Cellular and Subcellular Localization of the Dopamine Transporter in Rat Cortex

Sesack, Susan R.; Hawrylak, Valerie A.; Guido, Margaret A.; Levey, Aĺlan I.

doi:10.1016/s1054-3589(08)60720-6

Cited by 97 publications

(79 citation statements)

References 5 publications

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“…Together, these results indicate that D1-like receptor stimulation is necessary, but not sufficient, for the reinstatement of cocaine-seeking behavior, similar to instrumental responding maintained by conditioned reinforcement (Winstanley et al, 2006). Conditioned stimuli elicit prolonged increases in dopamine neurotransmission (Garris et al, 1993;Sesack et al, 1998), which may permit the OFC to maintain the internal motivational representation of cocaine-paired contextual stimuli by facilitating glutamatergic inputs to the OFC (Cepeda et al, 1998a;Lapish et al, 2006;Schultz, 2002;Seamans et al, 2003). Furthermore, this phenomenon likely involves glutamatergic afferents from the BLA (Fuchs et al, 2005(Fuchs et al, , 2004Lasseter et al, 2009Lasseter et al, , 2011.…”

Section: Discussionmentioning

confidence: 88%

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Lasseter

Xie

Arguello

et al. 2013

Neuropsychopharmacol

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Cocaine-seeking behavior triggered by drug-paired environmental context exposure is dependent on orbitofrontal cortex (OFC)-basolateral amygdala (BLA) interactions. Here, we present evidence supporting the hypothesis that dopaminergic input from the ventral tegmental area (VTA) to the OFC critically regulates these interactions. In experiment 1, we employed site-specific pharmacological manipulations to show that dopamine D1-like receptor stimulation in the OFC is required for drug context-induced reinstatement of cocaine-seeking behavior following extinction training in an alternate context. Intra-OFC pretreatment with the dopamine D1-like receptor antagonist, SCH23390, dose-dependently attenuated cocaine-seeking behavior in an anatomically selective manner, without altering motor performance. Furthermore, the effects of SCH23390 could be surmounted by co-administration of a sub-threshold dose of the D1-like receptor agonist, SKF81297. In experiment 2, we examined effects of D1-like receptor antagonism in the OFC on OFC-BLA interactions using a functional disconnection manipulation. Unilateral SCH23390 administration into the OFC plus GABA agonist-induced neural inactivation of the contralateral or ipsilateral BLA disrupted drug context-induced cocaine-seeking behavior relative to vehicle, while independent unilateral manipulations of these brain regions were without effect. Finally, in experiment 3, we used fluorescent retrograde tracers to demonstrate that the VTA, but not the substantia nigra, sends dense intra-and interhemispheric projections to the OFC, which in turn has reciprocal bi-hemispheric connections with the BLA. These findings support that dopaminergic input from the VTA, via dopamine D1-like receptor stimulation in the OFC, is required for OFC-BLA functional interactions. Thus, a VTA-OFC-BLA neural circuit promotes drug context-induced motivated behavior.

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Section: Discussionmentioning

confidence: 88%

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Lasseter

Xie

Arguello

et al. 2013

Neuropsychopharmacol

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“…This effect was interpreted as being secondary to effects of DAT on striatal function, given that the expression of DAT in the prefrontal cortex is relatively low (12,(33)(34)(35). However, DAT is generally present in higher concentrations in the parietal than the prefrontal cortex (4,6,67). This observation raises the possibility that variation in DAT may have relatively greater influence on the availability of dopamine in the synaptic cleft of dopaminergic terminals in the parietal cortex compared with cortical regions where removal of synaptic dopamine is primarily a function of COMT (5, 6, 9, 68).…”

Section: Discussionmentioning

confidence: 99%

“…The DAT is a presynaptic neuronal membrane protein, which removes dopamine from the synaptic cleft (1) and is thought to be particularly important as a regulator of phasic dopamine release in subcortical regions where DAT is most abundant (2)(3)(4). In cortical regions, where DAT is less abundant, postsynapatic intracellular degradation by the COMT enzyme is an important regulator of dopamine function (5)(6)(7)(8)(9). In the cortex, DAT is mainly extrasynaptic, and thus, seems better situated to regulating dopamine diffusion to the extrasynaptic space (10)(11)(12).…”

