INTRODUCTION

Intervening pharmacologically and in other manners during the prodromal stage of schizophrenia, primarily to prevent the onset of persistent psychosis and enduring cognitive impairment is a major goal of current strategies for reducing the disability associated with schizophrenia (Bilder et al, 1992; Klosterkötter et al, 2001). Intervention during this stage is intended to arrest or attenuate the progression of the underlying pathology (McGlashan and Fenton, 1993; Larson et al, 2010). Treatment of individuals in the prodromal period with atypical antipsychotic drugs (APDs) has been reported to reduce the rate of progression to first-episode psychosis in some high-risk indiviudals (Lee et al, 2005; Lieberman and Fenton, 2000; McGlashan et al, 2006; McGorry et al, 2008; Phillips et al, 2009; Ruhrmann et al, 2005; Salokangas and McGlashan, 2008). However, there are major concerns about this strategy, which include stigmatization, false positives, and metabolic and other side effects of the atypical APDs and stigmatization (Kaur and Cadenhead, 2010).

Even at the time of first diagnosis, deficits in multiple domains of cognition, including visual learning and declarative memory, are present in most patients with schizophrenia and are known to be a key factor leading to impaired work and social function (Saykin et al, 1991; Meltzer and McGurk, 1999). There is evidence that some of the atypical APDs, which are more potent serotonin (5-HT)2A than dopamine (DA) D2 antagonists, including the novel atypical APD, lurasidone, are more effective than typical APDs to attenuate some of these deficits (Hagger et al, 1993; Meltzer and McGurk, 1999; Woodward et al, 2005; Harvey et al, 2011), although not all studies are in accord (Keefe et al, 2007). The development of novel adjunctive or stand alone treatments that can improve some domains of cognition in schizophrenia, accompanied by functional improvement, is currently a major goal of pharmacologic research (Buchanan et al, 2010).

Hypoglutamatergic activity has been postulated to be a major cause of the cognitive impairment in schizophrenia (CIS; Goldman-Rakic and Selemon, 1997; Coyle, 2006). Important evidence that a deficit in glutamatergic function may be the basis for this component of schizophrenia is that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), dizocilpine (MK-801), and ketamine, induce schizophrenia-like cognitive impairment in healthy subjects (Javitt and Zukin, 1991; Krystal et al, 1999). The effects of NMDA receptor antagonists on cognitive function in rodents and monkeys have been intensively studied as an animal model of CIS (Gunduz-Bruce, 2009). Acute or subchronic administration of PCP, MK-801, or ketamine to rodents produces cognitive impairments that model CIS, eg, novel object recognition (NOR; Neill et al, 2010, Meltzer et al, 2011). Acute administration of atypical APDs (eg, clozapine), but not the typical APD, haloperidol, has been reported to reverse cognitive deficits induced by subchronic PCP treatment in rat NOR (Grayson et al, 2007; Snigdha et al, 2010; Horiguchi et al, 2011a). We recently reported that selective 5-HT2A inverse agonists (eg, pimavanserin) can potentiate the ability of sub-effective doses of several atypical APDs, including lurasidone, to ameliorate the PCP-induced NOR deficit (Snigdha et al, 2010). However, there are no reports that show a preventive effect of typical or atypical APDs.

Lurasidone is an atypical APD that has D2, 5-HT2A, and 5-HT7 receptor antagonist properties, as well as being a potent 5-HT1A partial agonist (Meyer et al, 2009; Ishibashi et al, 2010). We have recently reported that acute treatment with lurasidone ameliorates the subchronic PCP-induced NOR deficits in a 5-HT1A- and 5-HT7-dependent manner (Horiguchi et al, 2011b; Horiguchi and Meltzer, 2012).

