|Year : 2016 | Volume
| Issue : 4 | Page : 146-151
Role of norepinephrine reuptake inhibitors in attention deficit hyperactivity disorder: A mechanism-based short review
Prasad Govindrao Jamkhande, Abraruddin Khawaja
Department of Pharmacology, School of Pharmacy, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra, India
|Date of Submission||14-Jul-2016|
|Date of Acceptance||07-Sep-2016|
|Date of Web Publication||7-Oct-2016|
Prasad Govindrao Jamkhande
Department of Pharmacology, School of Pharmacy, Swami Ramanand Teerth Marathwada University, Dnyanteerth, Vishnupuri, Nanded 431 606, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Prevalence of neurobehavioral disorder is increasing worldwide. Attention deficit hyperactivity disorder (ADHD) is among the most common neurobehavioral disorder observed in the children. It is associated with behavioral symptoms such as hyperactivity, attention deficit, impulsivity, and excessive motor activity. The wide range of conditions and factors produces abnormality in neuronal functioning. Alteration in the prefrontal cortex and its links to the striatum and cerebellum; and change in the level of catecholamine are predominantly responsible for ADHD. Dopamine (DA) and norepinephrine (NE) released in these areas regulate network activity. Physiological actions of catecholamine are regulated through activation of receptors such as α1, α2 , β1, β2 , β3 , and D1. The less release of DA or NE leads to insufficient activation of postsynaptic D 1 and α2 A receptors, whereas overstimulation of these catecholamines in conditions such as stress creates abnormal behavioral response and attention. NE reuptake inhibitors selectively enhance the level of catecholamine by interfering with transport proteins, metabolizing enzyme, blocking different sites on receptor and neuronal activity index. The present review gives insights of the role of NE reuptake inhibitors in ADHD.
Keywords: Atomoxetine, attention deficit hyperactivity disorder, ciclazindol, guanfacine, monoamine reuptake inhibitors, norepinephrine reuptake inhibitors
|How to cite this article:|
Jamkhande PG, Khawaja A. Role of norepinephrine reuptake inhibitors in attention deficit hyperactivity disorder: A mechanism-based short review. Int J Nutr Pharmacol Neurol Dis 2016;6:146-51
|How to cite this URL:|
Jamkhande PG, Khawaja A. Role of norepinephrine reuptake inhibitors in attention deficit hyperactivity disorder: A mechanism-based short review. Int J Nutr Pharmacol Neurol Dis [serial online] 2016 [cited 2021 Nov 27];6:146-51. Available from: https://www.ijnpnd.com/text.asp?2016/6/4/146/191660
| Introduction|| |
Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric syndrome characterized by abnormal attention ability and motor activity. It mainly includes hyperactivity, attention deficit, impulsivity, and excessive motor movement. It is mostly diagnosed clinically in children, particularly school age and adolescent. , Inattention, impulsivity, and hyperactivity are the three fundamental symptoms of ADHD. American Psychiatric Association classified ADHD into three subtypes on the basis of fundamental symptoms. (1) Inattentive ADHD, (2) predominantly hyperactive or impulsive ADHD, (3) combined type of ADHD. The patients of inattentive ADHD have the inability to stay focused on any activity or task, lack of attention ability for the duration of task and generally avoid the task requiring sustained mental efforts.  Patients of this type of disorder are confused, daydreamers, and lethargic. Patients with hyperactive ADHD have difficulty in staying seated or completing task silently and usually nervous, very active, and talk continuously without thinking. Patient with impulsive subtype gets difficult to participate in tasks that require taking turns, whereas patients of combined ADHD type show both the types of symptoms; inattention and hyperactive-impulsive behavior. ,
| Prevalence|| |
ADHD is among the most common neurobehavioral disorder observed in the children of age 6-17 years. Prevalence is higher in developed countries. In the United States, 2%-18% of children of this age are suffering from this ADHD. Not only children but also adults suffering from ADHD and prevalence is near about 4%-4.5% in the United States.  Symptoms are observed in 3%-7% of school children indicating large population is suffering from ADHD. The prevalence is more in boys as compared to girls. Three to five boys diagnosed with ADHD for every girl.  This is because boys are referred more for behavioral problems while girls are referred more for learning problems, therefore, girls are at the risk of remaining under detected and untreated. 
| Etiology and Pathophysiology|| |
Abnormality in neuronal functioning is the main etiology of ADHD. Factors such as brain injury, neurological, and genetic abnormalities are responsible for ADHD. Studies such as neuropsychological and imaging revealed that alteration in prefrontal cortex (PFC) and its links to the striatum and cerebellum [Figure 1] are associated with the development of ADHD.  The right hemisphere of PFC is particularly responsible for regulation of behavior and attention. This part is very sensitive to surrounding chemical environment, including catecholamine release and modifies cognitive control of attention and behavior. Dysfunctioning of the transporter system decreases levels of dopamine (DA) and norepinephrine (NE) in these areas. 
