Atomoxetine Increases Histamine Release and Improves Learning Deficits in an Animal Model of Attention‐Deficit Hyperactivity Disorder: The Spontaneously Hypertensive Rat

Abstract

Substantial development in the pharmacological treatment for attention-deficit hyperactivity disorder (ADHD) has been made recently including approval of new non-stimulant agents targeting noradrenergic, histaminergic and dopaminergic systems. Among such, atomoxetine has been widely used, although its mechanism of action is poorly understood. It is known that central nervous system histamine is closely associated with cognition and it was recently shown that both atomoxetine and methylphenidate enhance cortical histamine release in rats. To that end, the aim of our study was to investigate the effect of atomoxetine (2 mg/kg, intraperitoneally) on histamine release using the microdialysis technique in the spontaneously hypertensive rat (SHR), a suitable genetic model for ADHD. Our data confirmed that atomoxetine increases extracellular levels of histamine in the prefrontal cortex, a brain region that is implicated in the pathophysiology of ADHD. Given the tie between histamine neurotransmission and treatment of cognitive dysfunction, we also assessed the effects of atomoxetine on learning and memory as measured by the Morris water maze in SHR. The results indicated that atomoxetine significantly ameliorated performance in the Morris water maze, consistent with its histamine-enhancing profile. In conclusion, the current study provides further support for the notion that the therapeutic effect of atomoxetine could involve activation of histamine neurotransmission within the prefrontal cortex.Attention-deficit hyperactivity disorder (ADHD) is one of the most commonly seen chronic health conditions featured by mental disorders in school-aged children and is characterized by elevated, age-inappropriate levels of inattention, impulsivity and excessive motor activity [1,2]. In addition, ADHD children usually experience problems with cognitive impulsiveness that are sometimes defined as planning deficits, forgetfulness and poor management of time [3].Spontaneously hypertensive rats (SHR) are considered as an animal model of ADHD because they display hyperactivity, impulsivity, poorly sustained attention and deficits in the learning and memory processes [4][5][6]. Furthermore, substandard performance has been noted in SHRs in a number of paradigms commonly used to evaluate learning and memory, such as the Morris water maze [7,8], the radial-arm maze [9] and the two-way shuttle box avoidance task [10]. For this reason, SHRs have been recommended as a unique model to evaluate pharmacological agents with therapeutic potential for disorders of memory and attention [8].To date, the 'dopaminergic hypothesis' based on a dysregulation in dopaminergic neurotransmission, has been the most widely accepted theory for behavioural alterations in both ADHD patients and SHR rats. There is considerable evidence suggesting that ADHD patients have disturbances in dopamine uptake, storage and/or metabolism [11][12][13][14][15]. Furthermore, SHR, a suitable model for ADHD, displays reduced release of dopamine in the prefrontal corte...

Effect of Pre- and Postnatal Manganese Exposure on Brain Histamine Content in a Rodent Model of Parkinson’s Disease

“…Interestingly, neonatally 6-OHDA-lesioned rats have also been established as a model for attention deficit hyperactivity disorder (ADHD), with adulthood hyperactivity being attenuated by acute amphetamine or methylphenidate treatments (Shaywitz et al 1976;Kostrzewa et al 1994Kostrzewa et al , 2007Davids et al 2003). Histamine too (Liu et al 2008) and manganese (Bouchard et al 2007;Farias et al 2010) also have demonstrated roles in ADHD animal modeling.…”

Monoamine Transporters

“…Rats trained in a five-choice serial reaction time task increased the percentage of correct responses and decreased the number of premature responses under the influence of reboxetine (89) or atomoxetine (90). In the spontaneously hypertensive rat, a genetic model for ADHD, atomoxetine ameliorated the learning deficits that typically exhibit these rats (91). Further, atomoxetine is an effective treatment for ADHD, especially in patients with comorbid disorders and those who do not tolerate well stimulant drugs (92).…”

Safety of Atomoxetine in Combination With Intravenous Cocaine in Cocaine-Experienced Participants

“…Atomoxetine and methylphenidate have also been shown to increase histamine release widely in the cortex (Fox, et al 2002). Through activation of histamine H3 receptor targets, atomoxetine improves spatial learning and memory deficits (Liu et al, 2008). Atomoxetine has been reported to exert beneficial effects on impairments of cognition due to a diversity of causes, including traumatic brain injury (Reid and Hamm, 2008), ADHD (Chamberlain et al, 2007) and schizophrenia (Rao et al, 2007; Friedman et al, 2004).…”