Attention Patrick M. Callahan and Alvin V. Terry Jr.
Contents 1 2
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Five-Choice Serial Reaction Time Task . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Task Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Neural Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Five-Choice Continuous Performance Task . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Task Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Neural Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Signal Detection Task . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Task Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Neural Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
162 163 163 164 166 176 176 177 177 178 178 179 179 181 181
Abstract
The ability to focus one’s attention on important environmental stimuli while ignoring irrelevant stimuli is fundamental to human cognition and intellectual function. Attention is inextricably linked to perception, learning and memory, and executive function; however, it is often impaired in a variety of neuropsychiatric disorders, including Alzheimer’s disease, schizophrenia, depression, and attention deficit hyperactivity disorder (ADHD). Accordingly, attention is considered as an important therapeutic target in these disorders. The purpose of P.M. Callahan • A.V. Terry Jr. (*) Department of Pharmacology and Toxicology, CB-3545, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA 30912-2450, USA Small Animal Behavior Core, Georgia Regents University, Augusta, GA 30912, USA e-mail: [email protected] # Springer International Publishing Switzerland 2015 K.M. Kantak, J.G. Wettstein (eds.), Cognitive Enhancement, Handbook of Experimental Pharmacology 228, DOI 10.1007/978-3-319-16522-6_5
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this chapter is to provide an overview of the most common behavioral paradigms of attention that have been used in animals (particularly rodents) and to review the literature where these tasks have been employed to elucidate neurobiological substrates of attention as well as to evaluate novel pharmacological agents for their potential as treatments for disorders of attention. These paradigms include two tasks of sustained attention that were developed as rodent analogues of the human Continuous Performance Task (CPT), the Five-Choice Serial Reaction Time Task (5-CSRTT) and the more recently introduced Five-Choice Continuous Performance Task (5C-CPT), and the Signal Detection Task (SDT) which was designed to emphasize temporal components of attention. Keywords
Sustained attention • Signal detection • Distractibility • Preclinical • Drug development • Animal model
1
Introduction
As is often the case in the fields of cognitive psychology and neuroscience, a precise definition for the concept “attention” is often the subject of debate and controversy. However, in simple terms, attention could be thought of as the allocation or concentration of mental resources on specific (environmentally relevant) stimuli while ignoring other (nonrelevant or less relevant) stimuli. While “attention” is often used as an umbrella or generic term, most theories in cognitive psychology describe at least three or four separate (but interrelated) subcategories of attention, including sustained attention or vigilance (attending to one stimulus over a significant period of time), selective attention (focus directed at one stimulus in lieu of competing, irrelevant stimuli), orienting attention (directional or spatial orientation toward a particular stimulus), and divided attention (simultaneously attending to two or more different stimuli or performing multiple tasks) (Posner and Petersen 1990; Robertson et al. 1996; Parasuraman et al. 1998). It is clear that attention is inextricably linked to intellectual function and the major components of human cognition including perception, learning and memory, and executive function. Moreover, attention is often impaired in a variety of neuropsychiatric disorders, including Alzheimer’s disease (Lawrence and Sahakian 1995; Parasuraman et al. 1998), schizophrenia (Laurent et al. 1999), depression (Brown et al. 1994), and attention deficit hyperactivity disorder (ADHD) (Biederman 2005). Accordingly, attention is considered as an important therapeutic target in these disorders. In selecting preclinical behavioral models of attention, priority should be given to behavioral paradigms that possess construct validity (i.e., the task accurately and specifically measures attentional processes and its performance relies on similar underlying neurophysiological circuitry as in humans), reliability, and task standardization across laboratories. Several preclinical behavioral tasks meet
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these criteria and have been used extensively to characterize the neural systems associated with attention as well as to assess pharmacological agents that may have therapeutic relevance in alleviating attentional impairments observed in neuropsychiatric disorders. For this review, we have chosen to discuss three commonly used paradigms: (1) the 5-choice serial reaction time task (5-CSRTT; Carli et al. 1983; Robbins 2002), (2) the 5-choice continuous performance task (5C-CPT; Young et al. 2009), and (3) the signal detection task (SDT; Bushnell 1995; McGaughy and Sarter 1995a, b; Rezvani et al. 2002). All of these behavioral tasks have features that are similar to the continuous performance task (CPT; Rosvold et al. 1956) that has been used successfully to detect attention deficits in clinical populations such as ADHD (Riccio et al. 2002; Loo et al. 2004), Alzheimer’s Disease (Levinoff et al. 2005), and schizophrenia (Nieuwenstein et al. 2001; Lee and Park 2006). In the CPT, subjects are required to respond to a specific visual stimulus (e.g., the letter X) within a list of letters. Since the letter X occurs less often, subjects must remain attentive during the session. When the letter X is presented the subject is required to press a button or click a computer mouse. This simple response requirement affords the investigator considerable information in addition to attention (correct response) such as false alarms (errors made when no X is presented), processing speed (latency to respond), and impulsivity (responding in the absence of the X stimulus). The behavioral tasks described below incorporate many of the CPT test attributes for measuring attention, information processing, and impulsivity.
2
Five-Choice Serial Reaction Time Task
2.1
Task Description
The 5-CSRTT (see Fig. 1) was developed as a means to assess attention based on Leonard’s five-choice sustained attention task in humans (Leonard 1959) and is the preclinical analogue of the CPT task, though there are task dissimilarities (Young et al. 2009). A large literature base exists for the 5-CSRTT with evidence demonstrating construct validity as a model of attention. As a test component within the CANTAB battery, the task has been used in both healthy volunteers and in subjects suffering from neuropsychiatric disorders (Barnett et al. 2010; Cambridge Cognition, camcog.com). The behavioral paradigm was originally developed for rats (Carli et al. 1983), but recently, versions have been developed for mice (Humby et al. 1999; Sanchez-Roige et al. 2012) and nonhuman primates (Weed et al. 1999; Spinelli et al. 2004). The 5-CSRTT assesses the subject’s ability to spatially divide its attention across multiple signal locations (usually five locations, but fewer can be used) in order to select the correct target stimulus (light in a single aperture hole location) that, in turn, produces a food reward (see Higgins and Breysse 2008 for paradigm and training description). This behavioral task measures attentiveness to multiple locations over time and, thereby, utilizes both sustained and selective attention (Levin et al. 2011). Selective attention occurs
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Fig. 1 Diagram of the five-choice serial reaction time task (5-CSRTT). In the 5-CSRTT, subjects are required to scan five apertures in an operant chamber for the appearance of a brief light stimulus (presented pseudorandomly) and to make a nose-poke response in the correct spatial location (i.e., the aperture where the light stimulus was presented) in order to receive a food reward
when the subject faces multiple stimuli and must make a choice among them; the choice is defined by the subject’s behavior. In this situation, novelty plays an important factor in determining the subsequent behavior of the animal and, thus, its attentional selection. Sustained attention occurs when the subject’s behavior is controlled by a single stimulus that occurs unpredictably in time and space. While selective and sustained attention are not independent functions within the 5-CSRTT, these events can be manipulated to preferentially place more “demand” on one function versus the other. For example, a greater demand on sustained attention can be achieved by increasing the temporal unpredictability of the stimulus presentation, whereas increasing the number of potential stimulus locations places greater demand on selective attention. In addition to measuring attention (choice accuracy), the 5-CSRTT can assess a number of other cognitive domains such as impulsivity (premature responses), cognitive flexibility/compulsivity (perseverative and timeout responses), and processing speed (response latency). Task difficulty can be modified by changing the brightness, duration, and temporal predictability of the target stimulus and a distractor stimulus (e.g., auditory tone or white noise) can be interpolated into the protocol to increase task difficulty and place greater attentional demand on the subject.