Stimulation of 5-HT1A receptors has been identified as a target for improving CIS, possibly by enhancing the release of cortical DA (Ichikawa et al, 2001, 2002). We have reported that the addition of tandospirone, a 5-HT1A partial agonist (Hamik et al, 1990), to the ongoing treatment with typical APDs of patients with schizophrenia, improved executive function, verbal learning, and memory (Sumiyoshi et al, 2000, 2001a, 2001b). We have also recently reported that acute administration of tandospirone or F15599, another 5-HT1A agonist, improved the NOR deficit induced by subchronic PCP and WAY100635, a 5-HT1A antagonist, blocked the acute attenuating effect of lurasidone (Horiguchi and Meltzer, 2012). These results indicate that acute stimulation of 5-HT1A receptors is adequate to ameliorate the PCP-induced impairment in NOR.

The aim of the current study was to test the preventive effect of lurasidone, tandospirone, haloperidol, a typical APD, and pimavanserin, a 5-HT2A inverse agonist, on the subchronic PCP-induced NOR deficit in rats. We also tested whether WAY100635, a 5-HT1A antagonist, blocks the preventive effect of lurasidone.

MATERIALS AND METHODS

Animals

Thirty-four female Long-Evans (LE) rats (8 or 9 weeks old; Harlan Sprague Dawley, Indianapolis, IN, USA) were used as subjects for experiments 1–2 (rat group 1). Forty-three rats (rat group 2) were used for experiment 3. Twenty-six rats (rat group 3) were used for experiment 4. LE rats were housed in groups of three or four on a 12 h light/dark cycle. Food and water were available ad libitum. All experiments were conducted during the light phase in accordance with the Vanderbilt Animal Committee Regulations.

Drugs

Lurasidone and tandospirone were provided by Dainippon Sumitomo Pharma (Osaka, Japan). Pimavanserin was provided by Acadia Pharmaceuticals (Torrence, CA, USA). Haloperidol was obtained from Sigma-Aldrich (St Louis, MO, USA). WAY100635 was a gift from Wyeth Laboratories (Philadelphia, PA). PCP was supplied as a generous gift from the National Institute of Drug Abuse (Bethesda, MD, USA).

Lurasidone was dissolved in 0.5% methylcellulose, 0.2% Tween80. The other drugs were dissolved in distilled water. All drugs or vehicle were administered intraperitoneally (i.p.) in a volume of 1 ml/kg body.

Drug Treatment

LE rats (rat group 1) were randomly assigned to four groups. For each of these groups, the first injection (A) was given 30 min before the second injection (B) twice daily for 7 days (day1–7). Group 1 (control group), A; vehicle (saline), B; vehicle (saline). Group 2 (subchronic PCP group), A; vehicle, B; PCP (2 mg/kg). Group 3 (lurasidone 0.1 mg/kg+PCP group), A; lurasidone (0.1 mg/kg), B; PCP (2 mg/kg). Group 4 (lurasidone 1 mg/kg+PCP group), A; lurasidone (1 mg/kg), B; PCP (2 mg/kg).

Rat group 2 were randomly assigned to five groups. For each of these groups, the first injection (A) was given 30 min before second injection (B) twice daily for 7 days (day1–7). Group 1 (control group), A; vehicle, B; vehicle. Group 2 (subchronic PCP group), A; vehicle, B; PCP (2 mg/kg). Group 3 (tandospirone 5 mg/kg+PCP group), A; tandospirone (5 mg/kg), B; PCP (2 mg/kg). Group 4 (haloperidol 1 mg/kg+PCP group), A; haloperidol (1 mg/kg), B; PCP (2 mg/kg). Group 5 (pimavanserin 3 mg/kg+PCP group), A; pimavanserin (3 mg/kg), B; PCP (2 mg/kg).

Rat group 3 were randomly assigned to three groups. For each of these groups, the first injection (A) and second injection (B) were given 45 min or 30 min, respectively, before the third injection (C) twice daily for 7 days (day1–7). Group 1 (control group), A; vehicle, B; vehicle, C; vehicle. Group 2 (subchronic PCP group), A; vehicle, B; vehicle, C; PCP (2 mg/kg). Group 3 (lurasidone 1 mg/kg+WAY100635 0.6 mg/kg+PCP group), A; WAY100635 (0.6 mg/kg), B; lurasidone (1 mg/kg), C; PCP (2 mg/kg).

