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. Author manuscript; available in PMC: 2018 Mar 27.
Published in final edited form as: Psychopharmacology (Berl). 2011 Sep 8;220(1):129–141. doi: 10.1007/s00213-011-2460-8

D1 receptor activation improves vigilance in rats as measured by the 5-choice continuous performance test

A BARNES Samuel 1, W YOUNG Jared 2, C NEILL Jo 1;,*
PMCID: PMC5870138  NIHMSID: NIHMS929270  PMID: 21901319

Abstract

Rationale

Impaired attention/vigilance is putatively core to schizophrenia. The dopaminergic D1 receptor system has been reported as one of the most promising targets for improving cognition in patients with schizophrenia, with some evidence suggesting D1 activation may improve sustained attention.

Objectives

The purpose of this study was twofold: firstly assessing the applicability of using rats in the 5-Choice Continuous Performance Test (5C-CPT), recently validated in mice. Secondly, the effect of systemic administration of a D1 partial agonist, SKF 38393, on task performance during baseline, and a challenge session consisting of a reduced event-rate was investigated.

Methods

: Animals were trained to perform the 5C-CPT with performance assessed following systemic SKF 38393 (2, 4 and 6 mg/kg) vs. vehicle administration.

Results

Rats could discriminate between target (requiring a response) and non-target (requiring the inhibition of response) trials within the 5C-CPT. Moreover, SKF 38393 treatment impaired performance during the baseline session reducing target detection, yet improved performance during the reduced event-rate challenge session, increasing target detection and improving signal discrimination indicating an SKF 38393-induced enhancement of vigilance. Thus, these data suggest that activation of the D1 system affected 5C-CPT performance in a baseline dependent manner.

Conclusion

Rats can be trained to perform the 5C-CPT, appropriately withholding from responding to non-target trials. Systemic administration of SKF 38393 impaired performance during baseline conditions. Following a task-related challenge, which reduced the event rate, activation of the dopamine (DA) D1 system improved performance by heightening the animals’ vigilance levels, quantified using signal detection theory.

Keywords: Attention, Vigilance, Schizophrenia, Dopamine, D1 Agonist, 5-Choice Continuous Performance Test, 5C-CPT

1. Introduction

Schizophrenia affects approximately 1% of the general population and is characterised by a myriad of symptoms, which can include positive and negative symptom coupled with cognitive impairment (Marder et al. 2004; Paine and Carlezon Jr 2009). Current treatments target only the positive symptoms and recognition that cognitive disruption correlates most closely with functional outcome (Green 1996) has galvanized research into trying to develop pro-cognitive treatments for schizophrenia. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative highlighted seven core domains of cognition affected in schizophrenia (Green et al. 2004; Marder and Fenton 2004). As such, one domain affected and putatively core to cognitive disruption in schizophrenia is impaired attention/vigilance (Cornblatt and Keilp 1994).

The continuous performance test (CPT) collectively describes a group of tests primarily used to assess attention/vigilance in humans, originally developed by Rosvold and colleagues (1956). Despite the variety of CPTs (Riccio et al. 2002), each task includes the core component of target trials requiring a response and non-target trials that must be ignored. Various response outcomes are possible – hits or misses during target trials, and correct rejections or false alarms during non-target trials – enabling signal detection theory (SDT) to be employed to further assess performance. SDT provides insight into the discrimination of trial types presented, generating a measure of sensitivity commonly used as an indicator of vigilance (Nestor et al. 1990; Chen and Faraone 2000). Furthermore, information regarding the response profile of the subject is generated, which can separate attentional or vigilance impairment/improvement from alterations in the subjects’ willingness to respond (Marston 1996; Robbins 1998; Steckler 2001; Young et al. 2009b). Improvement in signal discrimination may be due to an increased ability to detect the signal, or modifications in the decision criteria of the subject; SDT enables the elucidation of the process behind performance alterations (Marston 1996) and as a result, inclusion of SDT measures may provide an enhanced method of revealing changes in CPT performance that might not be obvious using omission or commission errors alone (Lam and Beale 1991; Riccio et al. 2002). Schizophrenia patients perform poorly in multiple versions of the CPT, confirming impaired attention/vigilance is inherent to the disorder (Rosvold et al. 1956; Kornetsky and Mirsky 1966; Wohlberg and Kornetsky 1973; Cornblatt and Keilip 1994; Kumar et al. 2010). Erroneous CPT performance is exemplified by a reduced hit rate and an increase in false alarms, ultimately resulting in impaired signal sensitivity (Nestor et al. 1990; Parasuraman 1998; Chen and Faraone 2000). Consequently, dysfunctional attention/vigilance, which may also affect additional cognitive processes (Parasuraman 1998), impairs the patient’s quality of life (Cornblatt and Keilip 1994; Marder and Fenton 2004), thus contributing to the poor functional and occupational outcome of schizophrenia (Green et al. 1996).

One of the most commonly used animal tasks that assesses attention is the 5-Choice Serial Reaction Time Task (5-CSRTT) (Carli et al. 1983), designed as being analogous to Leonard’s 5-choice test of sustained attention (Leonard 1959; Robbins 2002), used to study human attentional processes (Wilkinson 1963). Despite suggestions of analogy with CPTs (Bari et al. 2008; Navarra et al. 2008), the 5-CSRTT differs crucially from human CPTs as it includes only target trials in which the animal must respond (Robbins 2002; Young et al. 2009a). The 5-CSRTT lacks irrelevant trials requiring response inhibition (Riccio et al. 2002), possibly limiting its application to assess vigilance (Robbins 1998). Although the terms are often interchangeable, subtle differences exist between vigilance and sustained attention. Vigilance reflects a cognitive construct described as the ability to remain alert towards incoming stimulus information (Collings 2003; Egeland et al. 2009), facilitating the state of readiness to detect and respond to unpredictable and rare events. Thus, vigilance enables the discrimination between signal and noise (Mackworth 1957; Broadbent 1971), whereas sustained attention enables an individual to focus attention over a prolonged period enabling attentional goals to be maintained over time (Robbins 1998). As such, the current configuration of the 5-CSRTT restricts the ability to accurately evaluate vigilance (Robbins 1998) in a manner consistent with human CPTs, as in most vigilance experiments, the critical signals for detection fall within a backdrop of non-signal events (Warm and Dember 1987), events that are absent in the original 5-CSRTT.

A lever-based operant task developed by McGaughy and Sarter (1995) may accurately assess vigilance, requiring animals to determine whether a visual cue appeared or not, prior to the presentation of the two levers. Presentation of the signal required a response in one lever, generating a hit, whilst the operation of the remaining lever represented a miss. Alternatively, if the signal was absent, pressing those same levers resulted in either a false alarm or correct rejection respectively. As a result, the task encompasses response measures that are present in all variants of human CPTs (i.e. hits, misses, correct rejections and false alarms). However, false alarms typically constitute a failure to withhold from responding in contrast to correct rejections that usually require an inhibition of response (Eagle et al. 2008). Therefore, it could be maintained that the non-signal trial within this paradigm has limited analogy to the non-signal trials presented in human CPTs, as the correct rejection requires an active response (Young et al. 2009b).

Consequently, the 5-CSRTT has been modified to include non-target trials potentially generating a behavioural paradigm with enhanced analogy and cross-species translatability to human CPTs, named the 5-Choice Continuous Performance Test (5C-CPT) (Young et al. 2009b). Like the 5-CSRTT, target trials requiring a response are presented throughout the 5C-CPT. Importantly, however, the 5C-CPT also presents non-target trials requiring the inhibition of a response, with response disinhibition generating a false alarm. This adaptation improves the capability to assess vigilance in a preclinical paradigm that is consistent with human CPTs. Furthermore, SDT can be used to provide insight into the animals’ responsivity and give additional information on attentional performance in light of task or pharmacological manipulations (Dudchenko et al. 1992).