2.2
Neural Substrates
Considerable scientific work has been devoted to delineating the neural substrates involved in modulating 5-CSRTT performance and its response measures (for reviews, see Robbins 2002; Chudasama and Robbins 2004). Excitotoxic lesions of different subregions of the rat prefrontal cortex differentially affect the behavioral measures associated with the task. Gross lesions of the medial prefrontal
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cortex (mPFC) that include the dorsal pre-genual anterior cingulated cortex (area Cg1), medial prelimbic cortex (PrL), and to some extent the ventral infralimbic cortex (IL) show profound impairments in choice accuracy, increased perseverative responding, and slower response latencies (Muir et al. 1996). More selective lesions within the rat mPFC have identified precise anatomical loci responsible for controlling specific 5-CSRTT response measures. For example, specific lesions of the dorsal Cg1 area produce deficits in choice accuracy, whereas PrL and orbitofrontal cortex (OFC) lesions result in selective increases in perseverative responding (Passetti et al. 2002; Chudasama et al. 2003). In contrast, increases in premature responding occur following ventral IL cortical lesions (Chudasama et al. 2003). There are also data on the effects of specific anatomical loci of the striatum, subthalamic nucleus, pedunculopontine nucleus, and hippocampus (Chudasama et al. 2012) providing evidence of a systematic “top-down” anatomical connectivity in mediating attention, impulsivity and executive function. Complementing the data from anatomical-based lesion experiments, lesions and neurochemical evaluations/manipulations focused on neurotransmitter pathways (e.g., acetylcholine, dopamine, glutamate, noradrenaline, and serotonin) have provided further insights into the neurobiological substrates of 5-CSRTT performance. The outcome from this seminal research highlighted the dissociable roles that specific neurotransmitter systems have on attention, reaction time, and response control (see Robbins 2002). Probably the most extensively studied neurotransmitter system is the forebrain cholinergic system. Selective lesions of the nucleus basalis magnocellularis (NbM) with the cholinergic immunotoxin 192 lgG-saporin resulted in decreased PFC acetylcholine levels and choline acetyltransferase activity accompanied by poor choice accuracy, increases in trial omissions, and disruption in response control performance (McGaughy et al. 2002; Lehmann et al. 2003). Additional evidence (e.g., intra-NbM infusion of the GABA agonist muscimol, or intra-PFC infusion of scopolamine) further supported the importance of the basal forebrain cholinergic system and its innervation of the PFC to 5-CSRTT performance (Muir et al. 1992; Robbins 2002). Studies focused on the catecholamine system have indicated that 6-OHDA depletion of ventral striatal dopamine affects response vigor (i.e., omissions and response latency) with little to no effect on choice accuracy, whereas dorsal striatal dopamine lesions affect only response-related processes. In contrast, 6-OHDA lesions of the mPFC produce minimal effects unless task demands are increased (Robbins 2002). Likewise, lesions of the ascending dorsal noradrenergic (NA) bundle impair attention, but only when greater task demands (e.g., use of distracting stimuli or when the temporal presentation of the stimulus target is unpredictable) are placed on the subject, thereby requiring heightened awareness (Carli et al. 1983; Cole and Robbins 1992). Further support for the engagement of the NA system during challenging situations stems from the observation that increased mPFC noradrenaline efflux occurs only when task contingencies are manipulated, but remain unaltered during baseline conditions (Dalley et al. 2001). Interestingly, the opposite appears to occur for mPFC acetylcholine (i.e., under baseline conditions acetylcholine levels increase but remain unchanged during high
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task demand) demonstrating a dissociation between the two neurotransmitter systems in controlling specific aspects of attention (Dalley et al. 2001). Studies assessing the impact of serotonin (5-HT) depletion have also yielded dissociable profiles on 5-CSRTT performance (i.e., impulsivity and choice accuracy) that are related to the particular neurotoxin (PCPA or 5,7-DHT) and brain region (forebrain, dorsal or medial raphe nuclei) investigated (Harrison et al. 1997a, 1997b; Puumala and Sirvio 1998; Dalley et al. 2002). While there is clearly a definitive relationship between 5-HT function and inhibitory control, it appears that different forms of impulsivity (i.e., impulsive choice vs. impulsive action) are mediated by specific 5-HT receptor subtypes within distinct brain regions (Winstanley et al. 2004a, 2004b). Impulsive action (i.e., behavioral inhibition) is typically measured in the 5-CSRTT, and collectively, evidence has demonstrated that reductions in 5-HT activity can either induce or inhibit impulsive behavior which is purely dependent on the 5-HT receptor subtype (i.e., 5-HT2A vs. 5-HT2C) activated (see below).