Subsequently, animals were given a 7-day washout period (days 8–14) before NOR testing.

NOR Test

Testing was carried out according to a previously validated method (Snigdha et al, 2010). Briefly, all rats were habituated for 1 h to the NOR arena for three consecutive days (days 12–14) before the first NOR test. Rats were given a further 3-min habituation on the day of testing (days 15 or 21). After the 3-min habituation, the rats were given two 3-min trials (an acquisition trial and a retention trial) separated by a 1-min intertrial return to their home cage. During the acquisition trial, the animals were allowed to explore two identical objects (A1 and A2). During the retention trial, the animals explored a familiar object (A) from the acquisition trial and a novel object (B).

Behavior was recorded on video for blind scoring of object exploration. Object exploration is defined as an animal licking, sniffing, or touching the object with the forepaws while sniffing. The exploration time (s) of each object in each trial was recorded manually by the use of two stopwatches. The discrimination index (DI) [(time spent exploring the novel object−time spent exploring the familiar object)/total exploration time] was then calculated for retention trials.

If the exploration time in the aquisition or retention trials to either of two objects was <5 s, the data were excluded from analysis. This rarely occurred and did not affect the ability to complete the analysis using the data from the remaining animals of that group. All experimental groups consisted of six to nine rats.

Data Analysis

All data are expressed as the mean±SEM (n=6–9 per group). Exploration data were analyzed by a two-way ANOVA followed by the pairwise comparison when a significant effect was detected by the ANOVA. This analysis was used to detect the interaction of drug treatment and object exploration as well as main effects. When a significant effect was found, further analysis by a post hoc Student's t-test was performed to compare the time spent exploring the novel and familiar object. DI data were analyzed using one-way ANOVA followed by the Bonferroni test when a significant effect was detected by the ANOVA.

RESULTS

Effect of Co-Administration of Lurasidone on Subchronic PCP-Induced NOR Deficit on Day 15 (Experiment 1)

In the aquisition trial, no significant differences in time spent exploring the two identical objects were observed in any group (F7,54=0.9, p>0.05, Figure 1a). There were no significant effects of drugs on exploratory activity during the acquisition trial period (F5,42=0.64, p>0.05 for Supplementary Figure 1, F9,66=0.6, p>0.05 for Supplementary Figure 2, F5,44=0.48, p>0.05 for Supplementary Figure 3) in any of the experiments (Supplementary Figures 1–3). In the retention phase, the time spent exploring the novel vs familiar objects was significantly different among the groups (F7,54=3.8, p<0.005, Figure 1b). Using post-hoc analysis, vehicle-treated animals explored the novel object significantly longer than the familiar object (p<0.05, Figure 1b). The ability to discriminate novel and familiar objects was abolished by subchronic PCP treatment. Lurasidone (0.1 mg/kg) failed to prevent this deficit (Figure 1b). However, lurasidone (1 mg/kg) significantly attenuated the NOR deficit (p<0.005, Figure 1b). The model examining the group effect on DI was statistically significant (F3,27=5.7, p<0.005, Figure 1c). In the post-hoc analysis, the DI was significantly reduced following subchronic PCP-treatment (p<0.01). Co-administration of 1 mg/kg lurasidone significantly prevented the PCP-induced reduction in DI (p<0.01), but 0.1 mg/kg lurasidone did not (Figure 1c).

Figure 1
figure 1

Effect of co-treatment with lurasidone (LUR, 0.1, 1 mg/kg) on PCP-induced cognitive impairment in NOR test on day 15. (a) Effect of LUR (0.1, 1 mg/kg, i.p.) on exploration of two identical objects in the aquisition trial in NOR test on day 15. Data are shown as mean±SEM (n=6–9 per group). (b) Effect of LUR (0.1, 1 mg/kg, i.p.) on exploration of a novel and a familiar object in the retention trial in NOR test on day 15. Data are shown as mean±SEM (n=6–9 per group). ***p<0.001, *p<0.05, significant difference in time spent exploring the novel compared with the familiar object. (c) Effect of LUR (0.1, 1 mg/kg, i.p.) on the DI on day 15. Data are shown as mean±SEM (n=6–9 per group). **p<0.01, significant decrease in DI compared with the vehicle. ##p<0.01, significant reversal in DI compared with PCP group.