It has long been established that dopamine (DA) transmission is disrupted in the pathophysiology of schizophrenia; however, it is still not entirely clear how DA dysregulation and cognitive impairments in schizophrenia are connected (Cohen and Servan-Schreiber 1993). Despite this uncertainty it is evident that DA transmission in sub-cortical (Tomasi et al. 2010) and cortical brain regions (Sawaguchi and Goldman-Rakic 1991; Goldman-Rakic et al. 2004) is linked to various cognitive processes, including attentional functioning (Nieoullon 2002). The DA D1 receptor system has been identified as one of the most promising targets for developing pro-cognitive therapeutics for schizophrenia (Tamminga 2006), and there is some evidence that D1 agonists can improve attention, provided by improved accuracy of responding in the 5-CSRTT in rats with poor baseline performance (Granon et al. 2000). Enhancement of attentional performance via activation of D1 dopaminergic system has yet to be determined in the 5C-CPT. Additionally, validation of the 5C-CPT has previously only been carried out in mice (Young et al, 2009b) and so the purpose of the present study was to 1) identify whether rats could be trained to perform the 5C-CPT, and 2) investigate the effect of a D1 agonist on performance at stable baseline and following behavioural challenge.

2. Methods and Materials

2.1 Subjects

Female Lister-hooded rats (n=35; Charles River; 220 ± 10 g at the start of the experiment) were housed in groups of five on a 12 hour reversed light cycle (lights on at 7:00 pm) in a temperature (21 ± 2°C) and humidity (55 ± 5%) controlled environment. All experimentation took place in the dark cycle, under red lighting, and animals had free access to food (Special Diet Services, UK) and water until one week prior to the beginning of training, where food restriction reduced animal weight to 90% of the free-feeding body weight. Food restriction continued throughout training and testing, however water was available ad libitium whilst in the home cage. All experimentation was conducted in accordance with the UK Animals (Scientific Procedures) 1986 Act and local University of Bradford ethical guidelines.

2.2 Apparatus

The test apparatus consisted of eight 25 cm × 25 cm aluminium chambers, each enclosed within a wooden sound attenuating box. The rear wall of the testing chamber was concavely curved and contained nine individual apertures, four of which were occluded, leaving apertures 1, 3, 5, 7 and 9 free for exploration. Each aperture was 2.5 cm2, 4 cm deep and set 2 cm above floor level. Located at the rear of each aperture was a white LED, which provided the light stimulus. At the entrance to each aperture, an infrared photocell beam registered nose-poke responses. Located on the front wall of the test chamber was a food magazine that allowed retrieval of the food reward (45 mg Rodent Pellet, Sandown Scientific). A hinged panel covered the food magazine and a micro-switch reported the collection of food rewards. In addition to the sound attenuating box, there was also a low-level fan that provided ventilation along with a means to mask extraneous background noises. The floor of the test chamber consisted of a wire grid, under which was a removable tray that was covered with sawdust. All eight chambers were connected to a PC and data collection and initial analysis was controlled by K-Limbic software (Conclusive Solutions).

2.3 Behavioural Procedure

The 5C-CPT procedure is similar to the 5-CSRTT, in that both tasks contain target trials that the animal must respond. Briefly, rats were trained to detect and make a nose-poke response to the occurrence of a brief visual stimulus presented pseudo-randomly in one of the five available apertures following a variable (4.0, 4.5, 5.5, and 6.0 s) inter-trial interval (ITI). If the animal correctly reported the detection of the visual stimulus within the limited hold (LH; period following the stimulus presentation which animals can make a response, 2 s) (correct response), the animal was rewarded with a food pellet. Collection of the food pellet initiated the next trial. Failure to respond to the light stimulus (error of omission) or responding to an aperture where the light was not presented (incorrect response) resulted in the animal being exposed to a 5 s time out (TO) period, whereby the house light was illuminated and no food reward delivered. Failure to wait for the stimulus presentation, i.e. a nose-poke during the ITI, was recorded as a premature response and initiated a TO period. Animals also received a TO period following a single inappropriate repeat response following a correct response (perseverative response). The methodological difference, unique to the 5C-CPT procedure is the inclusion of non-target stimuli, in which all apertures are illuminated signalling the animal to inhibit from responding (correct rejection, CR) in order to obtain a reward. Responses made within the LH period during a non-target trial (false alarm, FA) resulted in a TO period (Young et al. 2009b). The session consisted of 120 trials, lasting no longer than 30 minutes. Coupled with measures typically calculated in the original 5-CSRTT paradigm, described above, Table 1 highlights the additional behavioural measures assessed by the 5C-CPT. Moreover, in previous 5-CSRTT studies, accuracy is also referred to as percent correct responses and the terms are often interchangeable. However, an important distinction exists and one that is often overlooked; accuracy is calculated independently from omissions, whereas percent correct responding is a percentage of correct responses to target trials, calculated from the total number of responses within the session (correct, incorrect and omissions). We have adopted this method of calculating accuracy and percent correct responses, as previously described by others (Amitai et al. 2007; Amitai and Markou 2009).

Table 1.

Description of the additional behavioural measures assessed in the 5C-CPT

Measure & Description
Percent Correct Rejections: Non-target trials correctly inhibited/(correct rejections + false alarms)*100 – a measure of correct rejection of non-target trials
Hit rate, p[HR]: The proportion of correct detections of the signal
False alarm rate, p[FA]: The proportion of the animal incorrectly reporting the detection of the signal: to assess response disinhibition
Sensitivity index, SI: Non-parametric measure of sensitivity to differentiate signals – a measure of vigilance
Responsivity index, RI: Non-parametric measure of the response bias or strategy of the animal
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Further information concerning the calculations of these measures are described in Young et al. 2009b

The following describes the methods used to calculate the indices used in SDT as originally described by Frey and Colliver (1973) and used in the mouse 5C-CPT (Young et al. 2009b). Correct, incorrect and omissions refer to possible response outcomes when presented with a target trial, FA indicates an incorrect response to non-target trial and CR refers to a correct rejection of non-target trial:

p[HR]=CorrectCorrect+Incorrect+Omissionp[FA]=FAFA+CR
SI=p[HR]−p[FA]2(p[HR]+p[FA])−(p[HR]+p[FA])2
RI=p[HR]+p[FA]−11−(p[FA]−p[HR])2

2.4 Training Schedule

Training was conducted in a manner similar to the original 5-CSRTT, with the exception that non-target trials were included. Animals were habituated to operant chambers for 2 days and response apertures baited to encourage exploration. Initially, the target and non-target ratio (100:20) was identical to that used in the original mouse version (Young et al. 2009b). However, this configuration proved inappropriate for rats as the level of correct rejections was unstable. Therefore, a greater emphasis was placed on the presentation of non-target trials, and the number per session was increased (77 target: 43 non-target) to encourage response inhibition. Once rats were able to reliably discriminate between trial types (p[HR] > p[FA]), the number of target trials per session was increased to 84 and non-target trials reduced to 36; a configuration used throughout the remainder of training and testing. The initial stimulus duration (SD) was 10 s and was progressively reduced (10, 8, 4, and 2 s) for individual rats as they reached criterion (>75% accuracy, <25% omission and >65% correct rejections of non-target trials, for three consecutive days). Training was conducted until animals achieved a stable performance at the desired testing parameters (1.5 s SD, 5 s TO, variable ITI with mean of 5 s and 2 s LH, parameters chosen in part to mirror the original mouse version; Young et al. 2009b) over three consecutive days. The entire training procedure, including the optimisation of the target and non-target ratio, took approximately 5 – 6 months. As part of the training schedule involved optimisation of the protocol, subsequent investigations utilising the increased number of non-target trials at the beginning of training would reduce the overall training period.

2.5 Experimental Design

2.5.1 Baseline Task Performance

The initial experiment investigated the effect of SKF 38393 on performance in the 5C-CPT using standard training conditions that consisted of 1.5 s SD, 5 s TO period, 2 s LH, a variable ITI (4.0, 4.5, 5.5, and 6.0 s) which averaged 5 s, in a session comprised of 84 target trials and 36 non-target trials. Following attainment of baseline stability, animals were randomly assigned to four treatment groups, whilst ensuring no performance variability existed between groups prior to drug treatment. Animals then received vehicle (distilled H2O), 2.0, 4.0, or 6.0 mg/kg (n = 8 – 9) SKF 38393 30 minutes before behavioural testing.

