α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex

Wang, Min; Ramos, Brian P.; Paspalas, Constantinos D.; Shu, Yousheng; Simen, Arthur A.; Duque, Alvaro; Vijayraghavan, Susheel; Brennan, Avis R.; Dudley, Anne; Nou, Eric; Mazer, James A.; McCormick, David A.; Arnsten, Amy F.T.

doi:10.1016/j.cell.2007.03.015

Cited by 607 publications

(802 citation statements)

References 43 publications

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“…Indeed, stimulation of a 2A -ARs does not always enhance working memory function. For example, iontophoresis of a low dose of guanfacine (at 5 nA) enhances delay-related firing, while a high dose (at 50 nA) does not (see Figure 2b of Wang et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…For example, previous studies show that stimulation of a 2 -ARs enhances PFC neuronal activity that is related to working memory Wang et al, 2007), while blockade of a 2 -ARs inhibits the working memory-related PFC neuronal activity Sawaguchi and Yamane, 1999;Wang et al, 2007). However, it is poorly understood how a 2 -ARs regulate synaptic transmission in the PFC.…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of α2-Adrenoceptors Suppresses Excitatory Synaptic Transmission in the Medial Prefrontal Cortex of Rat

Zhang

et al. 2007

Neuropsychopharmacol

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Stimulation of a 2 -, especially a 2A -adrenoceptor (AR), in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. a 2 -Adrenergic agonists like clonidine and guanfacine have been used experimentally and clinically for treatment of psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. However, the neurophysiological actions of a 2 -ARs in the PFC are poorly understood. In the present study, we recorded field excitatory post-synaptic potential (fEPSP) and evoked excitatory post-synaptic current (eEPSC) in the medial prefrontal cortex (mPFC) of rats, using in vivo field-potential recording and in vitro whole-cell patch-clamp recording techniques, and examined the effects of the a 2 -AR agonist clonidine and the selective a 2A -AR agonist guanfacine on fEPSP and eEPSC. Systemic or intra-mPFC application of clonidine or guanfacine significantly reduced fEPSP in the mPFC, either in anesthetized or freely moving rats. Consistently, bath-application of guanfacine suppressed eEPSC in layer V/VI pyramidal neurons, and this effect was blocked by the a 2 -AR antagonist yohimbine or the G i inhibitor NF023. Moreover, treatment with guanfacine had no effect on paired-pulse facilitation (PPF) of fEPSP and eEPSC. The present study provides the first electrophysiological evidence that stimulation of a 2A -AR inhibits excitatory synaptic transmission in the mPFC through a post-synaptic mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stimulation of α2-Adrenoceptors Suppresses Excitatory Synaptic Transmission in the Medial Prefrontal Cortex of Rat

Zhang

et al. 2007

Neuropsychopharmacol

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“…Given the beneficial effects of clonidine and related a 2 agonists on prefrontal cortical function (Li et al, 1999;Wang et al, 2007) as well as the important role of the prefrontal cortex in the positive actions of a 2 agonists on spatial working memory (Arnsten and Goldman-Rakic, 1985;see Arnsten, 2004 for review), it is likely that if clonidine improves memory in either model, this phenomenon would be linked to enhanced prefrontal cortical function. In the case of animals with hippocampal damage, the enhancement of prefrontal function could act to compensate for the loss of hippocampal modulation of spatial working memory.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Clonidine on Discrete-Trial Delayed Spatial Alternation in Two Rat Models of Memory Loss

Bardgett

Points

Ramsey-Faulkner

et al. 2007

Neuropsychopharmacol

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Spatial memory impairments observed in Alzheimer's disease and schizophrenia have been attributed to many factors, including glutamate hypofunction and reduced hippocampal volume. Clonidine, a non-specific a 2 adrenergic receptor agonist, improves spatial memory in animals treated with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine; however, its effects on memory deficits produced by other NMDA antagonists or hippocampal damage have not been fully characterized. The purpose of this study was to determine if clonidine could alleviate memory deficits produced by the NMDA antagonist, MK-801, or by excitotoxic hippocampal damage. In the first phase of the study, male rats were pretreated with clonidine (0.01 or 0.05 mg/kg) or saline, and treated with MK-801 (0.1 mg/kg) or saline prior to discrete-trial delayed alternation or radial-arm maze testing. MK-801 impaired delayed alternation performance and increased the number of arm revisits in the radial-arm maze. Clonidine pretreatment significantly alleviated these druginduced deficits. In the second phase of the study, excitotoxic damage was produced in the dorsal hippocampus with NMDA. Hippocampal damage produced a significant impairment in the delayed alternation task, yet pretreatment with clonidine did not alleviate this damage-induced deficit. Taken together, the data indicate that clonidine alleviates memory impairments produced by glutamate hypofunction, but not by hippocampal damage. This caveat may be important in designing treatments for memory disorders not linked to a single pathophysiological mechanism.

