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

Abstract

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...

Understanding the roles of central and autonomic activity during sleep in the improvement of working memory and episodic memory

“…This body of research emphasizes the role of increased inhibitory function during distracting conditions that serve to benefit WM specifically ( 41 ), while having no benefit for hippocampal memory ( 42 ). Interestingly, α2 adrenergic receptors preferentially increased prefrontal NE and maintain its optimal excitatory–inhibitory balance, which in turn improves prefrontal function ( 43 – 45 ), whereas α1 receptors override α2 receptor activity and impair WM function ( 38 ). The emerging picture is that different types of adrenergic receptors may play a role in optimizing the overall excitatory–inhibitory balance in the prefrontal cortex.…”

Potential Role of ADRA2A Genetic Variants in the Etiology of ADHD Comorbid With Tic Disorders

“…The α2-adrenoceptors are primarily located in the nervous system, with the highest density of α2A-adrenoceptors located in the PFC (Huss, Chen, & Ludolph, 2016). Animal studies have demonstrated that blockade of the α2A-adrenoceptors in the PFC causes several cognitive and behavioral problems, while stimulation of α2A-adrenoceptors improves prefrontal cognitive dysfunctions (Ma, Sun, Luo, & Li, 2015). In humans, α2-adrenoceptor agonists (such as clonidine and guanfacine) have been applied to treat ADHD and TD for decades (Egolf & Coffey, 2014; Huss et al, 2016; Oluwabusi, Parke, & Ambrosini, 2016).…”

Distinct Roles of Dopamine Receptors in the Lateral Thalamus in a Rat Model of Decisional Impulsivity

“…Impulsivity is simply defined as the tendency to act prematurely without foresight [1], and is generally separated into: (1) decisional impulsivity, defined as ''actions initiated without due deliberation of other possible options or outcome behaviors''; and (2) motor impulsivity, defined as behaviors that are ''premature, mistimed, difficult to control and suppress'' [2]. Many diseases are closely associated with impulsivity, such as attention deficit hyperactivity disorder, substance abuse disorder, Parkinson's disease, conduct disorder, and personality disorders [3][4][5][6][7]. Here, we focused on the decisional impulsivity for large rewards in a delay discounting task [8,9], which has been validated in humans and animals.…”