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Sensorimotor gating impairments induced by MK-801 treatment may be reduced by tolerance effect and by familiarization in monkeys.

Saletti PG, Maior RS, Hori E, Nishijo H, Tomaz C - Front Pharmacol (2015)

Bottom Line: Dizocilpine (MK-801) is a non-competitive NMDA antagonist that induces schizophreniclike effects.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).

View Article: PubMed Central - PubMed

Affiliation: Primate Center and Laboratory of Neurosciences and Behavior, Department of Physiological Sciences, Institute of Biology, University of Brasilia , Brasilia, Brazil.

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.

No MeSH data available.


Related in: MedlinePlus

Habituation effect of MK-801 over repeated PPI sessions. (A) Circles indicate percent of PPI of G1 group (n = 4), and triangles, of G2 group (n = 4). White symbols indicate response after VEH administration and black symbols indicate response after MK-801 administration, regardless of dose (mean ± SEM). *Indicates significant difference of MK-801/G2 compared to all of other. (MK-801/G2 vs. VEH/G1, p < 0.001; MK-801/G2 vs. MK-801/G1, p < 0.001; MK-801/G2 vs. VEH/G2, p = 0.032). (B) At the first test-week, startle amplitude on pulse trials did not differ between groups, unlike on prepulse+pulse trials. Bars indicate startle response amplitude. Black bars demonstrate startle response on pulse-alone trials, and gray bars demonstrate startle response on prepulse-pulse trials. *Indicates significant difference on pulse-alone trials between VEH/G2 and all other (p < 0.036). +Indicates significant difference on prepulse-pulse trials between MK-801/G1 and all other (p < 0.032). #Indicates statistical difference on prepulse+pulse trials between VEH/G1 and MK-801/G2 (p = 0.042).
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Figure 3: Habituation effect of MK-801 over repeated PPI sessions. (A) Circles indicate percent of PPI of G1 group (n = 4), and triangles, of G2 group (n = 4). White symbols indicate response after VEH administration and black symbols indicate response after MK-801 administration, regardless of dose (mean ± SEM). *Indicates significant difference of MK-801/G2 compared to all of other. (MK-801/G2 vs. VEH/G1, p < 0.001; MK-801/G2 vs. MK-801/G1, p < 0.001; MK-801/G2 vs. VEH/G2, p = 0.032). (B) At the first test-week, startle amplitude on pulse trials did not differ between groups, unlike on prepulse+pulse trials. Bars indicate startle response amplitude. Black bars demonstrate startle response on pulse-alone trials, and gray bars demonstrate startle response on prepulse-pulse trials. *Indicates significant difference on pulse-alone trials between VEH/G2 and all other (p < 0.036). +Indicates significant difference on prepulse-pulse trials between MK-801/G1 and all other (p < 0.032). #Indicates statistical difference on prepulse+pulse trials between VEH/G1 and MK-801/G2 (p = 0.042).

Mentions: In our test procedure, we used a repeated treatment design in which all subjects underwent the same treatments. As explained above, we divided the animals in two groups (G1 and G2) and compared the PPI response between these two groups at the first and fourth test-weeks. This procedure was conducted in order to evaluate a possible temporal effect of MK-801 administration. Figure 3 shows the temporal effect of MK-801 administration. A deficit in the percent of PPI can be seen in animals that received MK-801 at the first test-week (MK-801/G2, n = 4), regardless of the dose that each monkey received, in comparison to animals that received VEH at the first test-week (VEH/G1, n = 4) (Z = –3.830; p < 0.001). Additionally, 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. A statistical difference was also observed between MK-801 at first test-week (MK-801/G2) and VEH at fourth test-week (VEH/G2) (Z = –2.151; p = 0.032). There was no statistical difference between either VEH administrations regarding percentage of inhibition (Z = –0.414; p = 0.684). Also, no difference was found between VEH at fourth test-week (VEH/G2) and MK-801 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).