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confidence: 99%

Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia

Prata

Mechelli

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Dopamine has a crucial role in the modulation of neurocognitive function, and synaptic dopamine activity is normally regulated by the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT). Perturbed dopamine function is a key pathophysiological feature of schizophrenia. Our objectives were (i) to examine epistasis between the DAT 3 UTR variable number of tandem repeats (VNTR) and COMT Val158Met polymorphisms on brain activation during executive function, and (ii) to then determine the extent to which such interaction is altered in schizophrenia. Regional brain response was measured by using blood-oxygen-level-dependent fMRI during an overt verbal fluency task in 85 subjects (44 healthy volunteers and 41 patients with DSM-IV schizophrenia), and inferences were estimated by using an ANOVA in SPM5. There was a significant COMT ؋ DAT nonadditive interaction effect on activation in the left supramarginal gyrus, irrespective of diagnostic group (Z-score ‫؍‬ 4.3; familywise error (FWE) p ‫؍‬ 0.03), and in healthy volunteers alone (Z-score ‫؍‬ 4.7; FWEp ‫؍‬ 0.006). In this region, relatively increased activation was detected only when COMT Met-158/Met-158 subjects also carried the 9-repeat DAT allele, or when, reversely, Val-158/Val-158 subjects carried the 10/10-repeat genotype. Also, there was a significant diagnosis ؋ COMT ؋ DAT nonadditive interaction in the right orbital gyrus (Z-score ‫؍‬ 4.3; FWEp ‫؍‬ 0.04), where, only within patients, greater activation was only associated with a 9-repeat allele and Val-158 conjunction, and with a 10-repeat and Met-158 conjunction (Z-score ‫؍‬ 4.3; FWE p ‫؍‬ 0.04). These data demonstrate that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder.

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“…Since DA has higher affinity for NET than for DAT (Eshleman et al, 1999) and PFc DAT densities are relatively low (Sesack et al, 1998) in comparison with PFc NET densities (Schroeter et al, 2000), PFc DA uptake may depend more significantly on NET (Carboni et al, 1990;Moron et al, 2002). In caudate putamen (CPu) and NAc, where DAT densities predominate, DA uptake is likely to depend primarily on DAT (Moron et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Norepinephrine Transporter Blockade can Normalize the Prepulse Inhibition Deficits Found in Dopamine Transporter Knockout Mice

Yamashita

Fukushima

Shen

et al. 2006

Neuropsychopharmacol

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Dopamine transporter knockout (DAT KO) mice display deficits in sensorimotor gating that are manifested by reduced prepulse inhibition (PPI) of the acoustic startle reflex. Since PPI deficits may model some of the cognitive dysfunctions identified in certain neuropsychiatric patients, we have studied the effects of transporter blockers on PPI in wild-type and DAT KO mice. Treatments with High dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters (60 mg/kg cocaine or methylphenidate) significantly impaired PPI in wild-type mice. By contrast, these treatments significantly ameliorated the PPI deficits observed in untreated DAT KO mice. In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine (10 or 30 mg/kg) also significantly reversed PPI deficits in DAT KO mice. By contrast, while the SERT inhibitor fluoxetine (30 mg/kg) normalized these PPI deficits in DAT KO mice, citalopram (30 or 100 mg/kg) failed to do so. The 'paradoxical' effects of cocaine and methylphenidate in DAT KO mice are thus likely to be mediated, at least in part by the ability of these drugs to block NET, although serotonin systems may also have some role. Together with recent microdialysis data, these results support the hypothesis that prefrontal cortical NET blockade and consequent enhancement of prefrontal cortical extracellular dopamine mediates the reversal of PPI deficits in DAT KO mice.

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Cellular and Subcellular Localization of the Dopamine Transporter in Rat Cortex

Cited by 97 publications

References 5 publications

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia

Norepinephrine Transporter Blockade can Normalize the Prepulse Inhibition Deficits Found in Dopamine Transporter Knockout Mice

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