2.3
Pharmacology
The 5-CSRTT has also been used extensively to evaluate pharmacological agents in rodent models for effects on attention and inhibitory control (see Table 1). These studies have helped to further elucidate the important roles of various neurotransmitter systems on attentional processes and they have facilitated preclinical drug discovery efforts for neuropsychiatric disorders (e.g., ADHD, Alzheimer’s disease and schizophrenia). Here we provide an overview of some of the major pharmacological studies conducted to date (see also comprehensive reviews, Robbins 2002; Higgins and Breysse 2008; Barak and Weiner 2011; Sanchez-Roige et al. 2012). As discussed above, considerable evidence from lesion-based experiments supports the argument that the CNS cholinergic system plays a major role in attention. This evidence appears to be supported by pharmacologic experimentation as well. For example, systemic administration of the muscarinic receptor antagonist scopolamine impaired several response measures (accuracy and omissions) in rats (Jones and Higgins 1995; Mirza and Stolerman 2000) and mice (Humby et al. 1999; de Bruin et al. 2006; Pattij et al. 2007). However, task performance appeared to be unaltered following the acetylcholinesterase inhibitors (AChE) physostigmine and donepezil (Mirza and Stolerman 2000; Romberg et al. 2011), the muscarinic M1 receptor agonist oxotremorine (Mirza and Stolerman 2000), and the mixed AChEmuscarinic M2 receptor antagonist JWS-USC-75-IX (Terry et al. 2011). Interestingly, JWS-USC-75-IX did attenuate the impairments of choice accuracy and increases in premature responding associated with the NMDA antagonist MK-801 (Terry et al. 2011). Nicotine has been shown to improve attentional processing in humans (Sahakian et al. 1989; White and Levin 1999; Min et al. 2001) and, thus, it has been extensively characterized in the 5-CSRTT in rats (Mirza and Stolerman 1998; Blondel et al. 2000; Grottick and Higgins 2000; Stolerman et al. 2000; Grottick et al. 2003; Bizarro et al. 2004; van Gaalen
Standard/scopolamine reversal Standard Standard/MK-801 reversal Standard/distractor Standard MK-801 reversal
5C-CPT SDT SDT SDT SDT 5-CSRTT SDT
Unknown
α4β2 agonist
Cotinine (Metabolite of nicotine) A-82696
Standard
Standard
5-CSRTT
M1 agonist AChE inhibitor/ M2 antagonist Nonselective nicotinic agonist
Oxotremorine JWS-USC-75-IX 5-CSRTT
AChE inhibitor
Physostigmine
Nicotine
MK-801 reversal Standard Standard Standard Standard Standard MK-801 reversal Standard
SDT 5-CSRTT 5-CSRTT SDT 5-CSRTT 5-CSRTT
AChE inhibitor
Task condition
Taska
Target/mechanism
Drug Cholinergic Donepezil
Table 1 Effects of pharmacological agents in behavioral models of attention
Rats
Mice Rats Rats Rats Rats Rats
Mice
Rats Mice Rats Rats Rats Rats Rats Rats
Species
0
+ 0 + 0/+ + +
+
+ 0 0 0 0 0 + +
Effectb
(continued)
Turchi et al. (1995)
Rezvani et al. (2012) Romberg et al. (2011) Mirza and Stolerman (2000) McGaughy and Sarter (1998) Mirza and Stolerman (2000) Terry et al. (2011) Terry et al. (2011) Mirza and Stolerman (1998) Stolerman et al. (2000) Bizarro et al. (2004) Blondel et al. (2000) Grottick, and Higgins (2000) Grottick et al. (2003) de Bruin et al. (2006) Pattij et al. (2007) Young et al. (2004) Young et al. (2013) Turchi et al. (1995) Rezvani et al. (2002, 2008) Howe et al. (2010) Hillhouse and Prus (2013) Terry et al. (2012)
References
Attention 167
Standard Standard Standard
5C-CPT SDT 5-CSRTT 5-CSRTT SDT
α4β2 agonist α2–4β4 agonist α7 agonist
α7 agonist α7 agonist
DA releaser
SIB-1765F SIB-1553A ARR-17779
PNU 282987 RG 3487 Dopaminergic Amphetamine
Standard/scopolamine reversal Standard
5-CSRTT 5-CSRTT 5-CSRTT
α4β2 agonist α4β2 agonist α4β2 agonist α4β2 agonist α4β2 agonist
ABT-594 ADZ 3480 Epibatidine S-38232 Sazetidine-A
Task condition Standard Standard/scopolamine reversal Standard Standard Standard MK-801 reversal Standard Standard/distractor Standard/scopolamine, MK-801 reversal Standard MK-801 reversal Standard
Taska 5-CSRTT 5C-CPT SDT SDT 5-CSRTT SDT 5-CSRTT SDT SDT
Target/mechanism α4β2 agonist
Drug ABT-418
Table 1 (continued)
Rats
Mice
Rats
Mice Rats
Rats Rats Rats
Species Rats Mice Rats Rats Rats Rats Rats Rats Rats
0
+
0 +
+ + 0
Effectb + + 0 + + + + + +
Grottick and Higgins (2002) Bizarro et al. (2004) Loos et al. (2010) Yan et al. (2011) McGaughy and Sarter (1995a)
Grottick and Higgins (2000) Terry et al. (2002) Grottick and Higgins (2000) Grottick et al. (2003) Hahn et al. (2003) Young et al. (2013) Rezvani et al. (2009b)
References Hahn et al. (2003) Young et al. (2013) Turchi et al. (1995) McGaughy et al. (1999) Mohler et al. (2010) Rezvani et al. (2012) Hahn et al. (2003) Howe et al. (2010) Rezvani et al. (2011, 2012)
168 P.M. Callahan and A.V. Terry Jr.
5-CSRTT
5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT
DA D1 agonist
DA D2/3 agonist DA D2 agonist
NE reuptake inhibitor
NE reuptake inhibitor
NE reuptake inhibitor α1 agonist α2 agonist α2 agonist α2 antagonist β2 agonist
5-HT reuptake inhibitor 5-HT reuptake inhibitor
SKF 38393
Quinpirole Sumanirole Noradrenergic Atomoxetine
Desipramine
Reboxetine St-587 Clonidine Guanfacine Atipamezole Clenbuterol Serotonergic Sibutramine Fluoxetine
5-CSRTT
3-CSRTT 5-CSRTT 5-CSRTT 5C-CPT 5-CSRTT 5-CSRTT
DA reuptake inhibitor
Standard Standard
Standard Standard Standard Standard Standard Standard
Standard
Standard
Standard/MK-801, scopolamine reversal Standard Standard Standard Standard Standard Standard
SDT
Modafinil
Standard
5-CSRTT
DA reuptake inhibitor
Methylphenidate
Rats Rats
Rats Rats Rats Rats Rats Rats
Rats
Rats
Rats Rats Rats Rats Rats Rats
Rats
Rats
+ + + + + +
+
+
+ +
+
+
+
(continued)
Humpston et al. (2013) Humpston et al. (2013)
Navarra et al. (2008b) Fernando et al. (2012) Robinson (2012) Paine et al. (2007) Pattij et al. (2012) Robinson (2012) Puumala et al. (1997) Pattij et al. (2012) Fernando et al. (2012) Sirvio et al. (1993) Pattij et al. (2012)
Morgan et al. (2007) Waters et al. (2005) Grannon et al. (2000) Barnes et al. (2012) Fernando et al. (2012) Fernando et al. (2012)
Paine et al. (2007) Puumala et al. (1996) Bizarro et al. (2004) Navarra et al. (2008b) Rezvani et al. (2009b)
Attention 169
5-HT2A agonist
5-HT2A antagonist
5-HT2C agonist
5-HT2C agonist 5-HT3 antagonist 5-HT6 antagonist
DOI
M100907
Ro60-0175
WAY-163909 Ondansetron CMP 42
5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT
5-CSRTT 5-CSRTT
5-CSRTT 5-CSRTT
5-CSRTT
Taska 5-CSRTT 5-CSRTT
Standard MK-801, amphetamine, cocaine reversal Standard MK-801, amphetamine, cocaine reversal Standard Standard Standard Standard
Standard
Task condition Standard Standard
Mice Rats Rats Rats
Rats Rats
Rats Rats
Rats
Species Rats Rats
+ +
+ +
+ +
+
Effectb
Fletcher et al. (2013) Navarra et al. (2008b) Kirkby et al. (1996) de Bruin et al. (2013)
Fletcher et al. (2007) Fletcher et al. (2011)
References Humpston et al. (2013) Carli and Samanin (2000) Winstanley et al. (2003) Koskinen and Sirvio (2001) Fletcher et al. (2007) Fletcher et al. (2007) Fletcher et al. (2011)
b
Task abbreviations indicate 5-choice serial reaction time task (5-CSRTT), 5-choice continuous performance task (5C-CPT) or signal detection task (SDT) Symbols indicate performance improvement (+), performance impairment ( ) or no effect (0)
a
Target/mechanism 5-HT reuptake inhibitor 5-HT1A agonist
Drug Paroxetine 8-OH-DPAT
Table 1 (continued)