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Effect of Co-Administration of Lurasidone on Subchronic PCP-Induced NOR Deficit on Day 22 (Experiment 2)

In the retention trial, the time spent exploring the novel vs familiar objects was significantly different among the groups (F5,42=7.8, p<0.005, Figure 2a). The post-hoc analysis revealed that vehicle-treated animals showed preference for the novel object (p<0.005, Figure 2a). PCP-treated rats did not show preference for the novel object (Figure 2a). Co-treatment with lurasidone (1 mg/kg) significantly attenuated the PCP-induced deficit (p<0.005, Figure 2a) demonstrating an enduring preventive effect on the PCP-induced NOR deficit. Statistical analysis showed the model examing the group effect on DI was significant (F2,21=14.8, p<0.005, Figure 2b). Examing the post-hoc test, it was revealed that subchronic PCP-treatment significantly reduced the DI (p<0.005, Figure 2b). Co-administration of lurasidone (1 mg/kg) prevented the reduction of DI (p<0.005, Figure 2b).

Figure 2
figure 2

Effect of co-treatment with lurasidone (LUR, 0.1, 1 mg/kg) on PCP-induced cognitive impairment in NOR test on day22. (a) Effect of LUR (0.1, 1 mg/kg, i.p.) on exploration of a novel and a familiar object in the retention trial in NOR test on day 22. Data are shown as mean±SEM (n=7–9 per group). ***p<0.001, significant difference in time spent exploring the novel compared with the familiar object. (b) Effect of LUR (0.1, 1 mg/kg, i.p.) on the DI on day 22. Data are shown as mean±SEM (n=7–9 per group). ***p<0.001, significant decrease in DI compared with the vehicle. ###p<0.001, significant reversal in DI compared with PCP group.

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Effect of Co-Administration of Tandospirone, Haloperidol, or Pimavanserin on Subchronic PCP-Induced NOR Deficit on Day 15 (Experiment 3)

In the retention trial, the time spent exploring the novel vs familiar objects was significantly different among the groups (F9,66=3.8, p<0.005, Figure 3a). Using post-hoc analysis, it was found vehicle-treated rats showed exploratory preference for the novel object (p<0.005, Figure 3a). In PCP-treated rats, there was no significant difference between the time spent exploring the novel and the familiar object (Figure 3a). Tandospirone (5 mg/kg) significantly prevented the PCP-induced NOR deficit (p<0.04; Figure 3a). Neither haloperidol 1 mg/kg nor pimavanserin 3 mg/kg prevented this deficit (Figure 3a). The model examining the group effect on DI was statistically significant (F4,33=4.5, p<0.01, Figure 3b). In the post-hoc analysis, the DI was significantly reduced following subchronic PCP-treatment (p<0.005). Co-treatment with 5 mg/kg tandospirone (p<0.05), but not 1 mg/kg haloperidol or 3 mg/kg pimavanserin, significantly improved the DI reduction (Figure 3b).

Figure 3
figure 3

Effect of co-treatment with tandospirone (TAN, 5 mg/kg), haloperidol (HAL, 1 mg/kg), and pimavanserin (PIM, 3 mg/kg) on PCP-induced cognitive impairment in NOR test on day15. (a) Effect of TAN, HAL, and PIM (5, 1, and 3 mg/kg, respectively, i.p.) on exploration of a novel and a familiar object in the retention trial in NOR test on day 15. Data are shown as mean±SEM (n=7–9 per group). ***p<0.001, *p<0.05, significant difference in time spent exploring the novel compared with the familiar object. (b) Effect of TAN, HAL, and PIM (5, 1, and 3 mg/kg, respectively, i.p.) on the DI on day 15. Data are shown as mean±SEM (n=7–9 per group). ***p<0.001, significant decrease in DI compared with the vehicle. #p<0.05, significant reversal in DI compared with PCP group.