|Figure 1: Prefrontal cortex, striatum and cerebellum network in brain which regulates behavioral response and attention|
Click here to view
A network of neurons interconnects PFC, striatum and cerebellum parts of the brain, which together control behavior, thoughts, attention, and movement. DA and NE released in these areas act either presynaptically or postsynaptically; and regulates network activity. , Released neurotransmitters stimulate postsynaptic DA or adrenergic receptors and systematize attention, focus, and organization of thoughts and actions [Figure 2]. The conditions like fatigue cause less release of DA or NE that produce insufficient activation of postsynaptic D 1 and α2 A receptors. This further leads to distracted, inattentive, and impulsive behavior of individuals. Whereas conditions like stress, stimulate the excessive release of DA and NE resulting in overstimulation of D 1 and α2 A receptors and leads to abnormal behavioral response and attention. 
|Figure 2: Presynaptically released dopamine (DA) and norepinephrine (NE) binds to postsynaptic receptors and organize attention, focus, thoughts and actions|
Click here to view
| Norepinephrine and Its Physiological Actions|| |
Adrenergic neurons of the autonomic sympathetic nervous system, synthesize NE, a major neurotransmitter that regulates several behavioral activities. Critical conditions like stress and crisis enhance release of NE, which intern triggers the release of hormones from the limbic section of the brain that signal other stress hormones to act accordingly. In response to these stress conditions, NE also increases body temperature, metabolic rate, and stimulate the bronchial smooth muscles to assist breathing. NE indirectly reduces heart rate to manage reflex bradycardia due to its vasoconstrictive actions. It also reduces blood flow to the skeletal muscles, skin, and kidneys to increase coronary blood flow. 
Actions of NE are regulated through strong activation of α1, α2 , β1 , and β3 subtypes and relatively weaker activation of β2 adrenergic receptors that are located postsynaptically. Furthermore, at the neuroeffector junction NE activate presynaptic α2 and β2 adrenoceptors on sympathetic nerve terminals. 
Action on α1 receptors
NE produces an excitatory effect in most of the organs by acting on postsynaptic α1 receptors. These effects mainly include contractions of bronchi, uterus and radial muscles of the iris, contractions of vascular smooth muscles (causes increased blood pressure) while NE produces an inhibitory effect on intestinal smooth muscles leading to relaxation. ,
Action on α2 receptors
These are present presynaptically on sympathetic postganglionic neurons. NE decreases the further release of neurotransmitter by stimulating NE receptors. The activation of α2 receptors present on cholinergic nerve terminals on gut reduces acetylcholine secretion resulting in relaxation of the gut. Presynaptic or postsynaptic activation of α2 receptors in the brain decreases sympathetic actions. 
Action on β1 receptors
These receptors are mainly located postsynaptically at heart. NE causes positive inotropic and chronotropic effects by activating β1 receptors of the heart. In the kidney, NE activates these receptors and enhances the release of rennin. 
Action on β2 receptors
β2 receptors are predominantly present on the bronchi and blood vessels supplied to coronary arteries, uterus, skeletal muscles, gastrointestinal tract, and cardiac smooth muscles. NE produces an inhibitory (smooth muscle relaxation) effect by activating these receptors except in myocardium. It facilitates neurotransmitter release by acting on presynaptically located β2 receptors. ,
Action on β3 receptors
β3 receptors are located on adipocytes. Activation of these receptors by NE promotes lipolysis and thermogenesis . 
| Role of Norepinephrine in ADHD|| |
The amount of catecholamine secreted in PFC significantly affects working memory abilities of the PFC. Cognitive actions of the PFC are distinctly changes because of abnormal catecholamine receptor stimulation. Moderate amount of NE is required to sustain balanced prefrontal cortical functions. NE selectively acts on α2 A receptors present on postsynaptic to NE terminals and improves functioning of the PFC. 
