Elsevier

Biochemical Pharmacology

Volume 73, Issue 8, 15 April 2007, Pages 1123-1134
Biochemical Pharmacology

Differential effects of ciproxifan and nicotine on impulsivity and attention measures in the 5-choice serial reaction time test

https://doi.org/10.1016/j.bcp.2006.12.004Get rights and content

Abstract

Deficits in attention and response inhibition are apparent across several neurodegenerative and neuropsychiatric disorders for which current pharmacotherapy is inadequate. While it is difficult to model such executive processes in animals, 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. At Wyeth and Abbott, we recently investigated the utility of employing the 5-CSRTT in adult rats. This involved training and testing groups of rats over an extended period of several months and required the animals to learn to nose-poke into one of five apertures following presentation of a brief visual stimulus in that aperture in order to obtain a food reward. When the stimulus duration was short, the rat had to pay close attention to make a correct choice—a nose-poke into the aperture with the brief visual stimulus. We evaluated nicotine and the histamine H3 receptor antagonist, ciproxifan, since compounds targeting both nicotinic and histaminergic neurotransmission are currently under investigation for treating cognitive dysfunction in ADHD, AD and schizophrenia. After approximately 12 weeks of training, rats were tested with drug when they had achieved stable performance. Nicotine (0.2, 0.4 mg/kg s.c.) significantly improved accuracy and reduced errors of omission (reflecting improved attention and vigilance) when baseline performance was <90% correct. In contrast, nicotine tended to worsen accuracy when baseline performance was >90% correct. Using the same test paradigm, ciproxifan (3 mg/kg i.p.) reduced premature responding, a measure of impulsivity. Under conditions of variable stimulus duration, ciproxifan also improved accuracy and decreased impulsivity. In summary, we have replicated previous findings by others of positive effects of nicotine on attention, but also showed that this is dependent on baseline performance. We also expanded on previous positive findings by others with ciproxifan on attention and both Wyeth and Abbott demonstrate for the first time decreased impulsivity with this mechanism.

Introduction

Increased impulsivity and deficits in attention are key symptoms frequently observed across a number of different neuropsychiatric and neurodegenerative diseases [1], [2], [3], [4], [5], [6]. Both symptoms are co-morbid in attention deficit hyperactivity disorder (ADHD), which is estimated to affect 6–10% of school-aged children [7], and in schizophrenia, where poor functional outcome in the majority of patients is predicted by such cognitive and behavioral deficits [8]. In both ADHD and schizophrenia, these deficits ultimately lead to severe impairment of executive functioning, which remains largely untreated. To add to the complexity, the word ‘attention’ itself is an umbrella term for a collection of distinct executive processes, such as selective and divided attention, vigilance, and distractibility. In addition, impulsivity, which may be defined as the failure of response inhibition, has further been linked to increased probability of suicide, gambling, drug abuse and aggression. Indeed, schizophrenic patients with a history of substance abuse and addiction exhibit higher levels of sensation seeking and impulsivity [9] and are a high risk for suicide [10], [11]. Consequently, there is much interest in modeling executive function preclinically to help identify new pharmacological therapies for ADHD and schizophrenia.

The continuous performance test (CPT) has been widely used for over 50 years to measure attention performance in humans [12]: it is sensitive in detecting attention deficits across several disorders such as mild cognitive impairment (MCI) [13], schizophrenia [14], [15], [16], [17] and ADHD [1], [18], [19], [20]. In the CPT, subjects are required to respond to a specific visual stimulus (e.g. the letter “X”) presented on a visual display unit: this stimulus has a much lower probability of appearing 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 trial types. When the subjects see the letter “X” they are required to press a button/click a computer mouse. This simple response affords several measures to be taken from the subject regarding attentional accuracy (correct response on the button/computer mouse), false alarm hit rate (number of errors or responses when a letter other than “X” is presented), processing speeds (latency to press the button or click on the mouse when presented with “X”) and impulsivity measures (making a response prior to the presentation of a stimulus). There are now several versions of the CPT, some of which manipulate test parameters in order to increase the attentional load. For example, in the “AX” version of the CPT [14], the subject is required to respond to X only when it is preceded by the letter “A”. On the CPT, ADHD children show overall lower scores as measured by increased impulsive and incorrect responding. Moreover, these effects can be reversed with the stimulant methylphenidate (Ritalin®) [21], [19]. 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 [22], [23], [24]. 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, since some have abuse potential and may even aggravate symptoms [25].