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Effect of Co-Administration of WAY100635 Plus Lurasidone on Subchronic PCP-Induced NOR Deficit on Day 15 (Experiment 4)

In the retention trial, the time spent exploring the novel vs familiar objects was significantly different among the groups (F5,44=3.0, p<0.02, Figure 4a). Using post-hoc analysis, it was found that the vehicle-treated rats showed preference for the novel object (p<0.005); this preference was abolished by subchronic PCP-treatment (Figure 4a). WAY100635 (0.6 mg/kg) plus lurasidone (1 mg/kg) did not prevent this deficit (Figure 4a). The model examing the group effect on DI was statistically significant (F2,22=4.4, p<0.05, Figure 4b). In the post-hoc analysis, the DI was significantly reduced following subchronic PCP-treatment (p<0.05). Treatment with 0.6 mg/kg WAY100635 and 1 mg/kg lurasidone did not improve the reduction in the DI (Figure 4b).

Figure 4
figure 4

Effect of co-treatment with WAY100635 (WAY, 0.6 mg/kg) plus lurasidone (LUR, 1 mg/kg) on PCP-induced cognitive impairment in NOR test on day 15. (a) Effect of WAY (0.6 mg/kg, i.p.) plus LUR (1 mg/kg, i.p.) on exploration of a novel and a familiar object in the retention trial in NOR test on day 15. Data are shown as mean±SEM (n=7–9 per group). ***p<0.001, significant difference in time spent exploring the novel compared with the familiar object. (b) Effect of WAY (0.6 mg/kg, i.p.) plus LUR (1 mg/kg, i.p.) on the DI on day 15. Data are shown as mean±SEM (n=7–9 per group). *p<0.05, significant decrease in DI compared with the vehicle.

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DISCUSSION

NOR is a possible analog of declarative memory in humans (Winters et al, 2010) and a frequently studied model of CIS. In this study, we again confirmed that subchronic administration of PCP produces a severe deficit in NOR and that the co-treatment with lurasidone, an atypical APD with 5-HT1A partial agonism, or with tandospirone, a selective 5-HT1A agonist, prevented the NOR deficit induced by subchronic PCP. On the other hand, haloperidol, a typical antipsychotic with selective D2 antagonist properties, or pimavanserin, a selective 5-HT2A inverse agonist, did not prevent the PCP-induced deficit in NOR.

This is the first demonstration of the preventive effect of an atypical APD (lurasidone), or a 5-HT1A partial agonist (tandospirone) on subchronic PCP-induced disruption in NOR in rats. We also found that the preventive effect of lurasidone lasted at least 14 days after the final PCP injection (on day 22). It has been reported that lurasidone has cognitive benefits in some animal models of CIS, in which other APDs were ineffective or even worsened the impairment in cognition (Ishiyama et al, 2007; Enomoto et al, 2008). Lurasidone was reported to be somewhat more effective than ziprasidone to improve general cognitive function in patients with schizophrenia in a double-blind study of 21 days duration (Harvey et al, 2011). In the present experiment, co-administration of lurasidone, 0.1 mg/kg, did not show the preventive effect, although acute treatment with this dose of lurasidone can reverse the subchronic PCP-induced NOR deficit (Horiguchi et al, 2011a, 2011b). Acute treatment with lurasidone, 0.1 mg/kg, is sufficient to temporarily reverse the subchronic PCP-induced NOR deficit 30 min after administration, but when co-administration with subchronic PCP, this dose is insufficient to prevent the cognitive impairment in NOR induced by the subchronic PCP regimen. These results are inconsistent with several other preclinical reports using risperidone, suggest that lower doses of risperidone might be effective in some animal models of psychosis (Piontkewitz et al, 2011; Richtand et al, 2006). Thus, risperidone, at a dose of 0.045 mg/kg per day attenuated the abnormally elevated locomotor response to amphetamine following hippocampal lesions and behavioral abnormalities in the offsprings of poly I:C mother mice (Piontkewitz et al, 2011; Richtand et al, 2006). Our results suggest that for lurasidone or other atypical APDs higher doses than those needed to prevent recurrence of psychosis might be needed to impact CIS.