NE plays a regulatory role in tonic and phasic arousal, generalized alertness and activation of acute response, such as startle response to sudden change in the environment. It is also involved in executing critical aspects of functioning in learning, reasoning, and problem solving.  The excess level of NE produces impairment in the prefrontal functioning, and these actions are mediated through α1 receptors and β1 receptors.  Depleted levels of NE overall or in PFC alters working memory and attention regulation.  The intensity and duration of signal transduction mediated by NE are also affected by the presence of NE transporter (NET) protein, as it is involved in the reuptake of NE. Many times ADHD is also associated with abnormalities in NET functioning which leads to a disturbed level of NE. 
| Norepinephrine Reuptake Inhibitors|| |
Two types of drug therapies for ADHD management have been approved by Food and Drug Administration. Central nervous system stimulants like amphetamines and methylphenidate are used as first-line therapy and nonstimulants such as atomoxetine and α2 agonists like guanfacine are used as an alternative therapy for ADHD management. , Inhibition of DA and NE reuptake by interacting and inhibiting the DA transporter protein-1 and NET protein are the mechanism by which stimulants act. These agents also interfere with neurotransmitter metabolizing enzyme, monoamine oxidase (MAO). All these actions lead to increase in the synaptic level neurotransmitters.  Nonstimulants generally activate postsynaptic α2 adrenergic receptors. Agents such as atomoxetine selectively inhibit synaptic reuptake of NE and acts as NE reuptake inhibitors. 
Mechanism of action of norepinephrine reuptake inhibitors
NET proteins are present in the neuronal membrane. NE reuptake inhibitors selectively bind to these presynaptic proteins and inhibit their action mediated through an active amine pump (NET).  This leads to reduced NE reuptake from the synaptic cleft and increases amount of NE in the synaptic cleft of PFC thereby improving PFC functioning.  NE reuptake inhibitors are structurally characterized by the presence of phenyl ring and presence of the amino nitrogen group.  [Figure 3] shows the mechanism of agents that increase catecholamine level in the synaptic cleft.
|Figure 3: Names of agents which increase neurotransmitter levels in synaptic cleft, mechanism of action and their selective targets|
Click here to view
Atomoxetine selectively inhibits reuptake of NE. It resembles structurally with fluoxetine with the only difference of O-methyl group instead of p-trifluoromethyl group. It can interact Mg 2+ blocking site of the NR1 subunit present on N-methyl-D-aspartate receptor.  Because of structural similarity of atomoxetine and other selective NE reuptake inhibitors such as reboxetine  and ciclazindol  with catecholamine, they specifically binds with NET and blocks their reuptake. ,
Bupropion interferes with reuptake of NE and DA. It moderately inhibits reuptake of NE and DA. The active metabolite of bupropion, hydroxybupropion also exhibits similar action. These agents inhibit presynaptic reuptake of catecholamines and substantially increases their presynaptic availability. ,
Tapentadol is used for the treatment of moderate to severe pain. It is an opioid analgesic with a moderate affinity toward μ-opioid receptors. At synaptic cleft tapentadol significantly inhibits reuptake of NE. It selectively binds with NET and inhibits binding of NE to NET this intern increases the synaptic level of NE. ,
Maprotiline produces similar action to tricyclic antidepressants. It strongly inhibits reuptake of NE and selectively blocks NET. Maprotiline also inhibits MAO and reduces catecholamine degradation in the synaptic cleft. It has weak anticholinergic action. ,,
Viloxazine increases the synaptic level of catecholamines by inhibiting MAO enzyme. It is a newer antidepressant agent.  It also inhibits serotonin and NE reuptake at the synaptic cleft. 
Manzindol and amphetamine produce similar pharmacological actions. It is a derivative of phenylethylamine. As such, it does not interfere with the levels monoamine in the brain, but it enhances overall turnover of DA and NE. This change in monoamines turnover supposed to be a better index of neuronal activity than an alteration in the levels of monoamines. 
Tandamine is thiopyranoindole derivative and exhibits strong inhibitory action on NE reuptake. It produces more peripheral effects. It strongly antagonizes the hypothermia induced by reserpine and also guanethidine-induced depletion of NE in heart. 
| Conclusion|| |
ADHD is a major problem in school-age children. It is associated with multiple neurobehavioral symptoms such as impulsiveness, inattentiveness, and hyperactivity. Abnormal level of catecholamines in the PFC area of the brain is supposed to be the principal cause of ADHD development. Several drugs are employed to treat ADHD that selectively modulate levels of catecholamines. NE reuptake inhibitor is one of the options having ability to block NE uptake selectively from synaptic cleft thereby increasing synaptic availability of NE. The ability to selectively block NE uptake leads to increase in the synaptic level of catecholamines. Other drugs such as stimulants and nonstimulants also considered as the first-line treatment of ADHD. Overall NE reuptake inhibitor might be a good option to maintain catecholamine level in the brain and improves symptoms of ADHD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Tomas L. Attention Deficit Hyper Activity Disorder. A Guide to Evidence Based Integrative and Complementary Medicine. Australia: Churchill Livingstone, Elsevier; 2011. p. 127-50.
Identifying and treating attention deficit hyperactivity disorder: A resource for school and home. Washington, DC: American Institutes for Research; 2003. p. 1-23.
Bryant SM. Attention deficit hyperactivity disorder (ADHD) and ethnicity: A literature review. McNair Sch J 2005;9:35-44.