2.5.2 Reduced Event Rate Task Challenge

The second experiment followed the same design in which animals were randomly assigned to four separate treatment groups, ensuring no variability between treatment groups and treated with vehicle, 2.0, 4.0, or 6.0 mg/kg SKF 38393 (n = 8 – 9). The rats were then tested in the 5C-CPT. The testing parameters were identical to the previous experiment, with the exception that the variable ITI was extended from 5 s average to 10 s (8, 9, 11, and 12 s). One rat was excluded from analysis following reduced event-rate challenge (6 mg/kg treatment group) due to malfunction of operant chamber during testing.

Baseline and challenge session were separated by two days, during which all animals received normal training sessions to ensure performance was maintained at a stable baseline, while also identifying potential lasting effects resulting from drug treatment. A between-subjects design was used in opposition to a within-subjects Latin square design in order to avoid the potential learning confound that may result from repeated exposure to the extended ITI challenge session.

2.6 Drugs

SKF 38393 (Sigma, UK) was dissolved in distilled H2O to give the appropriate doses (2.0, 4.0 and 6.0 mg/kg) and was injected via the intraperitoneal (i.p.) route with a 30 minute pre-treatment time at a dose volume of 1 ml/kg. All drug doses were calculated as base equivalent weight. The doses used in this study were chosen from previous behavioural experimentation conduced within our laboratory and others, which showed efficacy within this dose range in behavioural tasks of cognition of relevance to schizophrenia (Hersi et al. 1995; McLean et al. 2009).

2.7 Statistical Analysis

Performance for each behavioural measure in the 5C-CPT was displayed as observed mean ± SEM. Data were analysed by one-way between subjects ANOVA with drug as the between subjects factor, followed by Planned Comparisons on the predicted means (Snedecor and Cochran 1989), dictated by performance measures assessed in the 5C-CPT. When using Planned Comparisons, no multiple comparison adustment was made to the p-values when comparing increasing doses to vehicle. Data presented over the duration of the session was displayed as observed mean ± SEM and analysed using a repeated measures ANOVA (treatment as fixed factor) followed by Planned Comparisons on the predicted means using Statistica v8.0 (Statsoft). Planned Comparisons were utilised to test the hypothesis that drug treatment would, depending on testing parameters, improve or impair performance. While the p-value obtained, coupled with assessment of the biological relevance of the effect, was considered during behavioural interpretation, no adjustments were made for multiple comparisons in the current investigation. Comparison of means in order to determine whether rats were able to discriminate between trial types and the determination of the effect reducing the event-rate had on task performance were displayed as mean ± SEM and analysed using a Students t test.

3. Results

3.1 Discrimination Between Trial Types

There was a significant difference (t=7.31, p<0.001) between p[HR] and p[FA] (Fig 1A). Analysis showed that there was a significant difference (t=9.97, p<0.001) when percent correct rejections was compared with percent omissions (Fig 1B), demonstrating a discrimination between trial types.

Fig. 1.

Fig. 1

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Performance of vehicle treated animals under standard training conditions highlighting the ability to perform the 5 C-CPT. There was a significant difference between hit rate and false alarm rate (a) in addition to a significant difference between percent correct rejections and percent omissions (b). Data are expressed as mean ± SEM, analysed by Student’s t-test. ***p < 0.0001

3.2 SKF 38393 and Baseline Task Performance

Table 2 demonstrates there was no significant ANOVA effect of drug treatment on accuracy [F(3,31)=2.01, ns], percent correct [F(3,31)=2.08, ns] or percent omissions [F(3,31)=1.95, ns]. However, Planned Comparisons revealed a significant effect at the highest dose of SKF 38393 on both percent correct (decrease) (p<0.05) and percent omissions (increase) (p<0.05). Treatment produced a significant increase in correct latency (CL) [F(3,31)=5.25, p<0.01]. Planned Comparisons indicated 4 mg/kg and 6 mg/kg SKF 38393 increased CL (p<0.05). Statistical analysis showed no significant change in incorrect latency (IL) [F>1, ns] or magazine latency (ML) [F(3,31)=1.47, ns]. SKF 38393 had no effect on premature [F>1, ns] or perseverative [F(3,31)=2.04, ns] responses made during the session, confirmed by the lack of effect following pair-wise comparisons (table 2).

Table 2.

Effect of SKF 38393 on Baseline Performance

Measures Vehicle 2.0mg/kg 4.0mg/kg 6.0mg/kg
Accuracy (%) Mean 94.35 ± 1.58 96.40 ± 0.94 95.33 ± 1.54 91.41 ± 1.75
p-value 0.35 0.64 0.17
Percent Correct Mean 76.81 ± 4.55 78.17 ± 6.88 71.28 ± 4.70 58.49 ± 8.16
p-value 0.88 0.52 0.04
Percent Omission Mean 18.90 ± 3.99 19.19 ± 6.71 25.46 ± 4.34 36.94 ± 8.29
p-value 0.98 0.44 0.04
Correct Latency Mean 0.71 ± 0.06 0.65 ± 0.03 0.93 ± 0.08 0.90 ± 0.05
p-value 0.48 0.01 0.03
Incorrect Latency Mean 0.55 ± 0.13 0.80 ± 0.21 1.03 ± 0.27 1.14 ± 0.18
p-value 0.91 0.45 0.49
Magazine Latency Mean 1.26 ± 0.06 1.29 ± 0.07 1.33 ± 0.07 1.46 ± 0.10
p-value 0.73 0.51 0.06
Premature Mean 6.00 ± 2.17 6.50 ± 1.24 5.56 ± 2.24 2.67 ± 0.99
p-value 0.85 0.86 0.20
Perseverative Mean 10.67 ± 3.36 10.75 ± 2.25 22.22 ± 4.94 20.89 ± 5.76
p-value 0.98 0.07 0.11
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Measures are shown as observed mean ± SEM along with unadjusted p-value obtained from pairwise comparison between treatment groups and vehicle group in italics. Significant values are in bold. Baseline parameters consisted of 1.5 s SD, 5 s TO period, 2 s LH, a variable ITI (4.0, 4.5, 5.5, and 6.0 s)

ANOVA showed no change in p[HR] [F(3,31)=2.08, ns]. Although Planned Comparisons showed no change with 2 mg/kg or 4 mg/kg, the highest dose of SKF 38393 (6 mg/kg) was revealed to produce a significant reduction in p[HR] (p<0.05, fig 2A). ANOVA indicated no effect on p[FA] [F(3,31)=1.17, ns], and no effect was evident following pair-wise comparisons (fig 2B). Additionally, no ANOVA effect was observed on the sensitivity index [F(3,31)=0.37, ns], coupled with no change following Planned Comparisons (fig 2C). Furthermore, the responsivity index was also unaffected [F(3,31)=2.25, ns], with Planned Comparisons indicating no change following drug treatment (fig 2D).

Fig. 2.

