontal cortex

Yates, Justin R.; Darna, Mahesh; Beckmann, Joshua S.; Dwoskin, Linda P.; Bardo, Michael T.

doi:10.1016/j.neuroscience.2015.11.033

Cited by 21 publications

(15 citation statements)

References 77 publications

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“…The k t is in good agreement with estimates of the endogenous tissue concentrations of p -tyramine, indicating that uptake by this transporter is likely to be physiologically relevant. The V max equates to a value of 1.8 pmol/mg protein/min and is similar to values reported for the selective transport of dopamine by DAT71 or serotonin by SERT72 in synaptosome preparations. Although we controlled for diffusion of p -tyramine into the synaptosomes, we cannot prevent diffusion back out, and this may well result in the apparent net V max obtained being an underestimate of the true value.…”

Section: Discussionsupporting

confidence: 84%

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

Berry

Hart

Pryor

et al. 2016

Sci Rep

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p-Tyramine is an archetypal member of the endogenous family of monoamines known as trace amines, and is one of the endogenous agonists for trace amine-associated receptor (TAAR)1. While much work has focused on the function of TAAR1, very little is known about the regulation of the endogenous agonists. We have previously reported that p-tyramine readily crosses lipid bilayers and that its release from synaptosomes is non-exocytotic. Such release, however, showed characteristics of modification by one or more transporters. Here we provide the first characterization of such a transporter. Using frontal cortical and striatal synaptosomes we show that p-tyramine passage across synaptosome membranes is not modified by selective inhibition of either the dopamine, noradrenaline or 5-HT transporters. In contrast, inhibition of uptake-2 transporters significantly slowed p-tyramine re-uptake. Using inhibitors of varying selectivity, we identify Organic Cation Transporter 2 (OCT2; SLC22A2) as mediating high affinity uptake of p-tyramine at physiologically relevant concentrations. Further, we confirm the presence of OCT2 protein in synaptosomes. These results provide the first identification of a high affinity neuronal transporter for p-tyramine, and also confirm the recently described localization of OCT2 in pre-synaptic terminals.

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Section: Discussionsupporting

confidence: 84%

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

Berry

Hart

Pryor

et al. 2016

Sci Rep

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“…Acute GBR 12909 increased impulsive choice and action in rats (Evenden and Ryan 1996, van Gaalen et al 2006, Baarendse and Vanderschuren 2012, therefore it has been postulated that DAT inhibition mediates impulsivity. Indeed, the results of the recent study, showing that that impulsive behavior in cued go/ no-go task is associated with inherent variation in DAT level (decreased DAT function) in OFC (Yates et al 2016), confirm that assumption. Our results, showing more commission errors in GBR 12909-treated in comparison with control mice but no differences between these groups of mice in the number of omission errors, fortify the assumption indicating that DAT inhibition, rather than up-regulation, influences impulsive behavior.…”

Section: Discussionsupporting

confidence: 54%

Potential role of dopamine transporter in behavioral flexibility

Cybulska-Kłosowicz¹,

Dąbrowska²,

Niedzielec³

et al. 2017

Acta Neurobiologiae Experimentalis

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Behavioral flexibility is subserved by the prefrontal cortex and the basal ganglia. Orbitofrontal cortex (OFC) and dorsomedial striatum (DMS) form a functional frontocorticostriatal circuit crucial for the mediation of flexibility during reversal learning via dopamine (DA) neurotransmission. The regulatory control in maintaining DA homeostasis and function is provided by the dopamine transporter (DAT), which therefore likely plays a significant role in controlling the influence of DA on cognitive processes. Here we used a gene knockout mouse model to investigate the role of DAT in the performance on the Attentional Set-Shifting Task (ASST) stages dependent upon the OFC and the DMS. Additionally, behavior of mice after repeated administration of selective DAT inhibitor, GBR 12909, was examined.The animals were treated with the inhibitor to elicit a compensatory DAT up-regulation following withdrawal. Learning was slower and the number of errors during reversal learning and intra-dimensional shift stages was higher in DAT+/− mutant mice than in WT mice. GBR 12909-treated mice had deficits in reversal stages of the ASST. Neuronal activation in the OFC and DMS during the ASST was examined with early growth response proteins 1 and 2 (egr-1, egr-2) immunohistochemistry. Density of egr-2 labeled cells in the OFC was lower in mutant mice than in wild-types during reversal learning and the expression of the egr-1 was lower in mutant mice in the OFC and DMS during reversal and intra-dimensional shift stages. Mice with decreased DAT levels displayed behavioral difficulties that were accompanied by a lower task-induced activation of neurons in brain regions involved in the reversal learning. Altogether, these data indicate the role of the DAT in the behavioral flexibility.

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“…However, it is also worth noting that much of this work was largely or exclusively conducted in males, and may therefore fail to identify circuitry or neurochemistry unique to females (see below), particularly given the male −female differences in executive function strategies we have previously described. The prefrontal cortex has received significant attention with regard to executive function, with links to attention, impulsivity, and working memory, including both medial PFC (mPFC) [118][119][120] and the orbitofrontal cortex (oPFC) [121,122]. Normal PFC function requires a balance between excitatory drive from glutamate neurons and inhibitory drive from GABA neurons, and both GABA [120,123,124] and glutamate [124,125] have been linked to executive function.…”

Section: Programmingmentioning

confidence: 99%

Let’s call the whole thing off: evaluating gender and sex differences in executive function

Grissom

Reyes

2018

Neuropsychopharmacol

195

144

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The executive functions allow for purposeful, deliberate, and intentional interactions with the world-attention and focus, impulse control, decision making, and working memory. These measures have been correlated with academic outcomes and quality of life, and are impacted by deleterious environmental events throughout the life span, including gestational and early life insults. This review will address the topic of sex differences in executive function including a discussion of differences arising in response to developmental programming. Work on gender differences in human studies and sex differences in animal research will be reviewed. Overall, we find little support for significant gender or sex differences in executive function. An important variable that factors into the interpretation of potential sex differences include differing developmental trajectories. We conclude by discussing future directions for the field and a brief discussion of biological mechanisms.

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Individual differences in impulsive action and dopamine transporter function in rat orbitofrontal cortex

Cited by 21 publications

References 77 publications

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

Potential role of dopamine transporter in behavioral flexibility

Let’s call the whole thing off: evaluating gender and sex differences in executive function

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