The results in this study are consistent with the acute reversal studies in which atypical APDs, including lurasidone and the 5-HT1A agonist, tandospirone, but not pimavanserin or haloperidol, are effective reversing PCP-induced cognitive deficits (Grayson et al, 2007; Snigdha et al, 2010; Horiguchi et al, 2011a, 2011b; Horiguchi and Meltzer, 2012). It is of interest to compare these results from acute reversal studies with studies in mice that showed a subchronic PCP (10 mg/kg)-induced NOR deficit in mice and examined the ability of subsequent subchronic administration of APDs to reverse the impairment (Hashimoto et al, 2005; Hagiwara et al, 2008; Nagai et al, 2009; Tanibuchi et al, 2009). This deficit was recovered by subsequent subchronic (14 days) administration of clozapine (5 mg/kg, i.p.), but not haloperidol (0.1 mg/kg, i.p.; Hashimoto et al, 2005). This deficit was also subsequently improved by subchronic treatment with perospirone or aripiprazole both of which are 5-HT1A partial agonists (Hagiwara et al, 2008; Nagai et al, 2009). Tanibuchi et al (2009) reported that subsequent treatment with quetiapine, another atypical APD with 5-HT1A partial agonism, also reversed the subchronic PCP-induced deficit in mice. On the other hand, in rat NOR, McKibben et al (2010) reported that treatment with risperidone (0.5 mg/kg, i.p.) twice daily for 10 days, beginning 3 days before the start of PCP administration (2 mg/kg, i.p., b.i.d. for 7 days), did not show a protective effect against the NOR deficit induced by subchronic PCP. More studies with other atypical APDs are needed to better understand the role of atypical APDs on cognitive impairments in NOR induced by subchronic PCP. These results suggest that at least some atypical APDs (eg, lurasidone) may be effective to prevent the development of cognitive impairmant in individuals who at high risk for schizophrenia.

Stimulation of 5-HT1A receptors has been identified as a target for improving CIS (Meltzer, 1999). In this study, not only lurasidone but also the 5-HT1A agonist, tandospirone, showed the preventive effect on subchronic PCP-induced NOR deficit. Moreover, WAY100635, a selective 5-HT1A antagonist, blocked the preventive effect of lurasidone, thereby demonstrating the involvement of 5-HT1A agonism in the effect of lurasidone. As mentioned above, these results are consistent with the acute studies with 5-HT1A agonists in this model (Horiguchi and Meltzer, 2012). These data suggest that tandospirone by itself or as an add on treatment with an atypical APD might have value to prevent the development of CIS. The 5-HT1A agonists, eg, tandospirone, have a lower side effect burden than most atypical APDs, especially of the metabolic variety (Feighner and Boyer, 1989). It is noteworthy that lurasidone shares important structural similarities with tandospirone, and that lurasidone is also a 5-HT1A partial agonist (Meltzer et al, 2011).

Postmortem studies have reported that the density of 5-HT1A receptors is increased in frontal and temporal cortices in schizophrenia (Burnet et al, 1996, 1997; Gurevich and Joyce, 1997; Hashimoto et al, 1991; Simpson et al, 1996; Sumiyoshi et al, 1996). Positron emission tomography studies confirm an increase in cortical 5-HT1A receptor binding in schizophrenia (Kasper et al, 2002; Tauscher et al, 2002). Subchronic treatment with PCP has been reported to increase 5-HT1A receptor binding in the medial- and dorsolateral-frontal cortex (Choi et al, 2009). Microdialysis studies report that acute administration of PCP increases cortical 5-HT release (Etou et al, 1998; Martin et al, 1998; Millan et al, 1999; Adams and Moghaddam, 2001; Amargós-Bosch et al, 2006). This effect is blocked by clozapine and olanzapine but not haloperidol (Amargós-Bosch et al, 2006). It is possible that lurasidone and tandospirone, through their 5-HT1A agonist properties, suppress cortical 5-HT release, thereby blocking effects of PCP related to 5-HT release that lead to interference with NOR.