The preclinical analogue of the CPT is the 5-choice serial reaction time test (5-CSRTT) [12]. In this operant-based test, which was originally developed by Robbins [12] from the CPT and has been widely characterized, animals are required to be attentive and withhold responding while monitoring five apertures for a brief (e.g. 1 s or less) illumination behind one of these apertures. Thus, in the 5-CSRTT in rats, the apertures are the equivalent of non-target letters in the CPT in humans; brief light stimuli are analogous to the presentation of the letter “X” in the CPT in humans. 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, omissions, premature responding, speed of response) can be recorded and quantitated.

While stimulants that are used to treat ADHD such as methylphenidate exert positive effects in the 5-CSRTT, one of the best-studied pharmacological effects is with nicotine, particularly at the labs of Stolerman and colleagues [26]. In serial preclinical studies in rats, acute nicotine administration increased response accuracy, reduced omission errors and decreased reaction time [12], [26]. Interestingly, these investigators also showed improved attention in the 5-CSRTT following repeated administration of nicotine. Concurrent with this, animals exposed to repeated nicotine treatment also demonstrated a decrease in correct response latency and an increase in anticipatory responding, implying a link between nicotine's locomotor stimulant effects and an increase in impulsive-like behavior. Clearly, depending on how nicotine is administered, differential activity can be observed in the 5-CSRTT, sometimes making interpretation difficult. This is important since several selective agonists targeting α4β2 neuronal nicotinic receptors (e.g. ABT-089, TC-1734) are already progressing through clinical development and offer great potential for translational studies.

Histaminergic neurotransmission is also the subject of intense investigation in recent years and histaminergic H3 receptors (H3Rs), which are constitutively active and highly expressed in the central nervous system (CNS) as auto- and heteroreceptors, have been implicated in sleep [27], [28], [29], [30], [31], [32], arousal [28], [31], [33], [34], information processing and cognition [32], [35], [36], [37], [38], [39], [40], [41]. In addition to direct regulation of histamine release, H3Rs also directly regulate cholinergic neurotransmission and can modulate the release of dopamine, serotonin and norepinephrine [30]. However, the effects of H3R ligands are much less well studied in the 5-CSRTT. A limited early study with ciproxifan did demonstrate an effect on attention measures, observed when demands on attention were increased [42]. The only other published 5-CSRTT study with a H3R ligand that we could find demonstrated a failure of the antagonist, thioperamide, to reverse a scopolamine-induced attention deficit [43]. Thus, there is a large gap in our ability to translate efficacy in rats using 5-CSRTT to CPT in humans for this mechanism and there are limited translational data available for nicotinic agonists in the same regard. In addition, it is not clear from the existing literature whether pro-cognitive efficacy resulting from blockade of H3Rs with specific antagonists or from selective activation of nicotinic receptors in other behavior models of ADHD is mediated through effects on attention or impulsivity or both. As a consequence, we sought to further characterize the effects of nicotine and ciproxifan in the 5-CSRTT in adult rats. Independent data sets originating from Neuroscience Departments at both Wyeth Research and Abbott Labs were compiled and we now present new data that corroborate differential effects of nicotine and ciproxifan on separate measures of attention and impulsivity under similar test conditions.

Section snippets

Animals and housing

Adult, male hooded Lister rats (Harlan, UK), weighing 350–400 g prior to training were used at Abbott while adult male Long Evans rats (Portage, MI, USA) were used at Wyeth. All rats had free access to water and were placed on a food-restricted diet to maintain them at 85% of their free-feeding body weights. Animals were single housed under a 12 h light:12 h dark schedule (lights on at 06:00 a.m.). All studies were conducted in the light phase and in accordance with Abbott and Wyeth Animal Care and

Abbott laboratories: effect of nicotine

Two separate experiments using a total of 15 rats in each case were designed to assess the effects of nicotine on attention, impulsivity and processing speed.

Experiment 1. All animals in the first experiment were drug naïve, except for pretreatement with nicotine (0.2 mg/kg s.c.) daily at 2 h after training for 3 consecutive days during the week prior to commencing testing. This was done in advance of testing in order to habituate the rats to any potential non-specific effects of the drug. Rats

Discussion

The 5-CSRTT has been used to investigate the effects of systemic administration of many drugs as well as the effects of specific neurochemical lesions on various aspects of attention that are relevant for neurological disorders (for a thorough review, see [12]) such as schizophrenia and ADHD. Indeed, the 5-CSRTT was originally developed to increase our understanding of the nature of the behavioral deficits observed in children with ADHD. However, this test is typically difficult to operate in a

Acknowledgements

The neuronal histamine H3 receptor (H3R) has attracted much interest in recent years as a target for new drugs aimed at treating an array of CNS disorders. To a large degree, preclinical evidence for efficacy following blockade of H3Rs with selective antagonists in animal models of attention deficit hyperactivity disorder (ADHD), schizophrenia, narcolepsy and Alzheimer's disease (AD) has driven this research, which is now leading to early clinical trials with several drug-like compounds. An

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