Fig. 2

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Performance of animals in the 5 C-CPT tested using standard conditions following SKF 38393 treatment and analysed using signal detection theory. Drug treatment produced a significant reduction in p[HR] (a). There was no effect of SKF 38393 on p[FA] (b), sensitivity index (c) or responsivity index (d). Data are expressed as mean ± SEM and analysed by one-way ANOVA followed by Planned Comparisons on the predicted means. *p < 0.05 relative to the vehicle (Veh) group

3.2 Effect of a Reduced Event-Rate on Task Performance

When the variable ITI was increased from an average of 5 s to 10 s, there was an impaired ability of control animals to perform the 5C-CPT (table 3). There was no effect on accuracy (t=1.23, ns), but a reduction in percent correct (t=2.90, p<0.05) and increase in percent omissions (t=2.67, p<0.05). CL and IL were unaffected (t=0.93, ns and t=0.36, ns, respectively) but there was a reduction in ML (t=2.47, p<0.05). Extending the ITI dramatically increased the number of premature response (t=4.87, p<0.001), but perseverative responding was unaffected (t=0.36, ns). Correct rejections were unaffected (t=1.54, ns). The p[HR] was significantly reduced (t=2.95, p<0.01), but the p[FA] was unchanged (t=1.16, ns). As a result, there was a significant reduction in SI (t=2.82, p<0.05), which occurred without alterations in the RI (t=1.05, ns). Furthermore, a comparison of the effect of SKF treatment (6 mg/kg) during baseline and challenge condition was made (table 3). There was no effect on accuracy (t=1.48, ns) or percent correct responding (t=1.86, ns), but a significant SKF-induced reduction in omissions was observed during the reduced event-rate (t=2.51, p<0.05). A significant reduction in CL (t=2.58, p<0.05) was observed in the challenge session, without alterations in IL (t=1.52, ns) or ML (t=0.38, ns). A significant increase in premature responding (t=4.59, p<0.001) was observed during the extended ITI session, but a significant reduction in perseverative responding (t=2.47, p<0.05) was demonstrated. SKF treatment had no effect on correct rejections (t=1.52, ns) between challenge conditions. Furthermore, there were no differences in p[HR] (t=1.86, ns), p[FA] (t=1.51, ns), SI (t=0.6, ns) or RI (t=1.81, ns) between test conditions in SKF treated animals.

Table 3.

Effect of a reduced event rate on 5C-CPT performance in both saline and SKF treated animals

Saline SKF 38393
Measures BL RER BL RER
Accuracy (%) 94.35 ± 1.58 88.92 ± 3.93 91.41 ± 1.75 94.58 ± 1.13
Correct (%) 76.81 ± 4.55 56.41 ± 5.27* 58.49 ± 8.16 76.14 ± 4.11
Omission (%) 18.90 ± 3.99 37.69 ± 5.60* 36.94 ± 8.29 13.92 ± 2.81*
Correct Latency 0.71 ± 0.06 0.79 ± 0.06 0.90 ± 0.05 0.74 ± 0.02*
Incorrect Latency 0.55 ± 0.13 0.69 ± 0.14 1.14 ± 0.18 0.73 ± 0.19
Magazine Latency 1.26 ± 0.06 1.06 ± 0.06* 1.46 ± 0.10 1.41 ± 0.10
Premature 6.00 ± 2.17 36.50 ± 5.59*** 2.67 ± 0.99 27.38 ± 5.62***
Perseverative 10.67 ± 3.36 9.40 ± 1.51 20.89 ± 5.76 5.50 ± 1.16*
Correct Rejections (%) 66.11 ± 5.56 55.43 ± 7.21 74.44 ± 4.93 61.98 ± 6.69
Hit Rate 0.77 ± 0.05 0.56 ± 0.05** 0.58 ± 0.08 0.76 ± 0.04
False Alarm Rate 0.34 ± 0.06 0.45 ± 0.07 0.26 ± 0.05 0.38 ± 0.07
Sensitivity Index 0.44 ± 0.09 0.13 ± 0.07* 0.36 ± 0.06 0.41 ± 0.06
Responsivity Index 0.15 ± 0.06 0.01 ± 0.11 −0.16 ± 0.13 0.15 ± 0.11
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Effect of reducing the event-rate had on 5C-CPT performance. Measures are shown as observable mean + SEM. Asterisks indicate statistically significant differences

*

p<0.05,

**

p<0.01,

***

p<0.0001) between baseline (BL) and reduced event-rate (RER) performance. BL parameters consisted of 1.5 s SD, 5 s TO period, 2 s LH, a variable ITI (4.0, 4.5, 5.5, and 6.0 s), whereas the RER had an extended variable ITI (8, 9, 11, 12 s). Only performance of saline and the highest dose of SKF (6 mg/kg) are displayed.

3.3 SKF 38393 and Reduced Event Rate Task Performance

Following an extended variable ITI challenge (Table 4), analysis showed that SKF 38393 treatment had no effect on accuracy [F3,30)=1.24, ns], percent correct [F(3,30)=2.19, ns] or percent omissions [F(3,30)=1.72, ns]. However, pair-wise comparisons indicated that 6 mg/kg of SKF 38393 resulted in an increase in the percent correct (p<0.05) and a reduction in the percent omission (p<0.05). Analysis revealed no significant effect of SKF 38393 on CL [F(3,30)=0.21, ns], IL [F(3,30)=0.27, ns] or ML [F(3,30)=1.41, ns]. SKF 38393 had no significant effect on either premature [F(3,30)=0.59, ns] or perseverative responding [F(3,30)=1.37, ns] when the variable ITI was extended. None of the Planned Comparisons obtained for CL, IL, ML, premature and perseverative responding reported a significant effect (table 4).

Table 4.

Effect of SKF 38393 following a reduced event-rate challenge

Measures Vehicle 2.0mg/kg 4.0mg/kg 6.0mg/kg
Accuracy Mean 88.92 ± 3.93 90.00 ± 2.83 94.74 ± 1.55 94.58± 1.13
p-value 0.78 0.12 0.15
Percent Correct Mean 56.41 ± 5.27 63.04 ± 8.88 67.87 ± 4.65 76.14 ± 4.11
p-value 0.42 0.14 0.01
Percent Omission Mean 37.69 ± 5.60 30.90 ± 7.39 28.66 ± 4.24 19.59 ± 3.95
p-value 0.55 0.31 0.03
Correct Latency Mean 0.79 ± 0.06 0.78 ± 0.05 0.78 ± 0.06 0.74 ± 0.02
p-value 0.94 0.93 0.47
Incorrect Latency Mean 0.69 ± 0.14 0.52 ± 0.10 0.74 ± 0.24 0.73 ± 0.19
p-value 0.52 0.83 0.86
Magazine Latency Mean 1.06 ± 0.06 1.29 ± 0.07 1.34 ± 0.22 1.41 ± 0.10
p-value 0.23 0.13 0.07
Premature Mean 36.50 ± 5.59 33.14 ± 6.05 29.67 ± 4.05 27.38 ± 5.62
p-value 0.66 0.35 0.22
Perseverative Mean 9.40 ± 1.51 7.71 ± 2.10 6.44 ± 1.41 5.50 ± 1.16
p-value 0.18 0.11 0.08
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Measures are shown as observed mean ± SEM, along with unadjusted p-value obtained from pairwise comparison between treatment groups and vehicle group in italics. Significant values are in bold. Reduced event-rate challenge parameters consisted of 1.5 s SD, 5 s TO period, 2 s LH, a variable ITI (8, 9, 11, and 12 s)

Analysis showed SKF38393 treatment had no significant effect on p[HR] [F(3,30)=2.19, ns]. Planned Comparisons indicated no effect at 2 or 4 mg/kg, although an increase in p[HR] at the highest dose (6 mg/kg) was demonstrated (p<0.05, fig 3A). ANOVA indicated SKF 38393 treatment had no effect on p[FA] [F(3,30)=0.81, ns], confirmed by Planned Comparisons (fig 3B). Analysis demonstrated drug treatment increased the SI [F(3,30)=4.39, p≤0.01]. This effect was not attributed to the lowest dose. However, Planned Comparisons showed that both 4 mg/kg and 6 mg/kg (p<0.01) significantly increased SI (fig 3C), which occurred without an alteration in RI [F(3,30)=0.42, ns] (fig 3D); an effect confirmed by non-significant pair-wise comparisons.

Fig. 3.