170 P.M. Callahan and A.V. Terry Jr.
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et al. 2006; Amitai and Markou 2009) and mice (Young et al. 2004; de Bruin et al. 2006; Pattij et al. 2007). Collectively, these studies suggest that nicotine improves choice accuracy and decreases trial omissions and response latencies, but that it also increases premature responding. Nicotine, therefore, may improve certain aspects of cognitive performance (processing speed, attention) while negatively affecting other cognitive domains (e.g., response inhibition/impulsivity; see Amitai and Markou 2009). A variety of additional experiments have been conducted to further explore the basis for the effects of nicotine on 5-CSRTT performance. These studies have included evaluations of the major nicotine metabolite, cotinine, as well as nicotinic (subtype-selective) ligands and transgenic receptor knockout mice (i.e., to investigate the role of the specific nicotinic receptor subtypes on 5-CSRTT performance). Cotinine had previously been shown to improve the performance of a standard and distractor version of a delayed-match-to-sample task (DMTS), a working/shortterm memory task in nonhuman primates (Terry et al. 2005). Moreover, cotinine reversed the DMTS performance deficits induced by the NMDA antagonist ketamine (Buccafusco and Terry 2009). The positive effects of cotinine (particularly in the distractor version of DMTS) led to further evaluations of cotinine for its effects on attention in the 5-CSRTT. In these studies, cotinine administered alone did not alter 5-CSRTT performance in the rat; however it was effective in attenuating the negative effects of MK-801 on choice accuracy and premature and timeout responses, suggesting that under particular circumstances cotinine might be therapeutically beneficial (Terry et al. 2012). Studies designed to assess the role of specific nicotinic acetylcholine receptor (nAChR) subtypes on attention in the 5-CSRTT have sometimes been difficult to interpret. Both the α4β2 nAChR antagonist di-hydro-β-erythroidine (DHβE) and the α7 nAChR antagonist methyllycaconitine (MLA) failed to alter task performance (Grottick and Higgins 2000), whereas the nonselective nAChR antagonist mecamylamine was found to decrease choice accuracy and increase trial omissions, correct response latencies, and perseverative responses in rats, effects opposite to those produced by nicotine (Grottick and Higgins 2000; Mirza and Stolerman 2000; Ruotsalainen et al. 2000). Increases in trial omissions and correct response latencies have also been observed in mice after mecamylamine administration (Pattij et al. 2007). To support the argument that the effects described above for mecamylamine are expressed via central nAChRs, the peripheral nAChR antagonist hexamethonium did not alter any task parameters (Blondel et al. 2000; Grottick and Higgins 2000). The information provided above might suggest that both highaffinity (α4β2) and low-affinity (α7) nAChRs (together) are required for detectable effects on 5-CSRTT performance; however, the α4β2/α7 nAChR agonist varenicline had no effect on any of the behavioral parameters assessed in the 5-CSRTT with the exception of premature responding, which was increased at low doses (Wouda et al. 2011). The results of additional studies designed to investigate the role of the particular nAChR subtypes (α4β2 vs. α7) in mediating nicotine’s response in 5-CSRTT have also been somewhat difficult to interpret. Initially, several studies in young and
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aged rats demonstrated that the effects of nicotine were attenuated by co-administration of either DHβE or mecamylamine, but not MLA, suggesting a more important role for the α4β2 nAChR subtype in 5-CSRTT performance (Blondel et al. 2000; Grottick and Higgins 2000; Grottick et al. 2003). However, more recently, Hahn and colleagues (2011) reported that DHβE was without effect on task accuracy produced by nicotine and that MLA co-administration counteracted the behavioral effects, thus defending the premise that α7 nAChRs have an important role 5-CSRTT performance. Other studies could be used to support either argument. For example, the important role of α4β2 nAChRs in attention can be derived from the positive observations with selective α4β2 receptor agonists (e.g., ABT-418, ABT-594, epibatidine, SIB-1765F) on 5-CSRTT performance, whereas the α7 nAChR agonist ARR-17779 lacked effects (Grottick and Higgins 2000; Grottick et al. 2003; Hahn et al. 2003; Mohler et al. 2010). Additionally, the α4β2 nAChR agonist ABT-418 was found to improve attention in adults with ADHD (Wilens et al. 1999). To further explore the contribution of α7 nAChRs to attention, transgenic knockout mice for the α7 receptor (α7 KO) have been developed and trained in the 5-CSRTT (Hoyle et al. 2006; Young et al. 2004). Results from Young and colleagues (2004) indicated that α7 KO mice took significantly longer to acquire the task and upon reaching stable performance exhibited higher levels of omissions compared to the aged-matched wild-type mice, but that no group differences were observed for choice accuracy and correct response latency. In a more detailed examination, Hoyle and colleagues (2006) demonstrated that α7 KO mice were less accurate, had slower correct response latencies, earned fewer rewards, and exhibited higher premature responses than the wild types. Interestingly, nicotine administration failed to alter 5-CSRTT performance for either genotype. When the authors refined the original task parameters (i.e., reduced the time allowed to make a response selection and punished premature responding with a timeout period), the α7 KO mice demonstrated higher omissions and earned fewer rewards than wild types, but there were no longer any differences in accuracy, response latency, or premature responses. Again, nicotine did not alter task performance in either mouse genotype. Results from these two studies thus suggest a role for α7 nAChRs on 5-CSRTT acquisition and selective task parameters, but additional work will be required to fully determine their role in sustained attention. Finally, other studies suggest that additional nAChR subtypes in the brain might have an important role in 5-CSRTT performance (i.e., studies where the α2-4β4 receptor agonist SIB-1553A was evaluated, Terry et al. 2002). The evaluation of dopamine (DA) receptor agonists and antagonists in the 5-CSRTT has also revealed important roles of dopamine and its receptors in attention-related processes. For example, intra-mPFC infusions of the DA D1 receptor agonist SKF 38393 improved choice accuracy and correct response latency in rats with low baseline accuracy (
Contents 1 2
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Five-Choice Serial Reaction Time Task . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Task Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Neural Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Five-Choice Continuous Performance Task . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Task Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Neural Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Signal Detection Task . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Task Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Neural Substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
162 163 163 164 166 176 176 177 177 178 178 179 179 181 181
Abstract
The ability to focus one’s attention on important environmental stimuli while ignoring irrelevant stimuli is fundamental to human cognition and intellectual function. Attention is inextricably linked to perception, learning and memory, and executive function; however, it is often impaired in a variety of neuropsychiatric disorders, including Alzheimer’s disease, schizophrenia, depression, and attention deficit hyperactivity disorder (ADHD). Accordingly, attention is considered as an important therapeutic target in these disorders. The purpose of P.M. Callahan • A.V. Terry Jr. (*) Department of Pharmacology and Toxicology, CB-3545, Georgia Regents University, 1120 Fifteenth Street, Augusta, GA 30912-2450, USA Small Animal Behavior Core, Georgia Regents University, Augusta, GA 30912, USA e-mail: [email protected] # Springer International Publishing Switzerland 2015 K.M. Kantak, J.G. Wettstein (eds.), Cognitive Enhancement, Handbook of Experimental Pharmacology 228, DOI 10.1007/978-3-319-16522-6_5
