Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test

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Abstract

Deficits in attention and response inhibition are apparent across several neurodegenerative and neuropsychiatric disorders for which current pharmacotherapy is inadequate. The 5-choice serial reaction time test (5-CSRTT), which originated from the continuous performance test (CPT) in humans, may serve as a useful translational assay for efficacy in these key behavioral domains. The selective norepinepherine reuptake inhibitor, atomoxetine, represents the first non-stimulant based drug approved for Attention Deficit Hyperactivity Disorder (ADHD) and has replaced methylphenidate (Ritalin®) as the first line in pharmacotherapy for the treatment of ADHD. Methylphenidate and atomoxetine have different cortical and sub-cortical neurochemical signatures that could predict differences in cognitive and non-cognitive functions. The present experiments investigated the effects of acute methylphenidate and atomoxetine in male long Evans rats in the 5-choice serial reaction time (5CSRT) test that is hypothesized to serve as a model of vigilance and impulsivity behaviors associated with ADHD. Long Evans rats were trained to perform at 75% correct responses with fewer than 20% missed trials in the 5CSRT test (500 ms stimulus duration, 5 s inter-trial interval (ITI)). By varying the ITI (10, 7, 5, and 4 s) on drug test days, impulsivity (as defined by premature responses) was dramatically increased with a concomitant decrease in attention (percent correct). Subsequently, animals were treated with methylphenidate (2.5 and 5 mg/kg, i.p.) or atomoxetine (0.1, 0.5 and 1 mg/kg, i.p.) using this design. In Experiment 1, treatment with methylphenidate modestly improved overall attention but the highest dose of methylphenidate (5.0 mg/kg) significantly increased impulsivity. In contrast, treatment with atomoxetine induced a marked decrease in impulsivity whilst modestly improving overall attention. Interestingly, no effect was observed on measures of performance (e.g. motivation/sedation) with atomoxetine, whilst moderate hyperactivity (faster overall response latencies; magazine, correct, incorrect) was observed in the methylphenidate group. Those data suggest that the 5CSRT test can be used to differentiate stimulant and non-stimulant pharmacotherapies on measures of impulsivity.

Introduction

Deficits in attention and impulsivity are found across a number of different neuropsychiatric and neurodegenerative diseases (Banaschewski et al., 2003b, Butler and Montgomery, 2005, Egeland et al., 2003, Potvin et al., 2003, Retz et al., 2004). Attention and impulsivity are characteristics of several disease states. Both symptoms are co-morbid in Attention Deficit Hyperactivity Disorder (ADHD) and schizophrenia along with severe deficits in executive functioning. Attention is an umbrella term for a collection of distinct executive processes, such as selective and divided attention, vigilance, and distractibility. Impulsivity can de defined as the failure of response inhibition (Robbins, 2005). As a trait or pathology, impulsivity has been linked to increased probability of suicide, gambling, drug abuse and aggression (Evenden, 1999, Martin et al., 1994, Pliszka, 2003, Potvin et al., 2003, Stanley et al., 2001). Schizophrenic patients with a history of substance abuse and addiction have higher levels of sensation seeking and impulsivity (Dervaux et al., 2001, Dervaux et al., 2004) and are a high risk for suicide (Baxter and Appleby, 1999, Verdoux et al., 1999). As such, pre-clinical models of attention and impulsivity can serve as useful tools for developing drugs to treat a wide range of neuropsychiatric symptoms.

ADHD, typified by a persistent pattern of abnormally high levels of impulsivity and inattention, affects 6% to 10% of school-aged children (Biederman and Faraone, 2005). The continuous performance test (CPT) is sensitive in detecting attention deficits across several disorders such as mild cognitive impairment (MCI) (Levinoff et al., 2005), schizophrenia (Lee and Park, 2006, Mass, 2002, Nestor et al., 1990, Nieuwenstein et al., 2001) and ADHD (Banaschewski et al., 2003a, Loo et al., 2004, Riccio et al., 2001, Teicher et al., 2004). In the CPT, subjects are required to respond to a specific visual stimulus (e.g. the letter “X”), which will occur at a lower probability than other stimuli (e.g. A, C, F, M). Since “X” occurs with less frequency, the ability to respond with a high percentage of correct responses requires the subjects to remain attentive during the trials. When the subjects see the letter “X” they are required to press a button/click a computer mouse. A rich array of independent and dependent data are afforded from this simple response allowing not just a thorough characterization of attentional (correct response on the button/computer mouse), false alarm hit rate (number of errors or responses when no “X” presented), information processing speeds (how latency to press the button or click on the mouse when presented with “X”) and impulsivity measures (making a response in the absence of a stimulus). In the “AX” version of the CPT (Lee and Park, 2006), the subject is required to respond to X only when it is preceded by the letter “A”. On the CPT, children with ADHD show overall lower scores as measured by increased impulsive and incorrect responding. Moreover, these effects can be reversed with the stimulant methylphenidate (Ritalin®) (Epstein et al., 2006, Riccio et al., 2001). The CPT is also used as an attention assay in the ‘measurement and treatment research to improve cognition in schizophrenia’ (MATRICS) test battery to evaluate the efficacy of pro-cognitive drugs in clinical trials in schizophrenic patients (Bromley, 2005, Buchanan et al., 2005, Green and Nuechterlein, 2004). However, stimulant based drugs that are used to treat attention deficits, such as amphetamine, caffeine, and methylphenidate, may not be suitable pro-attentive therapies for schizophrenia, as they have abuse potential and may aggravate symptoms (Morton and Stockton, 2000).