Fig. 3

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Effect of SKF 38393 on signal detection theory measures of performance in the 5 C-CPT during a reduced event rate challenge. Drug treatment resulted in a significant increase in p[HR] (a). No effect of drug was observed on p[FA] (b). SKF 38393 treatment resulted in a significant increase in the sensitivity index (c) without affecting the responsivity index of the animals (d). Data are expressed as mean ± SEM and analysed by one-way ANOVA followed by Planned Comparisons on the predicted means. *p < 0.05, **p < 0.01 relative to vehicle (Veh) group

3.4 Reduced Event Rate Challenge – Performance Across Session

To assess for a potential learning confound, we examined the effects of SKF 38393 on animals within the session. ANOVA analysis showed that SKF 38393 resulted in a significant increase in SI across the session (F(3,30)=2.79, p≤0.05). Planned Comparisons revealed that both 4.0mg/kg (p<0.05) and 6.0mg/kg (p<0.01) SKF 38393 treatment resulted in a significant increase in SI in the first half of the session and 6.0 mg/kg (p<0.05) SKF 38393 resulted in a significant increase in the latter half of the session (Fig 4.). A Dose*Trial interaction (F(3,30)=0.17, ns) was not observed.

Fig. 4.

Fig. 4

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Effect of SKF 38393 treatment on performance in 5 C-CPT across time in response to the reduced event rate challenge. Drug treatment (4.0 and 6.0 mg/kg, i.p.) resulted in a significant increase in sensitivity index (SI) during trials 0–60 and trials 61–120 (6.0 mg/kg i.p.). Data are expressed as mean ± SEM and analysed via one-way repeated measures ANOVA with treatment as fixed factor followed by Planned Comparisons on the predicted means. #p < 0.05 (4.0 mg/kg), *p < 0.05, **p < 0.01 (6.0 mg/kg) compared to vehicle group

4. Discussion

Firstly, these data demonstrate that rats can trained to respond to target trials and appropriately inhibit a response during the non-target trials presented within the 5C-CPT, consistent with human CPTs. Secondly, and more importantly, these data confirm that activating dopamine (DA) D1 receptors influences attention/vigilance in a baseline-dependent manner, and thirdly support the use of signal detection analysis as a means of quantifying attentional performance and strategic bias. Previously, it has been shown that mice can be trained to perform the 5C-CPT (Young et al. 2009b), however, to our knowledge, this is the first demonstration of rats performing the 5C-CPT.

The main finding that emerged from this study was that D1 receptor activation via systemic administration of a D1 partial agonist, SKF 38393, impaired 5C-CPT performance during baseline conditions, yet improved attention/vigilance during a demanding task challenge. These data support previous studies that revealed D1 receptor activation enhanced sustained attentional performance, as assessed within the 5-CSRTT, which was only evident in animals with a lower baseline performance (Granon et al. 2000). Within the current investigation, when the baseline performance was high (i.e. standard task protocol), SKF 38393 treatment deleteriously affected task performance. Target detection was reduced, an effect mediated by an increase in omissions. Additionally, an increase correct latency (CL) was observed. The slowed CL was unlikely to reflect general motoric impairment as incorrect and magazine latencies were not significantly affected. Thus, SKF 38393-induced slowing of CL was likely to be the result of deficits in the speed of informational processing (Robbins 2002; Young et al. 2009a). In contrast, when performance was challenged with an extended variable ITI reducing the event rate (Parasuraman 1998; Warm and Dember 1998), baseline performance was reduced. Impaired performance was illustrated by a reduced ability to respond to the target stimulus, increased premature responding and reduction in the sensitivity index (SI). This challenge-induced reduction in performance was attenuated by drug treatment. Augmentation of the dopaminergic D1 system increased the percentage of correct trials and reduced the number of trials omitted. As a result, the increase in vigilance, quantified by the increased SI, was likely driven by an increased p[HR] indicating increased capacity to detect and respond to the target stimulus. Sarter and colleagues (2001) described signal sensitivity as a method of quantifying changes in vigilance levels. Therefore, the drug-induced increase in SI suggests that activation of the D1 system increased the rats’ capability to detect and report the occurrence of signals suggesting improved discriminability between signal (target trial) and noise (non-target trials), which is a hallmark of enhanced vigilance (Warm and Dember 1998). No effect following SKF 38393 treatment on responsivity index (RI) was observed. Therefore, it is unlikely that performance in the task was altered due to a change in response bias or strategy, implying that the improved SI was cognitive in nature (Marston 1996; Steckler 2001). The ability of SDT to dissociate the SI and RI and reveal no change of RI in response to drug treatment indicates that improvements in performance may be specifically due to increases in attentional ability (Dudchenko et al. 1992). These findings demonstrate that stimulation of the D1 dopaminergic system via systemic administration of SKF 38393 enhanced the attentional/vigilance performance of the animals following a task-related intervention.

The impaired performance in the standard conditions in response to SKF 38393 treatment may have been as a result of an ‘inverted – U’ shaped dose response, whereby the level of DA stimulation is required to be at optimal levels for optimal performance. Too much or too little DA stimulation will result in less than optimal performance, as has been observed in spatial short-term memory not only in rats (Zahrt et al. 1997), but a variety of species (Vijayraghavan et al. 2007). This effect variation follows the concept of the Yerkes-Dodson principle and the link between the level of stress and arousal with the relationship to behavioural performance (Yerkes and Dodson 1908; Diamond et al. 2007). Thus, the effect SKF 38393 on task performance may depend on basal levels of DA and the optimal levels required, which may be dependent on the nature of the task. In the case of baseline conditions, it is likely that DA utilisation is already at a maximum. As a result, further stimulation of the dopaminergic system may have a detrimental effect on task performance. Lyon & Robbins (1975) suggested that in this case excessive dopaminergic transmission impairs performance by progressively increasing the frequency of multiple, concurrent behaviours and may lead to over-focused behaviour. This suggestion may hold true as there was a trend towards an increase in perseverative responding, indicating the inability to disengage from a previously rewarded response; however this effect was not significant in the current investigation. It is possible that the challenge session would demand an increase in catecholaminergic input, reducing baseline performance. Interestingly, comparisons of SKF treated animals during testing conditions revealed a drug-induced reduction in perseverative responding during the challenge session, potentially suggesting a reduction in basal DA levels during the extended ITI session. Under these conditions, stimulation of the D1 system exerted a beneficial effect on task performance. As SKF 38393 is only a partial agonist of the D1 DA receptor, future studies could investigate the effects of full DA D1 receptor agonists such as (+)-doxanthrine (Przybyla et al. 2009), and their effects on attention and vigilance. This could replicate the current findings and generate a more complete understanding of the involvement of DA D1 receptors and this particular cognitive domain. Moreover, future studies could investigate whether beneficial effects are mediated via D1 or D5 DA receptors, given the fact that SKF 38393 has equal affinity for D5 receptors also (Neumeyer et al. 2003; Qandil et al. 2003). SKF 38393 treatment most likely elicited beneficial effects via activation of D1 receptors located in the medial prefrontal cortex (mPFC). Previous work has demonstrated that lesions in this brain region impairs attentional function resulting in reduced choice accuracy in the 5-CSRTT (Muir et al. 1996), highlighting the importance of the mPFC in task performance. In addition, previous studies have demonstrated that SKF 38393 improved attentional processing in the 5-CSRTT in animals with a reduced performance (Granon et al. 2000; Fletcher et al. 2007), when administered by microinfusions directly into the mPFC. However, Pezze and colleagues (2007) have also demonstrated low dose of SKF 38393 infused within the nucleus accumbens enhanced attentional performance, and while beneficial effects through activation of sub-cortical regions within the current investigation cannot be ruled out, still supports the hypothesis of DA D1 involvement and attention.

