Wayment HK, Schenk JO, Sorg BA. Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition. J Neurosci 21: 35-44

Department of Chemistry, Washington State University, Pullman, Washington 99164, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2001; 21(1):35-44.
Source: PubMed

ABSTRACT In vitro rotating disk electrode (RDE) voltammetry and in vivo microdialysis were used to characterize dopamine clearance in the rat medial prefrontal cortex (mPFC). RDE studies indicate that inhibition by cocaine, specific inhibitors of the dopamine transporter (DAT) and norepinephrine transporter (NET), and low Na(+) produced a 50-70% decrease in the velocity of dopamine clearance. Addition of the monoamine (MAO) inhibitors, l-deprenyl, clorgyline, pargyline, or in vivo nialamide produced 30-50% inhibition. Combined effects of uptake inhibitors with l-deprenyl on dopamine clearance were additive (up to 99% inhibition), suggesting that at least two mechanisms may contribute to dopamine clearance. Dopamine measured extracellularly 5 min after exogenous dopamine addition to incubation mixtures revealed that most conditions of DAT/NET inhibition did not produce elevated dopamine levels above controls. Inhibition of MAO produced elevated dopamine levels only after long-term, but not short-term, incubation in vitro. Short-term incubation of l-deprenyl combined with DAT and NET uptake inhibitors increased dopamine above control levels, consistent with more than one mechanism of dopamine clearance. Local infusion of pargyline (100 or 300 microm) into the mPFC or striatum via microdialysis produced more pronounced and immediate increases in mPFC dopamine levels compared with striatum. Furthermore, dopamine elevation in the mPFC was not accompanied by a decrease in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, as found in the striatum. These findings may have revealed a unique mechanism of mPFC dopamine clearance and therefore contribute to the understanding of multiple behaviors that involve mPFC dopamine transmission, such as schizophrenia, drug abuse, and working memory function.