Sharma A, Couture J. A review of the pathophysiology, etiology, and treatment of attention deficit hyperactivity disorder (ADHD). Ann Pharmacother 2014;48(2):209-25.
Suvarna BS, Kamath A. Prevalence of attention deficit disorder among preschool age children. Nepal Med Coll J 2009;11:1-4.
Allen AJ. ADHD: Phenotypes and pathophysiologies. Adv Stud Med 2002;2:906-9.
Slate MK. Neurotransmitters: Their Role in the Body; 2013.
Sharma HL, Sharma KK. Principle of Pharmacology. New Delhi: Shahdra Publications; 2007. p. 163-7.
Tripathi KD. Essentials of Medical Pharmacology. New Delhi: Jaypee Brothers Medical Publishers Pvt. Limited; 2009.
Arnsten AF. Stimulants: Therapeutic actions in ADHD. Neuropsychopharmacology 2006;31:2376-83.
Hunt RD. Functional roles of norepinephrine and dopamine in ADHD. Medscape Psychiatry and Mental Health 2006;11:1-4.
Arnsten AF. Genetics of childhood disorders: XVIII. ADHD, Part 2: Norepinephrine has a critical modulatory influence on prefrontal cortical function. J Am Acad Child Adolesc Psychiatry 2000;39:1201-3.
McEvoy B, Hawi Z, Fitzgerald M, Gill M. No evidence of linkage or association between the norepinephrine transporter (NET) gene polymorphisms and ADHD in the Irish population. Am J Med Genet 2002;114:665-6.
Heffernan GD, Coghlan RD, Manas ES, McDevitt RE, Li Y, Mahaney PE, et al.
Dual acting norepinephrine reuptake inhibitors and 5-HT(2A) receptor antagonists: Identification, synthesis and activity of novel 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles. Bioorg Med Chem 2009;17:7802-15.
Koe BK. Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain. J Pharmacol Exp Ther 1976;199:649-61.
Ludolph AG, Udvardi PT, Schaz U, Henes C, Adolph O, Weigt HU, et al.
Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations. Br J Pharmacol 2010;160:283-91.
Hajós M, Fleishaker JC, Filipiak-Reisner JK, Brown MT, Wong EH. The selective norepinephrine reuptake inhibitor antidepressant reboxetine: Pharmacological and clinical profile. CNS Drug Rev 2004;10:23-44.
Levine S. A controlled comparative trial of a new antidepressant, ciclazindol. J Int Med Res 1979;7:1-6.
Medication guide: Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions. Morgantown, USA: Mylan Pharmaceuticals; 2014. p. 1-2.
Katzung BG. Basic and Clinical Pharmacology. New York: Lang Medical Publisher; 2012. p. 527-30 .
Royal R. Pharmacological aspects of tapentadol. Int J Pharma Bio Sci 2012;3:479-83.
Yildiz A, Gonul AS, Tamam L. Mechanism of actions of antidepressants: Beyond the receptors. Bull Clin Psychopharmacol 2002;12:194-200.
Martinez C, Dominiak P, Kees F, Grobecker. Inhibition of monoamine oxidase by viloxazine in rats. Arzneimforsch Drug Res 1986;36:801-3.
Lippman W, Pugsley TA. Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities. Can J Physiol Pharmacol 1976;54:494-509.
Carruba MO, Groppetti A, Mantegazza P, Vicentini L, Zambotti F. Effects of mazindol, a non-phenylethylamine anorexigenic agent, on biogenic amine levels and turnover rate. Br J Pharmacol 1976;56:431-6.
Lippmann W, Pugsley T. The effect of tandamine, a new potential antidepressant agent, on biogenic amine uptake mechanism and related activities. Biochem Pharmacol 1976;25:1179-86.
[Figure 1], [Figure 2], [Figure 3]
|This article has been cited by|
||Brain activation patterns in medicated versus medication-naïve adults with attention-deficit hyperactivity disorder during fMRI tasks of motor inhibition and cognitive switching
| ||Jatta Berberat,Ruth Huggenberger,Margherita Montali,Philipp Gruber,Achmed Pircher,Karl-Olof Lövblad,Hanspeter E. Killer,Luca Remonda |
| ||BMC Medical Imaging. 2021; 21(1) |
|[Pubmed] | [DOI]|
||Noradrenaline reuptake inhibitors (NRIs) for attention deficit hyperactivity disorder (ADHD) in adults
| ||Franco De Crescenzo,Liliya Eugenevna Ziganshina,Ekaterina V Yudina,Yusuf Cem Kaplan,Marco Ciabattini,Yinghui Wei,Charles HV Hoyle |
| ||Cochrane Database of Systematic Reviews. 2018; |
|[Pubmed] | [DOI]|