There is evidence to suggest that the DA D1 system is involved in other cognitive processes besides attention/vigilance, including delayed working memory (Arnsten et al. 1994; Sawaguchi and Goldman-Rakic 1994), spatial learning and memory (Hersi et al. 1995), visual learning and memory (Mclean et al. 2009) and reasoning and problem solving (Mclean et al. 2009). These domains have been shown to be dysfunctional in patients with schizophrenia (Young et al. 2009a), demonstrating the importance of this receptor system and cognitive processes. These data support evidence that activation of the D1 system may be a viable target for treating cognitive disruption in schizophrenia (Sawaguchi and Goldman-Rakic 1991; Sawaguchi and Goldman-Rakic 1994; Goldman-Rakic et al. 2004; Tamminga 2006). Interestingly, evidence is also emerging that suggests the DA D4 receptor involvement with attentional processes. Young and colleagues (2011) demonstrated reduced expression of DA D4 receptors increased false alarm responding in the 5C-CPT, without affecting premature responses. These findings, coupled with those observed in the current investigation, suggest dissociation in the role of dopamine and attentional performance with D4 receptors facilitating response inhibition and D1 receptors perhaps contributing to target detection.

Rats use a temporally mediating strategy when performing the 5-CSRTT with constant ITIs, responding to the cue in a semi-automatic manner (Spratt et al. 2000). This strategy was quantified by Spratt and colleagues (2000) following observations that rats responded 90% of the time following the ITI, when acutely challenged with blank trials instead of the expected stimulus. The current study has demonstrated that by utilising a variable ITI and a non-target stimulus throughout training, the development of a temporally mediated response strategy was minimised, resulting in appropriate response inhibition. The start of training required a greater emphasis being placed on the number of non-target trials presented, as initially animals were treating both trial types identically. Following continued training with increased non-target trials presentation, animals modified their response accordingly and acquired the ability of correct inhibition to non-target stimuli. This was quantified by the observation of an increased p[HR], compared to p[FA]. Furthermore, percent correct rejections and percent omissions were compared. In this instance, as both types of response essentially required the same action for target and non-target trials (i.e. a non response) it was important to establish that performance is dependent on the type of trial presented to the animal (Young et al. 2009b). It was evident that there was also a clear difference in non-responses that is dependent upon trial type (correct rejections > omissions). Thus, these data suggest rats can be trained to differentiate and respond appropriately to two different stimulus types within the same task. It should be noted, refinement of the training schedule in subsequent investigations has yielded a reduction in time taken to acquire the task, with total training time approximately 3 – 4 months.

As the challenge used within the present study was extending the temporal delay before a response was required, which resulted in increased premature responses compared to baseline, improvement in performance may have been confounded by enhanced learning; speeding the animals adjustment to the extended ITI and therefore not improving attention or vigilance per se (Young et al. 2009a). A drug-induced adaptation to the temporal challenge would likely be accompanied with a reduction in premature responding, an effect not observed, and so within-session learning was unlikely. These data suggest that the overall improvement in performance was a result of improved attention/vigilance and not due to improved temporal reintegration i.e. adjusting to the increased ITI duration. As a result, it is possible that augmentation of the dopaminergic D1 system improved performance by heightening the rats’ ability to detect the signal, without enhancing within-session learning, demonstrated in previous studies utilising a reduced event-rate challenge (McGaughy and Sarter 1995; Hahn et al. 2002). The absence of within-session learning in the present study, unlike previous studies that reduced the event-rate using a fixed ITI, was likely due to the fact a variable ITI was utilised, thus limiting the development and utilisation of a temporally mediated strategy. Further support for this interpretation can be seen when the performance is displayed over the course of the session. An overall ‘trial-independent’ increase in SI following SKF 38393 treatment was observed, whereas within-session learning would be exemplified by a performance increase as the session progressed. As such, this interpretation also supported by an improvement in performance observed at the beginning of the session, further suggesting increased performance was the result of improved ability to distinguish between stimuli.

In conclusion, the findings of the present study demonstrate that rats can be trained to perform the 5C-CPT, a rodent analogue of the human CPT. Moreover, these findings support suggestions that activation of DA D1 receptors can improve attentional performance in animals that are not encumbered by ceiling effects, therefore displaying a reduced baseline performance. Importantly, the present data suggest that these effects may be observed following systemic administration of the D1 agonists. Thus D1 agonists may prove therapeutically beneficial in attenuating the attentional dysfunction that is evident in patients with schizophrenia.

Acknowledgments

The authors would like to thank Dr Jeff Dalley for reviewing the manuscript prior to submission and David Fuller (Conclusive Solutions) for his constant help and advice while configuring the 5C-CPT control and data output system. Additionally, the input of Dr Simon Bate regarding the statistical design and analysis was greatly appreciated. Support was provided by the University of Bradford postgraduate studentship (SAB) and by NIH grant R21-MH085221 (JWY).