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this chapter is to provide an overview of the most common behavioral paradigms of attention that have been used in animals (particularly rodents) and to review the literature where these tasks have been employed to elucidate neurobiological substrates of attention as well as to evaluate novel pharmacological agents for their potential as treatments for disorders of attention. These paradigms include two tasks of sustained attention that were developed as rodent analogues of the human Continuous Performance Task (CPT), the Five-Choice Serial Reaction Time Task (5-CSRTT) and the more recently introduced Five-Choice Continuous Performance Task (5C-CPT), and the Signal Detection Task (SDT) which was designed to emphasize temporal components of attention. Keywords
Sustained attention • Signal detection • Distractibility • Preclinical • Drug development • Animal model
1
Introduction
As is often the case in the fields of cognitive psychology and neuroscience, a precise definition for the concept “attention” is often the subject of debate and controversy. However, in simple terms, attention could be thought of as the allocation or concentration of mental resources on specific (environmentally relevant) stimuli while ignoring other (nonrelevant or less relevant) stimuli. While “attention” is often used as an umbrella or generic term, most theories in cognitive psychology describe at least three or four separate (but interrelated) subcategories of attention, including sustained attention or vigilance (attending to one stimulus over a significant period of time), selective attention (focus directed at one stimulus in lieu of competing, irrelevant stimuli), orienting attention (directional or spatial orientation toward a particular stimulus), and divided attention (simultaneously attending to two or more different stimuli or performing multiple tasks) (Posner and Petersen 1990; Robertson et al. 1996; Parasuraman et al. 1998). It is clear that attention is inextricably linked to intellectual function and the major components of human cognition including perception, learning and memory, and executive function. Moreover, attention is often impaired in a variety of neuropsychiatric disorders, including Alzheimer’s disease (Lawrence and Sahakian 1995; Parasuraman et al. 1998), schizophrenia (Laurent et al. 1999), depression (Brown et al. 1994), and attention deficit hyperactivity disorder (ADHD) (Biederman 2005). Accordingly, attention is considered as an important therapeutic target in these disorders. In selecting preclinical behavioral models of attention, priority should be given to behavioral paradigms that possess construct validity (i.e., the task accurately and specifically measures attentional processes and its performance relies on similar underlying neurophysiological circuitry as in humans), reliability, and task standardization across laboratories. Several preclinical behavioral tasks meet
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these criteria and have been used extensively to characterize the neural systems associated with attention as well as to assess pharmacological agents that may have therapeutic relevance in alleviating attentional impairments observed in neuropsychiatric disorders. For this review, we have chosen to discuss three commonly used paradigms: (1) the 5-choice serial reaction time task (5-CSRTT; Carli et al. 1983; Robbins 2002), (2) the 5-choice continuous performance task (5C-CPT; Young et al. 2009), and (3) the signal detection task (SDT; Bushnell 1995; McGaughy and Sarter 1995a, b; Rezvani et al. 2002). All of these behavioral tasks have features that are similar to the continuous performance task (CPT; Rosvold et al. 1956) that has been used successfully to detect attention deficits in clinical populations such as ADHD (Riccio et al. 2002; Loo et al. 2004), Alzheimer’s Disease (Levinoff et al. 2005), and schizophrenia (Nieuwenstein et al. 2001; Lee and Park 2006). In the CPT, subjects are required to respond to a specific visual stimulus (e.g., the letter X) within a list of letters. Since the letter X occurs less often, subjects must remain attentive during the session. When the letter X is presented the subject is required to press a button or click a computer mouse. This simple response requirement affords the investigator considerable information in addition to attention (correct response) such as false alarms (errors made when no X is presented), processing speed (latency to respond), and impulsivity (responding in the absence of the X stimulus). The behavioral tasks described below incorporate many of the CPT test attributes for measuring attention, information processing, and impulsivity.
2
Five-Choice Serial Reaction Time Task
2.1
Task Description
The 5-CSRTT (see Fig. 1) was developed as a means to assess attention based on Leonard’s five-choice sustained attention task in humans (Leonard 1959) and is the preclinical analogue of the CPT task, though there are task dissimilarities (Young et al. 2009). A large literature base exists for the 5-CSRTT with evidence demonstrating construct validity as a model of attention. As a test component within the CANTAB battery, the task has been used in both healthy volunteers and in subjects suffering from neuropsychiatric disorders (Barnett et al. 2010; Cambridge Cognition, camcog.com). The behavioral paradigm was originally developed for rats (Carli et al. 1983), but recently, versions have been developed for mice (Humby et al. 1999; Sanchez-Roige et al. 2012) and nonhuman primates (Weed et al. 1999; Spinelli et al. 2004). The 5-CSRTT assesses the subject’s ability to spatially divide its attention across multiple signal locations (usually five locations, but fewer can be used) in order to select the correct target stimulus (light in a single aperture hole location) that, in turn, produces a food reward (see Higgins and Breysse 2008 for paradigm and training description). This behavioral task measures attentiveness to multiple locations over time and, thereby, utilizes both sustained and selective attention (Levin et al. 2011). Selective attention occurs
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Fig. 1 Diagram of the five-choice serial reaction time task (5-CSRTT). In the 5-CSRTT, subjects are required to scan five apertures in an operant chamber for the appearance of a brief light stimulus (presented pseudorandomly) and to make a nose-poke response in the correct spatial location (i.e., the aperture where the light stimulus was presented) in order to receive a food reward
when the subject faces multiple stimuli and must make a choice among them; the choice is defined by the subject’s behavior. In this situation, novelty plays an important factor in determining the subsequent behavior of the animal and, thus, its attentional selection. Sustained attention occurs when the subject’s behavior is controlled by a single stimulus that occurs unpredictably in time and space. While selective and sustained attention are not independent functions within the 5-CSRTT, these events can be manipulated to preferentially place more “demand” on one function versus the other. For example, a greater demand on sustained attention can be achieved by increasing the temporal unpredictability of the stimulus presentation, whereas increasing the number of potential stimulus locations places greater demand on selective attention. In addition to measuring attention (choice accuracy), the 5-CSRTT can assess a number of other cognitive domains such as impulsivity (premature responses), cognitive flexibility/compulsivity (perseverative and timeout responses), and processing speed (response latency). Task difficulty can be modified by changing the brightness, duration, and temporal predictability of the target stimulus and a distractor stimulus (e.g., auditory tone or white noise) can be interpolated into the protocol to increase task difficulty and place greater attentional demand on the subject.