The pre-clinical analogue of the CPT is the 5-choice serial reaction time test (5-CSRTT) (Robbins, 2002). In this operant-based test, which was originally developed from the CPT and has been widely characterized, animals are required to be attentive and withhold responding while monitoring 5 apertures for a brief (e.g. 1 s or less) illumination behind one of these apertures. Thus, in the 5-CSRTT in rats, the brief light stimuli are analogous to the presentation of different letters in the CPT in humans. The pre-clinical analogue of the CPT is the 5-choice serial reaction time (5CSRT) test. In this test, animals are required to monitor 5 apertures in an operant chamber. Over a period of 30 min individual apertures are briefly illuminated (e.g. 500 ms) and subjects are required to poke their noses into the previously lit aperture. While human subjects watch for the “correct” letter and push a button/click a computer mouse, rats performing the analogous task in the 5-CSRTT must nose-poke into the correct aperture (where the brief light stimulus was just presented) to receive a food reward. The same behavioral measures (accuracy, errors, speed of response, impulsivity) can be recorded and quantitated.

The selective norepinepherine (NE) reuptake inhibitor, atomoxetine is the first non-stimulant based drug approved for ADHD. However, the mechanism/s underlying its efficacy in ADHD are likely to extend beyond affecting noradrenergic neurotransmission. Depletion of cortical NE by localized injection of 6-hydroxydopamine has been shown to lead to attentional deficits under conditions where a task involved unpredictable or distractible operant components (Carli et al., 1983). Furthermore, NE has been shown to be elevated during periods of unexpected change in the contingencies of the 5CSRT test and not during the standard baseline training protocol (Dalley et al., 2001, Dalley et al., 2002). Both atomoxetine and methylphenidate have been shown to enhance extracellular NE and dopamine (DA) (Bymaster et al., 2002) as well as acetylcholine (Tzavara et al., 2005), although the neurochemical enhancements are longer lasting following atomoxetine treatment. Furthermore, these two treatments are differentiated by their effects on sub-cortical DA, as methylphenidate, but not atomoxetine, causes increases in DA in the nucleus accumbens (NAC) and striatum (Bymaster et al., 2002). Such observations may predict differential effects of atomoxetine and methylphenidate in pre-clinical cognitive tests. For example, previous reports have linked increased dorsal striatal DA to faster response reaction times on 5CSRT test performance measures (Baunez and Robbins, 1999). In addition, increased impulsivity induced by d-amphetamine can be blocked by depletion of DA in the NAC, further supporting the role of sub-cortical DA in impulsivity (Cole and Robbins, 1989, Robbins, 2002).

In the present experiments we sought to evaluate the effects of atomoxetine and methylphenidate on the 5CSRT under variable inter-trial conditions. It was predicted that methylphenidate would increase attention in the 5CSRT test, as this drug increases mPFC DA, NE and ACh. However, based on data demonstrating elevated sub-cortical DA, it was also predicted that methylphenidate would increase impulsivity and cause faster response latencies in the 5CSRT test. Furthermore, based on its neurochemical profile, it was hypothesized that atomoxetine would enhance attention without increasing impulsivity as this drug increases NE, DA and acetylcholine in the mPFC without affecting striatal and NACDA.

Section snippets

Drugs

Atomoxetine (Tocris Cookson, Ellisville, MO) and methylphenidate (Mallinckrodt Pharmaceuticals, St Louis, MO) were dissolved in 0.9% NaCl. The dosing volumes were 1 ml/kg, administered intraperitoneally (i.p.) 30 min prior to test session.

Animals

Thirty one male Long Evans rats (Charles River, Wilmington, MA) served as subjects and were 15 months old by the time of these experiments. Animals were individually housed and maintained under a 12-hour light/dark cycle with lights on at 6 a.m. Rats were food

Experiment 1: methylphenidate in variable ITI 5CSRT procedure

Percent correct: By extending the ITI from the 5 s to include 4, 7 and 10 s we observed a significant main effect of interval (F3,121 = 3.28, p < 0.05). A post-hoc analysis of this effect revealed that there was a significant decrease in the percent correct at the 10 s ITI compared to the 4 and 5 s ITIs (p < 0.05). Methylphenidate produced a main effect on the percent correct responding (F2,121 = 5.54, p < 0.05) with the 2.5 mg/kg dose of methylphenidate increasing the percent correct response as

Discussion

The current studies demonstrated that varying the ITI period induces (1) a modest decrease in attention and an independent increase in impulsivity (2) pre-treatment with methylphenidate 30 min before testing resulted in increased attention and impulsivity and (3) that atomoxetine increased attentional performance and reduced impulsivity in the 5CSRT test.

In Experiment 1, pre-treatment with methylphenidate 30 min before testing resulted in increased attention an effect consistent with a

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