References

  1. Amitai N, Semenova S, Markou A. Cognitive disruptive effects of the psychotomimetic phencyclidine and attenuation by atypical antipsychotic medication in rats. Psychopharmacology (Berl) 2007;193:521–537. doi: 10.1007/s00213-007-0808-x. [DOI] [PubMed] [Google Scholar]
  2. Amitai N, Markou A. Chronic nicotine improves cognitive performance in a test of attention but does not attenuate cognitive disruption induced by repeated phencyclidine administration. Psychopharmacology. 2009;202:275–286. doi: 10.1007/s00213-008-1246-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arnsten AFT, Cai JX, Murphy JL, Goldman-Rakic PS. Dopamine D1 receptor mechanisms in the cognitive performance of young and aged monkeys. Psychopharmacology. 1994;116:143–151. doi: 10.1007/BF02245056. [DOI] [PubMed] [Google Scholar]
  4. Bari A, Dalley JW, Robbins TW. The application of the 5-choice serial reaction time task for the assessment of visual attentional processes and impulse control in rats. Nature Protocols. 2008;3(5):759–767. doi: 10.1038/nprot.2008.41. [DOI] [PubMed] [Google Scholar]
  5. Van den Bosch RJ, Rombouts RP, van Asma MJO. What determines continuous performance task performance? Schizophrenia Bulletin. 1996;22(4):643–651. doi: 10.1093/schbul/22.4.643. [DOI] [PubMed] [Google Scholar]
  6. Broadbent DE. Decision and stress. London: Academic Press; 1971. [Google Scholar]
  7. Carli M, Robbins TW, Evended JL, Everitt BJ. Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; Implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behavioural Brain Research. 1983;9:361–380. doi: 10.1016/0166-4328(83)90138-9. [DOI] [PubMed] [Google Scholar]
  8. Chen WJ, Faraone SV. Sustained attention deficits as markers of genetic susceptibility to schizophrenia. American Journal of Medical Genetics. 2000;97:52–57. doi: 10.1002/(sici)1096-8628(200021)97:1<52::aid-ajmg7>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  9. Chudasama Y, Robbins TW. Psychopharmacological approaches to modulating attention in the five-choice serial reaction time task: Implications for schizophrenia. Psychopharmacology. 2004;174:86–98. doi: 10.1007/s00213-004-1805-y. [DOI] [PubMed] [Google Scholar]
  10. Cohen JD, Servan-Schreiber D. A theory of dopamine function and its role in cognitive deficits in schizophrenia. Schizophrenia Bulletin. 1993;19(1):85–104. doi: 10.1093/schbul/19.1.85. [DOI] [PubMed] [Google Scholar]
  11. Collings RD. Differences between ADHD inattentive and combined types on the CPT. Journal of Psychopathological and Behavioural Assessment. 2003;25:177–189. [Google Scholar]
  12. Cornblatt BA, Risch NJ, Faris G, Friedman D, Erlenmeyer-Kimling L. The Continuous Performance Test, identical pairs version (CPT-IP): I. New findings about sustained attention in normal families. Psychiatry Res. 1988;26:223–238. doi: 10.1016/0165-1781(88)90076-5. [DOI] [PubMed] [Google Scholar]
  13. Cornblatt BA, Keilp JG. Impaired attention, genetics, and the pathophysiology of schizophrenia. Schizophr Bull. 1994;20(1):31–46. doi: 10.1093/schbul/20.1.31. [DOI] [PubMed] [Google Scholar]
  14. Diamond DM, Campbell AM, Park CR, Halonen J, Zoladz PR. The temporal dynamics model of emotional memory processing: A synthesis on the neurobiological basis of stress-induced anmnesia, flashbulb and traumatic memories and the Yerkes-Dodson law. Neural Plasticity. 2007 doi: 10.1155/2007/60803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dudchenko P, Paul B, Sarter M. Dissociation between the effects of benzodiazepine receptor agonists on behavioural vigilances and responsivity. Psychopharmacology. 1992;109:203–211. doi: 10.1007/BF02245501. [DOI] [PubMed] [Google Scholar]
  16. Eagle DM, Bari A, Robbins TW. The neuropsychopharmacology of action inhibition: cross-species translation of the stop-signal and go/no-go tasks. Psychopharmacology. 2008;199:439–456. doi: 10.1007/s00213-008-1127-6. [DOI] [PubMed] [Google Scholar]
  17. Egeland J, Johansen SN, Ueland T. Differentiating between ADHD sub-types on CCPT measures of sustained attention and vigilance. Scandinavian Journal of Psychology. 2009;50:347–354. doi: 10.1111/j.1467-9450.2009.00717.x. [DOI] [PubMed] [Google Scholar]
  18. Fletcher PJ, Tenn CC, Sinyard J, Rizos Z, Kapur S. A sensitizing regime of amphetamine impairs visual attention in the 5-choice serial reaction time test: Reversal by a D1 receptor agonist injected into the medial prefrontal cortex. Neuropsychopharmacology. 2007;32:1122–1132. doi: 10.1038/sj.npp.1301221. [DOI] [PubMed] [Google Scholar]
  19. Frey PW, Colliver JA. Sensitivity and responsibility measures for discrimination learning. Learning and Motivation. 1973;4:327–342. [Google Scholar]
  20. Goldberg JO, Konstantareas MM. Vigilance in hyperactive and normal children on a self-paced operant task. Journal of Child Psychology and Psychiatry. 1981;22(1):55–63. doi: 10.1111/j.1469-7610.1981.tb00531.x. [DOI] [PubMed] [Google Scholar]
  21. Goldman-Rakic PS, Castner SA, Svennsson TH, Siever LJ, Williams GV. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology. 2004;174:3–16. doi: 10.1007/s00213-004-1793-y. [DOI] [PubMed] [Google Scholar]
  22. Granon S, Passetti F, Thomas KL, Dalley JW, Everitt BJ, Robbins TW. Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci. 2000;20(3):1208–1215. doi: 10.1523/JNEUROSCI.20-03-01208.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia. Am J Psychiatry. 1996;153(3):321–330. doi: 10.1176/ajp.153.3.321. [DOI] [PubMed] [Google Scholar]
  24. Hahn B, Shoaib M, Stolerman IP. Nicotine-induced enhancement of attention in the five-choice serial reaction time task: the influence of task demands. Psychopharmacology (Berl) 2002;162:129–137. doi: 10.1007/s00213-002-1005-6. [DOI] [PubMed] [Google Scholar]
  25. Hahn B, Sharples CG, Wonnacott S, Shoaib M, Stolerman IP. Attentional effects of nicotine agonists in rats. Neuropharmacology. 2003;44(8):1054–1067. doi: 10.1016/s0028-3908(03)00099-6. [DOI] [PubMed] [Google Scholar]
  26. Hersi AI, Rowe W, Gaudreau P, Quirion R. Dopamine D1 receptor ligands modulate cognitive performance and hippocampal acetylcholine release in memory-impaired aged rats. Neuroscience. 1995;69:1067–1074. doi: 10.1016/0306-4522(95)00319-e. [DOI] [PubMed] [Google Scholar]
  27. Kern RS, Nuechterlein KH, Green MF, Baade LE, Fenton WS, Gold JM, Keefe RS, Mesholam-Gately R, Mintz J, Seidman LJ, Stover E, Marder SR. The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization. Am J Psychiatry. 2008;165(2):214–220. doi: 10.1176/appi.ajp.2007.07010043. [DOI] [PubMed] [Google Scholar]
  28. Kornetsky C, Mirtsky AF. On certain psychopharmacological and physiological differences between schizophrenics and normal persons. Psychoparmacologia. 1966;8:309–318. doi: 10.1007/BF00453508. [DOI] [PubMed] [Google Scholar]
  29. Kumar CTS, Christodoulou T, Vyas NS, Kyriakopoulos M, Corrigall R. Deficits in visual sustained attention differentiate genetic liability and disease expression for schizophrenia from bipolar disorder. Schizophrenia Research. 2010;124:152–160. doi: 10.1016/j.schres.2010.07.006. [DOI] [PubMed] [Google Scholar]
  30. Lam CM, Beale IL. Relations among sustained attention, reading performances, and teachers’ ratings of behaviour problems. Remeadial and Special Education (RASE) 1991;12:40–47. [Google Scholar]
  31. Leonard JA. Anonymous, Med Res Council Appl Psychol Res Unit Rep. Great Britain: 1959. 5 choice serial reaction apparatus. [Google Scholar]
  32. Lyon M, Robbins TW. The action if central nervous system stimulant drugs. A general theory concerning amphetamine effects. In: Essman W, editor. Current developments in psychopharmacology. New York: Spectrum; 1975. [Google Scholar]
  33. Mackworth NH. Medical Research Council Special Report Series 268. London: His Majesty’s Stationery Office; 1950. Researches on the measurement of human performance. [Google Scholar]
  34. Mackworth NH. Some factors affecting vigilance. Adv Sci. 1957;53:389–393. [Google Scholar]
  35. Marder SR, Fenton W. Measurement and treatment research to improve cognition in schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr Res. 2004;72:5–9. doi: 10.1016/j.schres.2004.09.010. [DOI] [PubMed] [Google Scholar]
  36. Marder SR, Fenton W, Youens K. Schizophrenia, IX: Cognition in schizophrenia – the MATRICS initiative. Am J Psychiatry. 2004;161(1):25. doi: 10.1176/appi.ajp.161.1.25. [DOI] [PubMed] [Google Scholar]
  37. Marston HM. Analysis of cognitive function in animals, the value of SDT. Cognitive Brain Research. 1996;3:269–277. doi: 10.1016/0926-6410(96)00012-2. [DOI] [PubMed] [Google Scholar]