2.2
Neural Substrates
Considerable scientific work has been devoted to delineating the neural substrates involved in modulating 5-CSRTT performance and its response measures (for reviews, see Robbins 2002; Chudasama and Robbins 2004). Excitotoxic lesions of different subregions of the rat prefrontal cortex differentially affect the behavioral measures associated with the task. Gross lesions of the medial prefrontal
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cortex (mPFC) that include the dorsal pre-genual anterior cingulated cortex (area Cg1), medial prelimbic cortex (PrL), and to some extent the ventral infralimbic cortex (IL) show profound impairments in choice accuracy, increased perseverative responding, and slower response latencies (Muir et al. 1996). More selective lesions within the rat mPFC have identified precise anatomical loci responsible for controlling specific 5-CSRTT response measures. For example, specific lesions of the dorsal Cg1 area produce deficits in choice accuracy, whereas PrL and orbitofrontal cortex (OFC) lesions result in selective increases in perseverative responding (Passetti et al. 2002; Chudasama et al. 2003). In contrast, increases in premature responding occur following ventral IL cortical lesions (Chudasama et al. 2003). There are also data on the effects of specific anatomical loci of the striatum, subthalamic nucleus, pedunculopontine nucleus, and hippocampus (Chudasama et al. 2012) providing evidence of a systematic “top-down” anatomical connectivity in mediating attention, impulsivity and executive function. Complementing the data from anatomical-based lesion experiments, lesions and neurochemical evaluations/manipulations focused on neurotransmitter pathways (e.g., acetylcholine, dopamine, glutamate, noradrenaline, and serotonin) have provided further insights into the neurobiological substrates of 5-CSRTT performance. The outcome from this seminal research highlighted the dissociable roles that specific neurotransmitter systems have on attention, reaction time, and response control (see Robbins 2002). Probably the most extensively studied neurotransmitter system is the forebrain cholinergic system. Selective lesions of the nucleus basalis magnocellularis (NbM) with the cholinergic immunotoxin 192 lgG-saporin resulted in decreased PFC acetylcholine levels and choline acetyltransferase activity accompanied by poor choice accuracy, increases in trial omissions, and disruption in response control performance (McGaughy et al. 2002; Lehmann et al. 2003). Additional evidence (e.g., intra-NbM infusion of the GABA agonist muscimol, or intra-PFC infusion of scopolamine) further supported the importance of the basal forebrain cholinergic system and its innervation of the PFC to 5-CSRTT performance (Muir et al. 1992; Robbins 2002). Studies focused on the catecholamine system have indicated that 6-OHDA depletion of ventral striatal dopamine affects response vigor (i.e., omissions and response latency) with little to no effect on choice accuracy, whereas dorsal striatal dopamine lesions affect only response-related processes. In contrast, 6-OHDA lesions of the mPFC produce minimal effects unless task demands are increased (Robbins 2002). Likewise, lesions of the ascending dorsal noradrenergic (NA) bundle impair attention, but only when greater task demands (e.g., use of distracting stimuli or when the temporal presentation of the stimulus target is unpredictable) are placed on the subject, thereby requiring heightened awareness (Carli et al. 1983; Cole and Robbins 1992). Further support for the engagement of the NA system during challenging situations stems from the observation that increased mPFC noradrenaline efflux occurs only when task contingencies are manipulated, but remain unaltered during baseline conditions (Dalley et al. 2001). Interestingly, the opposite appears to occur for mPFC acetylcholine (i.e., under baseline conditions acetylcholine levels increase but remain unchanged during high
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task demand) demonstrating a dissociation between the two neurotransmitter systems in controlling specific aspects of attention (Dalley et al. 2001). Studies assessing the impact of serotonin (5-HT) depletion have also yielded dissociable profiles on 5-CSRTT performance (i.e., impulsivity and choice accuracy) that are related to the particular neurotoxin (PCPA or 5,7-DHT) and brain region (forebrain, dorsal or medial raphe nuclei) investigated (Harrison et al. 1997a, 1997b; Puumala and Sirvio 1998; Dalley et al. 2002). While there is clearly a definitive relationship between 5-HT function and inhibitory control, it appears that different forms of impulsivity (i.e., impulsive choice vs. impulsive action) are mediated by specific 5-HT receptor subtypes within distinct brain regions (Winstanley et al. 2004a, 2004b). Impulsive action (i.e., behavioral inhibition) is typically measured in the 5-CSRTT, and collectively, evidence has demonstrated that reductions in 5-HT activity can either induce or inhibit impulsive behavior which is purely dependent on the 5-HT receptor subtype (i.e., 5-HT2A vs. 5-HT2C) activated (see below).
