Abstract
Dizocilpine (MK-801) is a non-competitive NMDA antagonist that induces schizophreniclike effects. It is therefore widely used in experimental models of schizophrenia including prepulse inhibition (PPI) impairments in rodents. Nevertheless, MK-801 has never been tested in monkeys on a PPI paradigm. In order to evaluate MK-801 effects on monkeys’ PPI, we tested eight capuchin monkeys (Sapajus spp.) using three different doses of MK-801 (0.01; 0.02; 0.03 mg/kg). Results show PPI impairment in acute administration of the highest dose (0.03 mg/kg). PPI impairment induced by MK-801 was reversed by re-exposure to the PPI test throughout treatment trials, in contrast with rodent studies. These results indicate that tolerance effect and familiarization with PPI test may reduce the sensorimotor gating deficits induced by MK-801 in monkeys, suggesting a drug-training interaction.
Highlights
IntroductionPrepulse inhibition (PPI) impairment is characteristic of schizophrenic patients (Braff et al, 2001a; Ludewig et al, 2003), and usually observed in rodents after MK-801 injection (Long et al, 2006; Arai et al, 2008; Ishii et al, 2010; Gururajan et al, 2011; Gomes et al, 2014; Khella et al, 2014; Park et al, 2014)
There was an increase in PPI after repeated injections of MK-801 and repeated PPI tests (Z = −4.359; p < 0.001), as observed in PPI of MK-801/G2 and MK-801/G1
No difference was found between VEH at fourth test-week (VEH/G2) and MK801 at fourth test-week (MK-801/G1) (Z = −0.799; p = 0.429), nor between VEH at first test-week (VEH/G1) and MK-801 at fourth test-week (MK-801/G1) (Z = −1.116; p = 0.265; Figure 3A)
Summary
Prepulse inhibition (PPI) impairment is characteristic of schizophrenic patients (Braff et al, 2001a; Ludewig et al, 2003), and usually observed in rodents after MK-801 injection (Long et al, 2006; Arai et al, 2008; Ishii et al, 2010; Gururajan et al, 2011; Gomes et al, 2014; Khella et al, 2014; Park et al, 2014). PPI test is characterized as a slight stimulus (prepulse) presented at a specific interval before the startling stimulus (pulse), leading to a reduction of the startle response In this sense, PPI allows the evaluation of sensorimotor gating mechanisms through behavioral responses (Graham, 1975; Braff and Geyer, 1990; Geyer et al, 2001). As others NMDA antagonists—phencyclidine (PCP) and ketamine—MK-801 is extremely common in schizophrenia model studies This is due to the fact that these drugs trigger schizophrenic-like effects as seen in several studies with rodents. It has been demonstrated that MK-801 induces recognition memory impairments, hyperactivity and hyperlocomotion (Bradford et al, 2010; Park et al, 2014; Basurto et al, 2015), learning, memory and MK-801 effect on PPI reversed by familiarization spatial memory impairments (Hikichi et al, 2013; Karamihalev et al, 2014), social recognition deficits (Yoshimi et al, 2015), as well as impairments in cognitive set-shifting (Svoboda et al, 2015), and prepulse inhibition disruption (PPI) in rodents (Long et al, 2006; Arai et al, 2008; Ishii et al, 2010; Gururajan et al, 2011; Gomes et al, 2014; Khella et al, 2014; Park et al, 2014)
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