  38. McGaughy J, Sarter M. Behavioural vigilance in rats: task validation and effects of age, amphetamine, and benzodiazepine receptor ligands. Psychopharmacology. 1995;117:340–357. doi: 10.1007/BF02246109. [DOI] [PubMed] [Google Scholar]
  39. McLean SL, Idris NF, Woolley ML, Neill JC. D1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia. European Neuropsychopharmacology. 2009;19:440–450. doi: 10.1016/j.euroneuro.2009.01.009. [DOI] [PubMed] [Google Scholar]
  40. Muir JL, Everitt BJ, Robbins TW. The cerebral cortex of the rat brain and visual attentional function: Dissociable effects of mediofrontal, cingulate, anterior dorsolateral, and parietal cortex lesions on a five-choice serial reaction time task. Cerebral Cortex. 1996;6:470–481. doi: 10.1093/cercor/6.3.470. [DOI] [PubMed] [Google Scholar]
  41. Navarra R, Graf R, Huang Y, Logue S, Comery T, Hughes Z, Day M. Effects of atomoxetine and methyphenidate on attention and impulsivity in the 5 choice serial reaction time test. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2008;32:43–41. doi: 10.1016/j.pnpbp.2007.06.017. [DOI] [PubMed] [Google Scholar]
  42. Neill JC, Barnes SA, Cook S, Grayson B, Idris N, McLean SL, Snigdha S, Rajagopal L, Harte MK. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism. Pharmacol Ther. 2010 doi: 10.1016/j.pharmthera.2010.07.004. [DOI] [PubMed] [Google Scholar]
  43. Nestor PG, Faux SF, McCarley RW, Shenton ME, Sands SF. Measurement of visual sustained attention in schizophrenia using signal detection analysis and a newly developed computerized CPT task. Schizophrenia Research. 1990;3:329–332. doi: 10.1016/0920-9964(90)90018-3. [DOI] [PubMed] [Google Scholar]
  44. Neumeyer JL, Kula NS, Bergman J, Baldessarini RJ. Receptor affinities of dopamine D1 receptor-selective novel phenylbenzazepines. European Journal of Pharmacology. 2003;474:137–140. doi: 10.1016/s0014-2999(03)02008-9. [DOI] [PubMed] [Google Scholar]
  45. Neuchterlien KH, Green MF, Kern RS, et al. The MATRICS Consensus Cognitive Battery, Part 1: Test Selection, Reliability, and Validity. Am J Psychiatry. 2008;165:203–213. doi: 10.1176/appi.ajp.2007.07010042. [DOI] [PubMed] [Google Scholar]
  46. Nieoullon A. Dopamine and the regulation of cognition and attention. Progress in Neurobiology. 2002;67:53–83. doi: 10.1016/s0301-0082(02)00011-4. [DOI] [PubMed] [Google Scholar]
  47. Parasuraman R. A Bradford Book. The MIT Press; 1998. The Attentive Brain. [Google Scholar]
  48. Paine TA, Carlezon WA., Jr Effects of antipsychotic drugs on MK-801-induced attentional and motivational deficits in rats. Neuropharmacology. 2009;56:788–797. doi: 10.1016/j.neuropharm.2009.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Pezze MA, Dalley JW, Robbins TW. Differential roles of dopamine D1 and D2 receptors in the nucleus accumbens in attentional performance on the five-choice serial reaction time task. Neuropsychopharmacology. 2007;32:273–283. doi: 10.1038/sj.npp.1301073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Przybyla JA, Cueva JP, Chemel BR, Hsu KJ, Riese IIDJ, McCorvy JD, Chester JA, Nichols DE, Watts VJ. Comparison of the enantiomers of (±)- doxanthrine, a high efficacy full dopamine D1 receptor agonist, and a reversal of enantioselectivity at D1 versus alpha2C adrenergic receptors. European Neuropsychopharmacology. 2009;19(2):138–146. doi: 10.1016/j.euroneuro.2008.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Qandil AM, Lewis MM, Jassen A, Leonard SK, Mailman RB, Nichols DE. Synthesis and pharmacological evaluation of substituted napth[1, 2, 3-de]isoquinolines (dinapsoline analogues) as D1 and D2 dopamine receptor ligands. Bioorganic and Medicinal Chemistry. 2003;11:1451–1464. doi: 10.1016/s0968-0896(02)00561-8. [DOI] [PubMed] [Google Scholar]
  52. Riccio CA, Reynolds CE, Lowe, Moore JJ. The continuous performance test: A window on the neural substrates for attention? Achives of Clinical Neuropsychology. 2002;17:235–272. [PubMed] [Google Scholar]
  53. Robbins TW. Arousal and Attention: Pyschopharmacological and neuropsychological studies in experimental animals. In: Parasuraman R, editor. The Attentive Brain. The MIT Press; Cambridge, Massachusetts: 1998. pp. 189–219. [Google Scholar]
  54. Robbins TW. The 5-choice serial time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology. 2002;163:362–380. doi: 10.1007/s00213-002-1154-7. [DOI] [PubMed] [Google Scholar]
  55. Rosvold H, Mirsky A, Sarason I, Bransome ED, Jr, Beck LH. A continuous performance test of brain damage. Journal of Consulting Psychology. 1956;20:343–350. doi: 10.1037/h0043220. [DOI] [PubMed] [Google Scholar]
  56. Sarter M, Givens B, Bruno JP. The cognitive neuroscience of sustained attention: Where top-down meets bottom-up. Brain Research Reviews. 2001;35:146–160. doi: 10.1016/s0165-0173(01)00044-3. [DOI] [PubMed] [Google Scholar]
  57. Sawaguchi T, Goldman-Rakic PS. D1 dopamine receptors in prefrontal cortex: Involvement in working memory. Science. 1991;22:947–950. doi: 10.1126/science.1825731. [DOI] [PubMed] [Google Scholar]
  58. Sawaguchi T, Goldman-Rakic PS. The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysiol. 1994;71:515–528. doi: 10.1152/jn.1994.71.2.515. [DOI] [PubMed] [Google Scholar]
  59. Snedecor GW, Cochran WG. Statistical Methods. Eighth. Iowa State University Press; Ames, Iowa: 1989. pp. 226–228. [Google Scholar]
  60. Spratt C, Marston HM, Sharkey J, Kelly JS. Comparison of rat and mouse attentional performance in the 5-choice serial reaction time task. BNA. 2000;17:49.03. [Google Scholar]
  61. Steckler T. Using signal detection methods for analysis of operant performance in mice. Behavioural Brain Research. 2001;125:237–248. doi: 10.1016/s0166-4328(01)00305-9. [DOI] [PubMed] [Google Scholar]
  62. Tamminga CA. The neurobiology of cognition in schizophrenia. J Clin Psychiatry. 2006;67(9):9–13. [PubMed] [Google Scholar]
  63. Tomasi D, Volkow ND, Wang R, Telang F, Wang GJ, Chang L, Ernst T, Fowler JS. Dopamine transporters in striatum correlate with deactivation in the default mode network during visuospatial attention. PLoS ONE. 2010;4(6):e6102. doi: 10.1371/journal.pone.0006102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AFT. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nature Neuroscience. 2007;10(3):376–384. doi: 10.1038/nn1846. [DOI] [PubMed] [Google Scholar]
  65. Warm JS, Dember WN. Test of vigilance taxonomy. Parasuraman R, Warm JS, Dember WN (1987) Vigilance: taxonomy and utility. In: Mark LS, Warm JS, Huston RL, editors. Ergonomics and Human Factors. Springer; New York: 1987. [Google Scholar]
  66. Warm JS, Dember WN. Tests of vigilance taxonomy. In: Hoffman RR, Sherrick MF, Warm JS, editors. Viewing psychology as a whole: The intergrative science of William N Dember. Washington, DC: American Psychological Association; 1998. pp. 87–112. [Google Scholar]
  67. Wilkinson RT. Interaction of noise with knowledge of results and sleep deprivation. J Exp Psychol. 1963;66:332–337. doi: 10.1037/h0044161. [DOI] [PubMed] [Google Scholar]
  68. Wohlberg GW, Kornetsky C. Sustained attention in remitted schizophrenics. Arch Gen Psychiatry. 1973;28:533–537. doi: 10.1001/archpsyc.1973.01750340065011. [DOI] [PubMed] [Google Scholar]
  69. Yerkes RM, Dodson JD. The relation of strength of stimulus to rapidity of habit-formation. Journal of Comparative Neurology and Psychology. 1908;18(5):459–482. [Google Scholar]
  70. Young JW, Finlayson K, Spratt C, Marston HM, Crawford N, et al. Nicotine improves sustained attention in mice: evidence for involvement of the alpha7 nicotinic acetylcholine receptor. Neuropsychopharmacology. 2004;29:891–900. doi: 10.1038/sj.npp.1300393. [DOI] [PubMed] [Google Scholar]
  71. Young JW, Powell SB, Risbrough V, Marston HM, Geyer MA. Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophrenia. Pharmacology and Therapeutics. 2009a;122:150–202. doi: 10.1016/j.pharmthera.2009.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Young JW, Light GA, Marston HM, Sharp R, Geyer MA. The 5-Choice performance test: Evidence for a translational test of vigilance for mice. PLoS ONE. 2009b;4(1):e4227. doi: 10.1371/journal.pone.0004227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Young JW, Powell SB, Scott CN, Zhou X, Geyer MA. The effect of reduced dopamine D4 receptor expression in the 5-choice continuous performance task: Separating response inhibition from premature responding. Behavioural Brain Research. 2011 doi: 10.1016/j.bbr.2011.03.054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Zahrt J, Taylor JR, Mathew RG, Arnsten AF. Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance. J Neurosci. 1997;17:8528–8535. doi: 10.1523/JNEUROSCI.17-21-08528.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]

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