Haloperidol and pimavanserin did not show a preventive effect in this model. As mentioned above, these results are in agreement with the lack of effectiveness of these drugs to acutely reverse the effects of subchronic PCP on NOR (Grayson et al, 2007; Snigdha et al, 2010). Subchronic treatment with haloperidol also did not reverse the NOR deficit induced by subchronic PCP in mice (Hashimoto et al, 2005; Nagai et al, 2009). Haloperidol (1 mg/kg) has been reported to reverse PCP-induced morphologic deficits in the auditory system, but not to reverse PCP-induced decreases in prefrontal cortical GABAergic interneurons in rats (Cochran et al, 2003). Pimavanserin (3 mg/kg) has been shown to achieve essentially 100% 5-HT2A receptor occupancy (Vanover et al, 2006) and potentiated the ability of sub-effective doses of atypical APDs to reverse the NOR deficit induced by subchronic PCP (Snigdha et al, 2010). It is noteworthy that haloperidol and pimavanserin effectively block acute NMDA receptor antagonist (eg, PCP, MK-801)-induced hyperlocomotion, considered a model of psychosis (Maurel-Remy et al, 1995; Vanover et al, 2006; Gardell et al, 2007). Ritanserin, another 5-HT2A inverse agonist, was able to block the ability of PCP to increase cortical 5-HT efflux (Amargós-Bosch et al, 2006). Co-administration of haloperidol or pimavanserin with PCP was ineffective in restoring performance in the NOR test in subchronic PCP-treated rats, indicating that D2 or 5-HT2A receptor blockade alone is insufficient to reverse cognitive impairment induced by subchronic PCP treatment, unlike the blockade of the effect of acute PCP or MK-801 on locomotor activity.

It has been reported that subchronic PCP induces a reduction in the density of paravalbumin-containing GABAergic interneurons in the hippocampus in both male and female rats (Abdul-Monim et al, 2007; Jenkins et al, 2008). A number of groups have conducted studies investigating the neuroprotective effects of atypical APDs. Chronic PCP treatment decreases parvalbumin mRNA expression and chronic administration of clozapine, but not haloperidol, reversed the PCP-induced decreases in parvalbumin mRNA expression in prefrontal cortical GABAergic interneurons (Cochran et al, 2003). Chronic treatment with olanzapine, but not haloperidol, has been reported to slow volume loss in the prefrontal cortex in a prefrontal cortical dopamine denervation model of schizophrenia (Wang and Deutch, 2008). Some clinical reports also suggest some atypical APDs may have a neuroprotective effect. A study of patients with first-episode schizophrenia reported that basal ganglia volume is increased in patients treated with risperidone (Massana et al, 2005). Treatment with risperidone increased the volume of gray matter in neuroleptic-naive patients (Molina et al, 2005). Further studies with lurasidone and tandospirone on the subchronic PCP-induced GABAergic interneuron deficit could provide valuable insight into the mechanism of subchronic PCP to induce cognitive impairment in rat NOR.

Female rats were used in this study primarily because they have been found to perform significantly better than male rats in the NOR task (Sutcliffe et al, 2007). Further, no effect of estrous cycle on performance in the NOR task has been found (Sutcliffe et al, 2007). Finally, female rats have been shown to differ in pharmacokinetics of PCP metabolism rendering them more sensitive to PCP than males, because of slower metabolism and higher PCP tissue levels (Nabeshima et al, 1984).

In conclusion, these results indicate that lurasidone or tandospirone, but not haloperidol, a typical APD, nor pimavanserin, may prevent the development of cognitive impairment in individuals who are at the risk for schizophrenia or related disorders with cognitive impairment, eg, bipolar disorder.