Rats tested after a washout period from sub-chronic PCP administration exhibited impaired performance in the 5-Choice Continuous Performance Test (5C-CPT) when the attentional load was increased
Highlights
► Sub-chronic PCP treatment had no impact on the ability to conduct the 5C-CPT under baseline conditions following a 7-day washout period. ► Following an increase in the attentional load, animals sub-chronically treated with PCP exhibited an attentional impairment in the drug-free state. ► Sub-chronic PCP treatment induced a baseline-dependent attentional impairment in rats.
Introduction
Schizophrenia affects approximately 1% of the general population and is characterised by a myriad of symptoms including positive and negative symptoms as well as cognitive impairment across a number of domains (Marder et al., 2004, Paine and Carlezon, 2009, Young et al., 2009a, Ibrahim and Tamminga, 2010). One domain affected and putatively core to cognitive disruption in schizophrenia is attention, specifically vigilance (Cornblatt and Keilp, 1994, Nuechterlein et al., 2008). Vigilance in humans reflects the ability to remain alert towards incoming stimulus information (Collings, 2003, Egeland et al., 2009) and is commonly measured using one of the many variants of the Continuous Performance Test (CPT) (Riccio et al., 2002). The CPT-Identical Pairs (CPT-IP) was chosen by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS.ucla.edu) initiative to be a part of their test battery (Nuechterlein et al., 2004, Buchanan et al., 2005) for assessing putative therapeutics for the treatment of cognitive disruption in schizophrenia. Patients with schizophrenia perform poorly in all CPT tasks, compared to healthy volunteers (Nuechterlein et al., 2008, Kern et al., 2008), including the CPT-IP (Cornblatt and Malhotra, 2001).
Attention in rodents is most commonly measured using the 5-Choice Serial Reaction Time Task (5-CSRTT) (Carli et al., 1983, Bari et al., 2008), based on Leonard’s human five-choice serial reaction task (Leonard, 1959, Wilkinson, 1963). Various manipulations to basic 5-CSRTT parameters have been extensively utilised to challenge standard task performance, providing a valid means of further taxing attentional processing (Carli et al., 1983, Mirza and Stolerman, 1998, Stolerman et al., 2000, Grottick and Higgins, 2002, Hahn et al., 2002, Hahn et al., 2003, Winstanley et al., 2003, Chudasama et al., 2003, Young et al., 2007), manipulations that include reducing the stimulus duration or extending the session length. While the 5-CSRTT has some commonalities with human CPTs (Bari et al., 2008), it consists of only target trials to which the animal must respond. The 5-CSRTT therefore lacks non-target trials requiring the inhibition of response that are present in all forms of human CPTs, limiting the application of the 5-CSRTT to accurately assess vigilance in a manner consistent with human CPTs (Robbins, 1998). Responses during non-target trials in go/no-go tasks (e.g. CPTs) may be the result of inattentiveness, stimulus discrimination inability, or poor impulse control (Eagle et al., 2008) and are important to consider, when assessing vigilance (Mackworth, 1968).
A lever-based operant task developed by McGaughy and Sarter (1995) may accurately assess vigilance, requiring animals to determine whether a visual cue appears or not prior to the presentation of the two levers. Presentation of the signal required a response on 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 a correct rejection, that usually requires 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-target trials presented in human CPTs, as the correct rejection requires an active response (Young et al., 2009b).
Consequently, the 5-CSRTT has recently been modified to include non-target trials, improving the similarity to human CPTs in a task known as the 5-Choice Continuous Performance Test (5C-CPT), originally validated for mice (Young et al., 2009b). As in the 5-CSRTT, target trials are presented requiring a response generating hits and misses. Importantly, the 5C-CPT also presents non-target trials, requiring the animal to correctly inhibit a response. A failure in action restraint (responding to the non-target stimulus) constitutes a false alarm. As a result, this adaptation improves the capability to assess vigilance in a pre-clinical paradigm in a manner more consistent with human CPTs (Riccio et al., 2002). Although it is impossible to completely replicate the human CPT in a pre-clinical setting, various response outcomes are possible in the 5C-CPT (e.g. hits, misses, correct rejections and false alarms) mirroring those generated in human CPT testing. These responses enable signal detection theory (SDT) to be employed. SDT is often used in human CPT analysis (Nestor et al., 1990) and further assesses performance and provides insight into the animals’ responsivity, while also generating additional information on attentional performance in light of task or pharmacological manipulations (Dudchenko et al., 1992, Marston, 1996, Steckler, 2001).
