Characterization of extracellular dopamine clearance in the medial prefrontal cortex: Role of monoamine uptake and monoamine oxidase inhibition

ArticleinThe Journal of Neuroscience : The Official Journal of the Society for Neuroscience 21(1):35-44 · February 2001with13 Reads
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.
    • "For an overview of MAO and its role in depression, see Duncan et al., 2012; Finberg, 2014), or (2) uptake by glia cells via DAT and then degraded by either MAO or catechol-O-methyltransferase (COMT, Männistö and Kaakkola, 1999; Karhunen et al., 1995; Schott et al., 2010), or (3) uptake into the postsynaptic neuron by a DAT-independent but yet unknown mechanism and then degraded by COMT (Karhunen et al., 1995; Schott et al., 2010). Notably, the expression of DAT in the PFC is low and dopamine is reuptake by both DAT and norepinephrine transporter (Sesack et al., 1998; Wayment et al., 2001). In addition, D2-like receptors (autoreceptors) are also expressed on the midbrain dopamine neurons and on their axon terminals in projection areas. "
    [Show abstract] [Hide abstract] ABSTRACT: Despite being considered primarily a mood disorder, major depressive disorder (MDD) is characterized by cognitive and decision making deficits. Recent research has employed computational models of reinforcement learning (RL) to address these deficits. The computational approach has the advantage in making explicit predictions about learning and behavior, specifying the process parameters of RL, differentiating between model-free and model-based RL, and the computational model-based functional magnetic resonance imaging and electroencephalography. With these merits there has been an emerging field of computational psychiatry and here we review specific studies that focused on MDD. Considerable evidence suggests that MDD is associated with impaired brain signals of reward prediction error and expected value (‘wanting’), decreased reward sensitivity (‘liking’) and/or learning (be it model-free or model-based), etc., although the causality remains unclear. These parameters may serve as valuable intermediate phenotypes of MDD, linking general clinical symptoms to underlying molecular dysfunctions. We believe future computational research at clinical, systems, and cellular/molecular/genetic levels will propel us towards a better understanding of the disease.
    Full-text · Article · May 2015
    • "Consistent with the existence of a central Uptake 2 system , the residual MPP + uptake observed after suppression of Uptake 1 by cocaine was shown to be sensitive to the selective Uptake 2 inhibitor disprocynium24 (Russ, Sonna, Keppler, Baunach, & Schomig, 1993; Russ, Staust, Martel, Gliese, & Schomig, 1996 ). Other studies also revealed distinct components for DA uptake in rat striatal preparations (Mireylees, Brammer, & Buckley, 1986) and prefrontal cortex (Wayment, Schenk, & Sorg, 2001 ). While some of these early observations may be explained by the strong promiscuity for substrate selectivity between the high-affinity transporters – DA can be transported by the NET and SERT (Larsen et al., 2011) and NE by the DAT and SERT (Vizi, Zsilla, Caron, & Kiss, 2004 ) – a role for OCT devoted solely to peripheral transport had to be reconsidered. "
    [Show abstract] [Hide abstract] ABSTRACT: Organic cation transporters (OCTs) are polyspecific facilitated diffusion transporters that contribute to the absorption and clearance of various physiological compounds and xenobiotics in mammals, by mediating their vectorial transport in kidney, liver or placenta cells. Unexpectedly, a corpus of studies within the last decade has revealed that these transporters also fulfill important functions within the brain. The high-affinity monoamine reuptake transporters (SERT, NET and DAT) exert a crucial role in the control of aminergic transmission by ensuring the rapid clearance of the released transmitters from the synaptic cleft and their recycling into the nerve endings. Substantiated evidence indicate that OCTs may serve in the brain as a compensatory clearance systems in case of monoamine spillover after high-affinity transporter blockade by antidepressants or psychostimulants, and in areas of lower high-affinity transporter density at distance from the aminergic varicosities. In spite of similar anatomical profiles, the two brain OCTs, OCT2 and OCT3, show subtle differences in their distribution in the brain and their functional properties. These transporters contribute to shape a variety of central functions related to mood such as anxiety, response to stress and antidepressant efficacy, but are also implicated in other processes like osmoregulation and neurotoxicity. In this review, we discuss the recent knowledge and emerging concepts on the role of OCTs in the uptake of aminergic neurotransmitters in the brain and in these various physiological functions, focusing on the implications for mental health.
    Full-text · Article · Sep 2014
    • "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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Sep 2014
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