2.3
Pharmacology
The 5-CSRTT has also been used extensively to evaluate pharmacological agents in rodent models for effects on attention and inhibitory control (see Table 1). These studies have helped to further elucidate the important roles of various neurotransmitter systems on attentional processes and they have facilitated preclinical drug discovery efforts for neuropsychiatric disorders (e.g., ADHD, Alzheimer’s disease and schizophrenia). Here we provide an overview of some of the major pharmacological studies conducted to date (see also comprehensive reviews, Robbins 2002; Higgins and Breysse 2008; Barak and Weiner 2011; Sanchez-Roige et al. 2012). As discussed above, considerable evidence from lesion-based experiments supports the argument that the CNS cholinergic system plays a major role in attention. This evidence appears to be supported by pharmacologic experimentation as well. For example, systemic administration of the muscarinic receptor antagonist scopolamine impaired several response measures (accuracy and omissions) in rats (Jones and Higgins 1995; Mirza and Stolerman 2000) and mice (Humby et al. 1999; de Bruin et al. 2006; Pattij et al. 2007). However, task performance appeared to be unaltered following the acetylcholinesterase inhibitors (AChE) physostigmine and donepezil (Mirza and Stolerman 2000; Romberg et al. 2011), the muscarinic M1 receptor agonist oxotremorine (Mirza and Stolerman 2000), and the mixed AChEmuscarinic M2 receptor antagonist JWS-USC-75-IX (Terry et al. 2011). Interestingly, JWS-USC-75-IX did attenuate the impairments of choice accuracy and increases in premature responding associated with the NMDA antagonist MK-801 (Terry et al. 2011). Nicotine has been shown to improve attentional processing in humans (Sahakian et al. 1989; White and Levin 1999; Min et al. 2001) and, thus, it has been extensively characterized in the 5-CSRTT in rats (Mirza and Stolerman 1998; Blondel et al. 2000; Grottick and Higgins 2000; Stolerman et al. 2000; Grottick et al. 2003; Bizarro et al. 2004; van Gaalen
Standard/scopolamine reversal Standard Standard/MK-801 reversal Standard/distractor Standard MK-801 reversal
5C-CPT SDT SDT SDT SDT 5-CSRTT SDT
Unknown
α4β2 agonist
Cotinine (Metabolite of nicotine) A-82696
Standard
Standard
5-CSRTT
M1 agonist AChE inhibitor/ M2 antagonist Nonselective nicotinic agonist
Oxotremorine JWS-USC-75-IX 5-CSRTT
AChE inhibitor
Physostigmine
Nicotine
MK-801 reversal Standard Standard Standard Standard Standard MK-801 reversal Standard
SDT 5-CSRTT 5-CSRTT SDT 5-CSRTT 5-CSRTT
AChE inhibitor
Task condition
Taska
Target/mechanism
Drug Cholinergic Donepezil
Table 1 Effects of pharmacological agents in behavioral models of attention
Rats
Mice Rats Rats Rats Rats Rats
Mice
Rats Mice Rats Rats Rats Rats Rats Rats
Species
0
+ 0 + 0/+ + +
+
+ 0 0 0 0 0 + +
Effectb
(continued)
Turchi et al. (1995)
Rezvani et al. (2012) Romberg et al. (2011) Mirza and Stolerman (2000) McGaughy and Sarter (1998) Mirza and Stolerman (2000) Terry et al. (2011) Terry et al. (2011) Mirza and Stolerman (1998) Stolerman et al. (2000) Bizarro et al. (2004) Blondel et al. (2000) Grottick, and Higgins (2000) Grottick et al. (2003) de Bruin et al. (2006) Pattij et al. (2007) Young et al. (2004) Young et al. (2013) Turchi et al. (1995) Rezvani et al. (2002, 2008) Howe et al. (2010) Hillhouse and Prus (2013) Terry et al. (2012)
References
Attention 167
Standard Standard Standard
5C-CPT SDT 5-CSRTT 5-CSRTT SDT
α4β2 agonist α2–4β4 agonist α7 agonist
α7 agonist α7 agonist
DA releaser
SIB-1765F SIB-1553A ARR-17779
PNU 282987 RG 3487 Dopaminergic Amphetamine
Standard/scopolamine reversal Standard
5-CSRTT 5-CSRTT 5-CSRTT
α4β2 agonist α4β2 agonist α4β2 agonist α4β2 agonist α4β2 agonist
ABT-594 ADZ 3480 Epibatidine S-38232 Sazetidine-A
Task condition Standard Standard/scopolamine reversal Standard Standard Standard MK-801 reversal Standard Standard/distractor Standard/scopolamine, MK-801 reversal Standard MK-801 reversal Standard
Taska 5-CSRTT 5C-CPT SDT SDT 5-CSRTT SDT 5-CSRTT SDT SDT
Target/mechanism α4β2 agonist
Drug ABT-418
Table 1 (continued)
Rats
Mice
Rats
Mice Rats
Rats Rats Rats
Species Rats Mice Rats Rats Rats Rats Rats Rats Rats
0
+
0 +
+ + 0
Effectb + + 0 + + + + + +
Grottick and Higgins (2002) Bizarro et al. (2004) Loos et al. (2010) Yan et al. (2011) McGaughy and Sarter (1995a)
Grottick and Higgins (2000) Terry et al. (2002) Grottick and Higgins (2000) Grottick et al. (2003) Hahn et al. (2003) Young et al. (2013) Rezvani et al. (2009b)
References Hahn et al. (2003) Young et al. (2013) Turchi et al. (1995) McGaughy et al. (1999) Mohler et al. (2010) Rezvani et al. (2012) Hahn et al. (2003) Howe et al. (2010) Rezvani et al. (2011, 2012)
168 P.M. Callahan and A.V. Terry Jr.
5-CSRTT
5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT
DA D1 agonist
DA D2/3 agonist DA D2 agonist
NE reuptake inhibitor
NE reuptake inhibitor
NE reuptake inhibitor α1 agonist α2 agonist α2 agonist α2 antagonist β2 agonist
5-HT reuptake inhibitor 5-HT reuptake inhibitor
SKF 38393
Quinpirole Sumanirole Noradrenergic Atomoxetine
Desipramine
Reboxetine St-587 Clonidine Guanfacine Atipamezole Clenbuterol Serotonergic Sibutramine Fluoxetine
5-CSRTT
3-CSRTT 5-CSRTT 5-CSRTT 5C-CPT 5-CSRTT 5-CSRTT
DA reuptake inhibitor
Standard Standard
Standard Standard Standard Standard Standard Standard
Standard
Standard
Standard/MK-801, scopolamine reversal Standard Standard Standard Standard Standard Standard
SDT
Modafinil
Standard
5-CSRTT
DA reuptake inhibitor
Methylphenidate
Rats Rats
Rats Rats Rats Rats Rats Rats
Rats
Rats
Rats Rats Rats Rats Rats Rats
Rats
Rats
+ + + + + +
+
+
+ +
+
+
+
(continued)
Humpston et al. (2013) Humpston et al. (2013)
Navarra et al. (2008b) Fernando et al. (2012) Robinson (2012) Paine et al. (2007) Pattij et al. (2012) Robinson (2012) Puumala et al. (1997) Pattij et al. (2012) Fernando et al. (2012) Sirvio et al. (1993) Pattij et al. (2012)
Morgan et al. (2007) Waters et al. (2005) Grannon et al. (2000) Barnes et al. (2012) Fernando et al. (2012) Fernando et al. (2012)
Paine et al. (2007) Puumala et al. (1996) Bizarro et al. (2004) Navarra et al. (2008b) Rezvani et al. (2009b)
Attention 169
5-HT2A agonist
5-HT2A antagonist
5-HT2C agonist
5-HT2C agonist 5-HT3 antagonist 5-HT6 antagonist
DOI
M100907
Ro60-0175
WAY-163909 Ondansetron CMP 42
5-CSRTT 5-CSRTT 5-CSRTT 5-CSRTT
5-CSRTT 5-CSRTT
5-CSRTT 5-CSRTT
5-CSRTT
Taska 5-CSRTT 5-CSRTT
Standard MK-801, amphetamine, cocaine reversal Standard MK-801, amphetamine, cocaine reversal Standard Standard Standard Standard
Standard
Task condition Standard Standard
Mice Rats Rats Rats
Rats Rats
Rats Rats
Rats
Species Rats Rats
+ +
+ +
+ +
+
Effectb
Fletcher et al. (2013) Navarra et al. (2008b) Kirkby et al. (1996) de Bruin et al. (2013)
Fletcher et al. (2007) Fletcher et al. (2011)
References Humpston et al. (2013) Carli and Samanin (2000) Winstanley et al. (2003) Koskinen and Sirvio (2001) Fletcher et al. (2007) Fletcher et al. (2007) Fletcher et al. (2011)
b
Task abbreviations indicate 5-choice serial reaction time task (5-CSRTT), 5-choice continuous performance task (5C-CPT) or signal detection task (SDT) Symbols indicate performance improvement (+), performance impairment ( ) or no effect (0)
a
Target/mechanism 5-HT reuptake inhibitor 5-HT1A agonist
Drug Paroxetine 8-OH-DPAT
Table 1 (continued)