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“…Our work showed that both systemic administration and local infusion of guanfacine into the PFC improve visuomotor associative learning [70,75] . Using an iontophoretic technique, stimulation of α 2A -adrenoceptors in the PFC was found to increase the spiking activity associated with working memory in behaving monkeys [37,76] .Neuronal activity in the PFC associated with working memory can be enhanced by α 2A -adrenoceptor stimulation through cAMP-HCN signaling pathways [76,77] . Our work suggested that under normal physiological conditions, the α 2A -adrenoceptors in pyramidal cells can be activated through Gi-cAMP-HCN signaling [78] .…”

mentioning

confidence: 99%

“…On the other hand, PFC functions might occur via the Gi-cAMP-PKA-CaMKII-AMPAR signaling pathway [76] . Both mechanisms together optimize the synaptic inputs to pyramidal neurons and determine the synaptic outputs for PFC cognitive functions.Indeed, it has been reported that guanfacine at relatively high doses suppresses evoked excitatory postsynaptic currents, and has no enhanced effect or even suppresses delay-related activity [76] . conform to a theoretical rationale for ADHD, account for the neurobiology, and respond to therapeutic interventions both behaviorally and pharmacologically [79] .…”

mentioning

confidence: 99%

Prefrontal cortical α2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder

Sun

Luo

et al. 2015

Neurosci. Bull.

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Attention deficit and hyperactivity disorder (ADHD), a prevalent syndrome in children worldwide, is characterized by impulsivity, inappropriate inattention, and/or hyperactivity. It seriously afflicts cognitive development in childhood, and may lead to chronic under-achievement, academic failure, problematic peer relationships, and low self-esteem. There are at least three challenges for the treatment of ADHD. First, the neurobiological bases of its symptoms are still not clear. Second, the commonly prescribed medications, most showing short-term therapeutic efficacy but with a high risk of serious side-effects, are mainly based on a dopamine mechanism. Third, more novel and effi cient animal models, especially in nonhuman primates, are required to accelerate the development of new medications. In this article, we review research progress in the related fi elds, focusing on our previous studies showing that blockade of prefrontal cortical α 2A -adrenoceptors in monkeys produces almost all the typical behavioral symptoms of ADHD.Keywords: prefrontal cortex; α 2A -adrenoceptors; cognitive functions; attention defi cit and hyperactivity disorder; animal models ·Review· IntroductionAttention deficit and hyperactivity disorder (ADHD) is one of the most prevalent childhood neurodevelopmental conditions, affecting 3-5% of grade-school children worldwide [1] . It is characterized by i nappropriate levels of inattention, i mpulsivity, and/or hyperactivity [2][3][4] . These symptoms develop in childhood, and can persist into adolescence and adulthood [5] . ADHD seriously affects cognitive development [6][7][8] , and, without appropriate treatment, has consequences for the risk of anxiety, substance abuse, and depression in adulthood [ 2, 5, 9] .T he neurobiological bases o f ADHD symptoms are still not clear [10] . Clarifying them can help better understand the biological vulnerabilities that may underlie ADHD in a specifi c patient and how to modulate the responses to treatment, thereby contributing to better and more effective therapy.It has been suggested that the symptoms involve a dopaminergic mechanism in the prefrontal cortex (PFC) and striatum [11, 12] . Experimentally decreased dopamine (DA) release in the PFC results in ADHD-like symptoms [13, 14] .To date, DA dysregulation is thought to be central to the neurobiology of ADHD, and its pharmacological treatment, such as m ethylphenidate (MPH, i.e. Ritalin) [15][16][17] , levels the DA c oncentration in the synapse and extrasynaptic space in the PFC as a blocker of the DA transporter. MPH ameliorates inappropriate inattention [18][19][20] , decreases impulsivity [21] , and enhances inhibitory control [22] . However, as MPH is a prescription psychostimulant, there are strong concerns over drug dependence, paranoia, schizophrenia, and behavioral sensitization that might be caused by longterm therapy, similar to other stimulants [23][24][25].Converging evidence indicates that the pathophysiology of ADHD has multiple origins [26][27][28][29][30][31][32] ; for i...

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α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex

Cited by 607 publications

References 43 publications

Stimulation of α2-Adrenoceptors Suppresses Excitatory Synaptic Transmission in the Medial Prefrontal Cortex of Rat

Stimulation of α2-Adrenoceptors Suppresses Excitatory Synaptic Transmission in the Medial Prefrontal Cortex of Rat

The Effects of Clonidine on Discrete-Trial Delayed Spatial Alternation in Two Rat Models of Memory Loss

Prefrontal cortical α2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder

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