Dopamine D<sub>4</sub>Receptors Modulate GABAergic Signaling in Pyramidal Neurons of Prefrontal Cortex

Wang, Xun; Zhong, Ping; Yan, Zhen

doi:10.1523/jneurosci.22-21-09185.2002

Cited by 148 publications

(125 citation statements)

References 60 publications

(69 reference statements)

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“…The presence of D 4 receptor in pyramidal neurons places this receptor in an ideal location to modulate working memory. Indeed, electrophysiological studies using D 4 selective ligands or knockout mice provided strong evidence that physiological property of PFC pyramidal neurons is regulated by D 4 receptor in normal condition (Rubinstein et al, 2001;Wang et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Zhang

Grady

Tsapakis

et al. 2004

Neuropsychopharmacol

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Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D 1 and D 2 receptors, with most evidence suggesting a dominant role for the D 1 receptor. Since the dopamine D 4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D 4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D 4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D 4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D 4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D 4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D 4 receptor in working memory, and suggest innovative, D 4 -based, treatment of cognitive deficits associated with neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Zhang

Grady

Tsapakis

et al. 2004

Neuropsychopharmacol

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“…6,8,12,13 However, mice deficient in D4 expression display increased anxiety 14 and altered exploratory behavior. 15 Dopamine D4 receptor activation can modulate many intracellular signaling cascades in heterologous expression systems, 1 and has been shown to inhibit adenylyl cyclase, 16,17 inhibit GABAa currents, 18 and stimulate extracellular regulated kinase (ERK) and depress NMDA channel activity via transactivation of the plateletderived growth factor receptor-b in the central nervous system. 19 The biological role of this receptor is less well established, but studies with D4-deficient mice and selective D4 receptor antagonists support a role of this receptor in attention and cognition.…”

Section: Introductionmentioning

confidence: 99%

The human dopamine D4 receptor repeat sequences modulate expression

2003

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Genetic studies have implicated a polymorphic repeat sequence in exon 3 of the human dopamine D4 receptor in various behavioral and psychiatric disorders. Functionally various repeat variants are nearly identical, but whether these have different effects on gene expression has not been studied. To study the role of the repeat sequences on expression independently from its structural and functional effects at the protein level, we introduced these sequences immediately upstream of the promoter and in the 3 0 untranslated region of a luciferase reporter vector. In this report, we demonstrate that the repeat sequence can both modulate promoter activity and alter expression post-transcriptionally. The repeat sequence can serve as a substrate for a nuclear binding factor and all the three repeat variants can suppress promoter activity. Placement of the three repeat variants downstream from the luciferase gene in the expression vector shows, however, that the D4.7 repeat sequence has significantly suppressed expression of the reporter compared to the D4.2 and D4.4 repeats, likely via mechanisms involving RNA stability or translational efficiency. These data indicate that the various D4 repeat sequences have different effects on expression, which may explain its potential role in behavioral disorders.

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“…Evidence for an inhibitory action of D2-D4 receptors in the frontal cortex is derived from studies in which D4-deficient mice exhibit spontaneous hyperexcitability in PFC pyramidal neurons (Rubinstein et al, 2001); however, this could be due to enhanced expression of NMDA and D1 receptors in D4 knockout mice (Gan et al, 2004). In contrast, a D2 subtype (D4)-mediated DA facilitatory action on membrane excitability in PFC pyramidal neurons was also reported (Ceci et al, 1999), and D4 receptor activation decreases GABA A receptor-mediated synaptic currents in dissociated prefrontal pyramidal neurons (Wang et al, 2002). Thus, there is no consensus as to which DA receptor subtype is involved in the inhibitory action of DA on PFC neuron excitability.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

Onn

Wang

Lin

et al. 2005

Neuropsychopharmacol

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Although dopamine (DA) effects in the prefrontal cortex (PFC) have been studied extensively, the function of steady-state ambient levels of DA in the regulation of afferent excitatory transmission in PFC pyramidal neurons remains relatively unexplored. Using intracellular sharp-electrode and whole-cell recordings combined with intracellular labeling in brain slices, we found that D1/D5 receptor blockade did not alter synaptic responses in the PFC, but D1/D5 receptor activation consistently enhanced recurrent synaptic excitation in the majority of pyramidal neurons tested. In contrast, D4 receptor blockade resulted in an evoked complex multiple spike discharge pattern that contained both early and late (presumably multisynaptic) components of the evoked response that is contingent upon the preservation of axon collaterals of the neuron under study. Moreover, GABAergic interneurons were found to play a role in both responses; blockade of GABA a -mediated inhibition caused bath application of DA to convert monosynaptic excitatory postsynaptic potentials (EPSPs) to complex spike bursts riding on the late component of the EPSP. On the other hand, during the blockade of GABA amediated conductances, administration of a D4 receptor antagonist failed to facilitate evoked multiple spike discharge. Morphological analysis of axon collaterals of labeled neurons revealed that neurons in which the D4 receptor blockade induced the putative polysynaptic response had axon collaterals that were largely preserved. These data suggest that DA exerts a bidirectional modulation of PFC pyramidal neurons in brain slices provided that local network connections with interneurons are preserved, with D4 receptors under tonic stimulation by ambient low levels of DA, whereas D1/D5 receptors activated upon phasic DA input.

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Dopamine D₄Receptors Modulate GABAergic Signaling in Pyramidal Neurons of Prefrontal Cortex

Cited by 148 publications

References 60 publications

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Regulation of Working Memory by Dopamine D4 Receptor in Rats

The human dopamine D4 receptor repeat sequences modulate expression

Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

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Dopamine D4Receptors Modulate GABAergic Signaling in Pyramidal Neurons of Prefrontal Cortex

Cited by 148 publications

References 60 publications

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Regulation of Working Memory by Dopamine D4 Receptor in Rats

The human dopamine D4 receptor repeat sequences modulate expression

Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

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Dopamine D₄Receptors Modulate GABAergic Signaling in Pyramidal Neurons of Prefrontal Cortex