Catecholamines in Attention-Deficit Hyperactivity Disorder: Current Perspectives

WKHA rats constitute a recombinant inbred rat strain derived by phenotypic selection of the progeny of hybrid F2 crosses between SHR and WKY rats. WKHA are normotensive and show some features of hyperactivity and of hyper-reactivity to stress, but their utility as model of attention deficit/hyperactivity disorder (ADHD) has not yetWistar-Kyoto-derived Hyperactive (WKHA) rats constitute an inbred strain that has been derived from the progeny of hybrid Wistar-Kyoto (WKY)/ Spontaneously Hypertensive Rats (SHR) F2 crosses. The WKHA rats were developed initially in 1980 by Hendley and associates in the attempt to remove a prominent behavioral abnormality (hyperactivity) from the hypertensive trait of SHR that had been fixed in this strain during intensive inbreeding (Hendley and Ohlsson 1991;Hendley 2000). Using cross-breeding of SHR with WKY followed by recombinant selected inbreeding, Hendley and Ohlsson (1991) (Deschepper et al. 1997). WKHA display marked locomotor hyperactivity and hyperreactivity to stress when compared with WKY. The activity score obtained with WKHA in an exploration test in a novel environment is much higher than the score observed in the WKY strain (Sagvolden et al. 1992). Moreover, the WKHA also seems to display "attentional problems" when compared with WKY (Sagvolden et al. 1992). Although these characteristics are reminiscent of those observed in children diagnosed with attention deficit disorder (ADHD), the utility of this strain as a potential model of ADHD has not received extensive experimental attention.Accordingly, the present study was conducted to assess the face validity of the WKHA strain as a model of ADHD. To do so, we compared the performance of WKHA to both WKY (genetic control) and Wistar (outbred control) strains in two behavioral tests. First, we measured activity levels of the three strains in an exploration test in a novel environment. Second, we examined the behavior of the three strains in the prepulse inhibition (PPI) test of the acoustic startle reflex. This test assesses sensorimotor gating, or the extent to which a weak acoustic stimulus draws cognitive processing away from a more pronounced acoustic stimulus (Ralph et al. 1999;Wood et al. 1998). Although there is considerable debate as to whether PPI reflects the operation of an attentional (as opposed to a preattentional) mechanism, it is clear that PPI is involved in stimulus selection or stimulus filtering, a process that appears to be aberrant in ADHD (Ralph et al. 1999). Moreover, some evidence also exists for a deficit in sensorimotor gating in a sub-population of ADHD children (Castellanos et al. 1996). A third reason justifying our use of the PPI test is that, like locomotor activity, sensorimotor gating is modulated by central dopaminergic substrates (Swerdlow et al. 1994), and there is extensive clinical evidence implicating alterations in dopaminergic function in the pathophysiology of ADHD (Pliszka et al. 1996).We also examined the extent to which the performances of the three strains in both the locom...

Section: Wkha Rats Constitute a Recombinant Inbred Rat Strain Derivedmentioning

confidence: 99%

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confidence: 99%

Comparisons of Behavioral and Neurochemical Characteristics between WKY, WKHA, and Wistar Rat Strains

Drolet

Proulx

Pearson

et al. 2002

“…Norepinephrine has also been proposed to play a key role in the pathophysiology and pharmacotherapy of ADHD (Zametkin and Rapoport 1987;Pliszka et al 1996;Arnsten et al 1996;Biederman and Spencer 1999). The noradrenergic system is involved in attentional processes and has been shown to prime the prefrontal cortex (PFC) for response to sensory stimuli (Segal and Bloom 1976;Aston-Jones et al 1991;Berridge et al 1993).…”

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confidence: 99%

“…The noradrenergic system is involved in attentional processes and has been shown to prime the prefrontal cortex (PFC) for response to sensory stimuli (Segal and Bloom 1976;Aston-Jones et al 1991;Berridge et al 1993). Increased basal activity of locus coeruleus noradrenergic cell bodies may decrease the response of the PFC and thus treatments that reduce locus coeruleus activity have been hypothesized to improve attentional, arousal, and cognitive processes (Pliszka et al 1996).…”

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confidence: 99%

Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder

Bymaster

Katner

Nelson

et al. 2002

994

790

“…21 , NO . 2 Methylphenidate and Attention in ADHD Children 219 chemical imbalance in catecholarnine regulation (Malone et al 1994;McCracken 1991;Pliszka et al 1996).Methylphenidate effectively reduces hyperactivity, impulsivity, and inattention in 60-90% of children diagnosed with ADHD (Whalen and Henker, 1991). Improved social skills and school performance have also been documented (e.g., Swanson et al 1995).…”

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confidence: 99%

Effect of Methylphenidate on Attention in Children with Attention Deficit Hyperactivity Disorder (ADHD) ERP Evidence

Sunohara

Malone

Rovet³

et al. 1999

109

Methylphenidate is the most common treatment for attention deficit hyperactivity disorder (ADHD) Attention deficit hyperactivity disorder (ADHD) is the most common pediatric psychiatric disorder (Swanson et al. 1995), with an estimated childhood prevalence of 9% in boys and 3% in girls (Szatmari et al. 1989). Surface symptoms of inattentiveness and impulsivity (Shue and Douglas 1992;Shaywitz and Shaywitz 1988) are often, though not invariably, accompanied by hyperactivity (Gittelman and Mannuzza 1985). ADHD is highly heterogeneous with several distinct subtypes and often comorbid with learning, anxiety, and conduct problems. During childhood, ADHD is associated with greater risk of low academic achievement, grade failure, delinquency (Barkley 1997) and during adulthood, with psychiatric disorders and substance abuse (Wender 1987). Stimulant medication, primarily methylphenidate, is the most common treatment for ADHD. Because methylphenidate may be associated with altered neurotransmitter levels (Mefford and Potter 1989; Voeller 1991), several investigators have attributed ADHD to a neuroFrom the Novartis Pharmaceuticals Canada Inc., (GAS), Dorval, Quebec, Canada; and The Hospital for Sick Children, Divisions of Neurology (MAM, TH, WR, MJT) and Psychology Research (JR), Toronto, Ontario, Canada.Address correspondence to: Dr. Molly A. Malone, Child Development Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.Received August 26, 1998; revised December 30, 1998; accepted February 05, 1999. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 2 Methylphenidate and Attention in ADHD Children 219 chemical imbalance in catecholarnine regulation (Malone et al. 1994;McCracken 1991;Pliszka et al. 1996).Methylphenidate effectively reduces hyperactivity, impulsivity, and inattention in 60-90% of children diagnosed with ADHD (Whalen and Henker, 1991). Improved social skills and school performance have also been documented (e.g., Swanson et al. 1995). However, the optimal dosages have not yet been established and clinical anecdotal descriptions report some children as becoming overfocused, cognitively constricted, introverted, and "zombie-like" on higher doses (Swanson et al. 1991; Thurston et al. 1979). These descriptions are not consistently substantiated by empirical studies, however, which show both linear improvements with dose (Douglas et al. 1995;Solanto and Wender 1989) and adverse effects of high dose levels (Dyme et al. 1982;Malone et al. 1988;Sprague and Sleator 1977). A recent study by Tannock and Schachar (1992) has shown opposing effects of a high dose level at different test sessions with children making more perseverative errors in the first session and fewer in the second, while another study by this same group reported that despite clinical observations of overfocusing, measured attention performance was not affected by a high dose (Tannock et al. 1989).Children with ADHD are thought to have a primary attentional deficit in inhibitory (Barkley 1994;Schachar ...