170 P.M. Callahan and A.V. Terry Jr.
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et al. 2006; Amitai and Markou 2009) and mice (Young et al. 2004; de Bruin et al. 2006; Pattij et al. 2007). Collectively, these studies suggest that nicotine improves choice accuracy and decreases trial omissions and response latencies, but that it also increases premature responding. Nicotine, therefore, may improve certain aspects of cognitive performance (processing speed, attention) while negatively affecting other cognitive domains (e.g., response inhibition/impulsivity; see Amitai and Markou 2009). A variety of additional experiments have been conducted to further explore the basis for the effects of nicotine on 5-CSRTT performance. These studies have included evaluations of the major nicotine metabolite, cotinine, as well as nicotinic (subtype-selective) ligands and transgenic receptor knockout mice (i.e., to investigate the role of the specific nicotinic receptor subtypes on 5-CSRTT performance). Cotinine had previously been shown to improve the performance of a standard and distractor version of a delayed-match-to-sample task (DMTS), a working/shortterm memory task in nonhuman primates (Terry et al. 2005). Moreover, cotinine reversed the DMTS performance deficits induced by the NMDA antagonist ketamine (Buccafusco and Terry 2009). The positive effects of cotinine (particularly in the distractor version of DMTS) led to further evaluations of cotinine for its effects on attention in the 5-CSRTT. In these studies, cotinine administered alone did not alter 5-CSRTT performance in the rat; however it was effective in attenuating the negative effects of MK-801 on choice accuracy and premature and timeout responses, suggesting that under particular circumstances cotinine might be therapeutically beneficial (Terry et al. 2012). Studies designed to assess the role of specific nicotinic acetylcholine receptor (nAChR) subtypes on attention in the 5-CSRTT have sometimes been difficult to interpret. Both the α4β2 nAChR antagonist di-hydro-β-erythroidine (DHβE) and the α7 nAChR antagonist methyllycaconitine (MLA) failed to alter task performance (Grottick and Higgins 2000), whereas the nonselective nAChR antagonist mecamylamine was found to decrease choice accuracy and increase trial omissions, correct response latencies, and perseverative responses in rats, effects opposite to those produced by nicotine (Grottick and Higgins 2000; Mirza and Stolerman 2000; Ruotsalainen et al. 2000). Increases in trial omissions and correct response latencies have also been observed in mice after mecamylamine administration (Pattij et al. 2007). To support the argument that the effects described above for mecamylamine are expressed via central nAChRs, the peripheral nAChR antagonist hexamethonium did not alter any task parameters (Blondel et al. 2000; Grottick and Higgins 2000). The information provided above might suggest that both highaffinity (α4β2) and low-affinity (α7) nAChRs (together) are required for detectable effects on 5-CSRTT performance; however, the α4β2/α7 nAChR agonist varenicline had no effect on any of the behavioral parameters assessed in the 5-CSRTT with the exception of premature responding, which was increased at low doses (Wouda et al. 2011). The results of additional studies designed to investigate the role of the particular nAChR subtypes (α4β2 vs. α7) in mediating nicotine’s response in 5-CSRTT have also been somewhat difficult to interpret. Initially, several studies in young and
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aged rats demonstrated that the effects of nicotine were attenuated by co-administration of either DHβE or mecamylamine, but not MLA, suggesting a more important role for the α4β2 nAChR subtype in 5-CSRTT performance (Blondel et al. 2000; Grottick and Higgins 2000; Grottick et al. 2003). However, more recently, Hahn and colleagues (2011) reported that DHβE was without effect on task accuracy produced by nicotine and that MLA co-administration counteracted the behavioral effects, thus defending the premise that α7 nAChRs have an important role 5-CSRTT performance. Other studies could be used to support either argument. For example, the important role of α4β2 nAChRs in attention can be derived from the positive observations with selective α4β2 receptor agonists (e.g., ABT-418, ABT-594, epibatidine, SIB-1765F) on 5-CSRTT performance, whereas the α7 nAChR agonist ARR-17779 lacked effects (Grottick and Higgins 2000; Grottick et al. 2003; Hahn et al. 2003; Mohler et al. 2010). Additionally, the α4β2 nAChR agonist ABT-418 was found to improve attention in adults with ADHD (Wilens et al. 1999). To further explore the contribution of α7 nAChRs to attention, transgenic knockout mice for the α7 receptor (α7 KO) have been developed and trained in the 5-CSRTT (Hoyle et al. 2006; Young et al. 2004). Results from Young and colleagues (2004) indicated that α7 KO mice took significantly longer to acquire the task and upon reaching stable performance exhibited higher levels of omissions compared to the aged-matched wild-type mice, but that no group differences were observed for choice accuracy and correct response latency. In a more detailed examination, Hoyle and colleagues (2006) demonstrated that α7 KO mice were less accurate, had slower correct response latencies, earned fewer rewards, and exhibited higher premature responses than the wild types. Interestingly, nicotine administration failed to alter 5-CSRTT performance for either genotype. When the authors refined the original task parameters (i.e., reduced the time allowed to make a response selection and punished premature responding with a timeout period), the α7 KO mice demonstrated higher omissions and earned fewer rewards than wild types, but there were no longer any differences in accuracy, response latency, or premature responses. Again, nicotine did not alter task performance in either mouse genotype. Results from these two studies thus suggest a role for α7 nAChRs on 5-CSRTT acquisition and selective task parameters, but additional work will be required to fully determine their role in sustained attention. Finally, other studies suggest that additional nAChR subtypes in the brain might have an important role in 5-CSRTT performance (i.e., studies where the α2-4β4 receptor agonist SIB-1553A was evaluated, Terry et al. 2002). The evaluation of dopamine (DA) receptor agonists and antagonists in the 5-CSRTT has also revealed important roles of dopamine and its receptors in attention-related processes. For example, intra-mPFC infusions of the DA D1 receptor agonist SKF 38393 improved choice accuracy and correct response latency in rats with low baseline accuracy (