Phencyclidine (PCP) and its congener, ketamine, have been used to model aspects of schizophrenia since Luby et al. (1959) described PCP as a schizophrenomimetic drug based on observations that PCP intoxication resembled the psychotic symptoms of schizophrenia. Furthermore, it became evident that this class of drug not only induced positive-like symptoms, but also posses the ability to mimic the negative symptomatology and are associated with cognitive disruption (both transient and persistent) in humans (Allen and Young, 1978, Carlin et al., 1978; Cosgrove and Newell, 1991, Javitt and Zukin, 1991, Krystal et al., 1994, Jentsch and Roth, 1999, Morgan et al., 2004, Morgan et al., 2010). PCP is a non-competitive NMDA receptor antagonist and its actions contributed to the development of the glutamatergic hypofunction hypothesis of schizophrenia. This hypothesis implicates dysfunctional NMDA receptor(s) and/or abnormal downstream NMDA receptor effects being core to the pathophysiology of the disease (Olney and Faber, 1995, Olney et al., 1999, Goff and Coyle, 2001), potentially providing a more compelling model than the hyperdopaminergic hypothesis of schizophrenia (Coyle, 2006).
PCP administration (both acute and sub-chronic) disrupts cognitive performance in animals in a variety of paradigms (see Neill et al., 2010 for review), providing support that NMDA receptor antagonism may model cognitive impairment exhibited in schizophrenia (Jentsch and Roth, 1999). In animals, in several paradigms assessing the various domains of cognition affected in schizophrenia, a sub-chronic PCP treatment regimen (twice daily for 7 days followed by at least 7 days drug-free) has been shown to induce robust and long-lasting cognitive impairment (Neill et al., 2010).
NMDA receptor antagonism can disrupt attentional processing, demonstrated when animals were acutely or repeatedly administered PCP, and tested while under the influence of PCP (Amitai et al., 2007, Amitai and Markou, 2009). Additionally, intra-medial prefrontal cortical (mPFC) infusion of the competitive NMDA antagonist, 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) also disrupts 5-CSRTT performance (Murphy et al., 2005, Baviera et al., 2008). These data further highlight the involvement of the NMDA receptor in attentional function and moreover, implicate the mPFC in attentional processing.
To date, studies have only shown disruption of 5-CSRTT performance while animals were ‘acutely’ intoxicated with NMDA antagonists (Le Pen et al., 2003, Amitai et al., 2007, Amitai and Markou, 2009, Auclair et al., 2009) and not following a significant washout period. In addition to cognitive impairment, sub-chronic PCP administration followed by a significant washout period has been shown to induce a number of neurochemical, morphological and metabolic disturbances in the drug-free state, mirroring alterations evident in pathology of the disorder (Jentsch et al., 1997a, Jentsch et al., 1997b, Cochran et al., 2003, Hajszan et al., 2006, Abdul-Monim et al., 2007, Jenkins et al., 2008, Snigdha et al., 2010). These findings are not evident following acute administration (Jentsch and Roth, 1999, Cochran et al., 2003). Due to the paucity of information regarding attentional impairment in the drug-free state following a sub-chronic PCP treatment regimen and 5-CSRTT performance, there is clearly a need to understand the enduring effects of long-term NMDA antagonism on attention/vigilance. Thus, the purpose of the present study was to determine the effect of sub-chronic PCP treatment followed by at least a 7-day washout period, on performance in the 5C-CPT, at both baseline conditions and when the attentional load of the task was increased.
Section snippets
Subjects
Female hooded-Lister rats (n = 35; Charles River; approx 220 ± 10 g at the start of the experiment) were housed in groups of five on a 12 h reversed light cycle (lights on at 7:00pm) 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
Stable baseline performance
A one-way ANOVA analysis revealed sub-chronic PCP treatment had no significant effect on baseline performance for any measure (Table 2).
A two-way repeated measures analysis of the baselines also revealed the performance did not alter with session (data not shown). No significant Dose × Trial interaction were observed for any measure.
Overall performance
A vSD was then used to challenge performance (Table 3). Statistical analysis revealed no significant difference in accuracy between treatments [F(2,29) = 2.01, NS]
Discussion
The present study supports the hypothesis that attentional impairment is evident following a sub-chronic PCP treatment regimen and at least a 7-day washout period. The performance disruption observed is consistent with impaired vigilance seen in schizophrenia patients and was evident up to 11 days after cessation of treatment. Importantly, here we use the 5C-CPT, which may have improved translational validity for assessing vigilance in rodents consistent with CPT testing in humans (Young
Acknowledgments
The authors would like to thank Dr Simon Bate for his most helpful and consistent advice regarding the statistical design and analysis. Support was provided by the University of Bradford postgraduate studentship (SAB) and by NIMH grant R21-MH85221 (JWY).
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