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    • "In the present study, BUP administration accelerated extinction in WKY rats, supporting a positive DA involvement in extinction learning. Moreover, PFC DA is important for cognitive processes such as decision-making and avoidance, but PFC has very low DAT distribution in rats and the reuptake of DA in this region mainly relies on NET (Wayment et al., 2001; Moron et al., 2002). Therefore, both DES and BUP may elicit similar effects (i.e., increased synaptic DA and NE levels) within PFC, which is a possible mechanism underlying their similar effects on extinction in WKY rats. "
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    ABSTRACT: Avoidance and its perseveration represent key features of anxiety disorders. Both pharmacological and behavioral approaches (i.e. anxiolytics and extinction therapy) have been utilized to modulate avoidance behavior in patients. However, the outcome has not always been desirable. Part of the reason is attributed to the diverse neuropathology of anxiety disorders. Here, we investigated the effect of psychotropic drugs that target various monoamine systems on extinction of avoidance behavior using lever-press avoidance task. Here we used the Wistar-Kyoto (WKY) rat, a unique rat model that exhibits facilitated avoidance and extinction resistance along with malfunction of the dopamine (DA) system. Sprague Dawley (SD) and WKY rats were trained to acquire lever-press avoidance. WKY rats acquired avoidance faster and to a higher level compared to SD rats. During pharmacological treatment, bupropion, and desipramine significantly reduced avoidance response selectively in WKY rats. However, after the discontinuation of drug treatment, only those WKY rats that were previously treated with desipramine exhibited lower avoidance response compared to the control group. In contrast, none of the psychotropic drugs facilitated avoidance extinction in SD rats. Instead, desipramine impaired avoidance extinction and increased non-reinforced response in SD rats. Interestingly, paroxetine, a widely used antidepressant and anxiolytic, exhibited the weakest effect in WKY rats and no effects at all in SD rats. Thus, our data suggest that malfunctions in brain catecholamine system could be one of the underlying etiologies of anxiety-like behavior, particularly avoidance perseveration. Pharmacological manipulation targeting DA and norepinephrine is more effective to facilitate extinction learning in this strain. The data from the present study may shed light on new pharmacological approaches to treat patients with anxiety disorders who are not responding to serotonin re-uptake inhibitors.
    Frontiers in Behavioral Neuroscience 09/2014; 8:322. DOI:10.3389/fnbeh.2014.00322 · 3.27 Impact Factor
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    • "One likely mechanism would be the norepinephrine (NE) input to the mPFC, which is known to be activated by stress and appears to regulate DA-mediated function [47]. In the mPFC, for instance, DA re-uptake appears to be mediated as much, if not more, by the NET than by the DAT [48]. Thus, it is likely that some of the group and hemispheric differences in the mPFC dopaminergic activity in response to acute stress might reflect alterations in NET levels. "
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    ABSTRACT: There is increasing evidence that maternal stress may have long-term effects on brain development in the offspring. In this study, we examined whether pre-gestational stress might affect offspring rats on the medial prefrontal cortical (mPFC) dopaminergic activity in response to acute stress in puberty and if so, whether such effects exhibited hemispheric asymmetry or sexual dimorphism. We used behavioural tests to assess the model of chronic unpredictable stress (CUS). We found that the activity in the open field test and sucrose intake test were lower for maternal rats in the CUS group than those in the control group. Offspring rats in the CUS group floated more and swam or climbed less as compared to the offsprings in the control group in the forced swimming test. The floating time was longer and swimming or climbing time was shorter in the female offspring rats than those in the males. Serum corticosterone and corticotrophin-releasing hormone levels were significantly higher for CUS maternal rats and their offsprings than the respective controls. The ratio of dihydroxy-phenyl acetic acid (DOPAC) to dopamine (DA), DA transporter (DAT), norepinephrine transporter (NET) were lower in the mPFC of offspring rats in the CUS group than the control group. Levels of catechol-O-methyltransferase (COMT) in the left mPFC of female offspring rats and in the right mPFC of both female and male offspring rats were lower in the CUS group than those in the controls, but there was no difference in the left mPFC of male offspring between the CUS and control groups. DOPAC, the ratio of DOPAC to DA, NET and COMT were lower in the right mPFC than in the left mPFC of offspring rats in the CUS group. The ratio of DOPAC to DA in the right mPFC was lower in the female offspring rats than male offspring rats in the CUS group. The NET and COMT levels in both left and right mPFC were lower in the female offspring rats than those of the male offsprings in the CUS group. Our data provide evidence that the effect of pre-gestational stress on the mPFC dopaminergic activity in response to acute stress exhibited hemispheric asymmetry and sexual dimorphism in the pubertal offspring rats.
    BMC Neuroscience 07/2013; 14(1):67. DOI:10.1186/1471-2202-14-67 · 2.67 Impact Factor
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    • "As a second DA candidate, we chose to investigate the DAT1 VNTR, referring to a variable number of tandem repeats (VNTR) polymorphism within the dopamine transporter (DAT) gene. In contrast to the COMT, the DAT is highly abundant in the striatum, where it serves as the key protein for DA reuptake [33] [34]. The gene coding for the DAT (DAT1) contains a VNTR polymorphism that determines transporter availability [35] [36] [37] and hence, striatal DA reuptake. "
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    ABSTRACT: The late positive components of the human event-related brain potential comprise electrocortical reflections of stimulus-driven attentional capture (the anteriorly distributed P3a) and top-down control detection of relevant events (the posteriorly distributed P3b). As of yet, the neuropharmacologic and neurogenetic origin of the P3a and P3b is not fully understood. In this study, we address the contribution of dopaminergic and serotoninergic mechanisms. Sixty healthy females completed an active auditory novelty oddball paradigm while EEG was recorded. In all subjects, genetic polymorphisms within the dopamine system (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT val158met]) and the serotonin system (serotonin transporter [5HTTLPR]) were assessed. Across genotypes, novels (relative to standards) elicited a fronto-centrally distributed P3a, and targets (relative to standards) a parieto-centrally distributed P3b. Genotypes effects were observed for both P3a (COMT, 5HTTPLR) and P3b (DAT1, COMT, 5HTTLPR) only at prefrontal electrode location (Fz). Specifically, the frontal P3a was enhanced in COMT met/met homozygotes, but not in DAT1 9R. The target-related P3b was enhanced in COMT met/met and DAT1-9R relative to its genetic counterparts, but only at frontal electrodes. This 'anteriorized' enhancement may reflect either an additional frontal component in the target-related P3 dependent on dopamine, or a more subtle shift in the neural ensemble that generates the target-related P3. Results for 5HTTLPR short allele homozygotes mimicked those in COMT met/met homozygotes. In all, the present findings suggest involvement of frontal-cortical dopaminergic and serotoninergic mechanisms in bottom-up attentional capture (COMT val158met, 5HTTLPR), with an additional top-down component sensitive to striatal signals (DAT1).
    Behavioural brain research 04/2013; 249. DOI:10.1016/j.bbr.2013.04.013 · 3.03 Impact Factor
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