Sensorimotor gating impairments induced by MK-801 treatment may be reduced by tolerance effect and by familiarization in monkeys.

Saletti PG, Maior RS, Hori E, Nishijo H, Tomaz C - Front Pharmacol (2015)

Habituation effect of MK-801 over repeated PPI sessions. (A) Circles indicate percent of PPI of G1 group (n = 4), and triangles, of G2 group (n = 4). White symbols indicate response after VEH administration and black symbols indicate response after MK-801 administration, regardless of dose (mean ± SEM). *Indicates significant difference of MK-801/G2 compared to all of other. (MK-801/G2 vs. VEH/G1, p < 0.001; MK-801/G2 vs. MK-801/G1, p < 0.001; MK-801/G2 vs. VEH/G2, p = 0.032). (B) At the first test-week, startle amplitude on pulse trials did not differ between groups, unlike on prepulse+pulse trials. Bars indicate startle response amplitude. Black bars demonstrate startle response on pulse-alone trials, and gray bars demonstrate startle response on prepulse-pulse trials. *Indicates significant difference on pulse-alone trials between VEH/G2 and all other (p < 0.036). +Indicates significant difference on prepulse-pulse trials between MK-801/G1 and all other (p < 0.032). #Indicates statistical difference on prepulse+pulse trials between VEH/G1 and MK-801/G2 (p = 0.042).
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Figure 3: Habituation effect of MK-801 over repeated PPI sessions. (A) Circles indicate percent of PPI of G1 group (n = 4), and triangles, of G2 group (n = 4). White symbols indicate response after VEH administration and black symbols indicate response after MK-801 administration, regardless of dose (mean ± SEM). *Indicates significant difference of MK-801/G2 compared to all of other. (MK-801/G2 vs. VEH/G1, p < 0.001; MK-801/G2 vs. MK-801/G1, p < 0.001; MK-801/G2 vs. VEH/G2, p = 0.032). (B) At the first test-week, startle amplitude on pulse trials did not differ between groups, unlike on prepulse+pulse trials. Bars indicate startle response amplitude. Black bars demonstrate startle response on pulse-alone trials, and gray bars demonstrate startle response on prepulse-pulse trials. *Indicates significant difference on pulse-alone trials between VEH/G2 and all other (p < 0.036). +Indicates significant difference on prepulse-pulse trials between MK-801/G1 and all other (p < 0.032). #Indicates statistical difference on prepulse+pulse trials between VEH/G1 and MK-801/G2 (p = 0.042).
Mentions: In our test procedure, we used a repeated treatment design in which all subjects underwent the same treatments. As explained above, we divided the animals in two groups (G1 and G2) and compared the PPI response between these two groups at the first and fourth test-weeks. This procedure was conducted in order to evaluate a possible temporal effect of MK-801 administration. Figure 3 shows the temporal effect of MK-801 administration. A deficit in the percent of PPI can be seen in animals that received MK-801 at the first test-week (MK-801/G2, n = 4), regardless of the dose that each monkey received, in comparison to animals that received VEH at the first test-week (VEH/G1, n = 4) (Z = –3.830; p < 0.001). Additionally, 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. A statistical difference was also observed between MK-801 at first test-week (MK-801/G2) and VEH at fourth test-week (VEH/G2) (Z = –2.151; p = 0.032). There was no statistical difference between either VEH administrations regarding percentage of inhibition (Z = –0.414; p = 0.684). Also, no difference was found between VEH at fourth test-week (VEH/G2) and MK-801 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).

Bottom Line: Dizocilpine (MK-801) is a non-competitive NMDA antagonist that induces schizophreniclike effects.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).

View Article: PubMed Central - PubMed

Affiliation: Primate Center and Laboratory of Neurosciences and Behavior, Department of Physiological Sciences, Institute of Biology, University of Brasilia , Brasilia, Brazil.

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.

No MeSH data available.


Related in: MedlinePlus