Non-competitive NMDA receptor antagonists, such as MK-801, are shown to produce complex symptoms that mimic positive and negative symptoms, as well as the cognitive deficits of schizophrenia. MK-801 (hydrogen maleate) impairs learning and memory functions that depend on the hippocampus and the amygdala. MK-801 also produces various effects on rodent behavior including deficits in sensory processing, hyperactivity, stereotypy and ataxia. Antipsychotic drugs, such as clozapine, used in the treatment of schizophrenia have been shown to improve MK-801 induced cognitive impairment in mice.
C57Bl/6 mice were injected with 0.2 mg/kg MK-801 and immediately analyzed.
Figure 1: Open field test. A: Distance traversed of MK-801-treated animals compared to sham treated control (CTRL) B: Hyperactivity level of MK-801-treated animals compared to sham treated control. Mean ± SEM; Two-way ANOVA with Bonferroni’s post hoc test. *p<0.05; **p<0.01; ***p<0.001.
Amphetamine (AMPH) or Phencyclidine (PCP) Treated Rat Model
The most widely validated animal models of the positive, negative and cognitive symptoms of schizophrenia involve administration of the dopamine-releasing drug, d-amphetamine in combination with the benzodiazepine Chlordiazepoxide (AMPH) or an open channel NMDA receptor blocker, phencyclidine (PCP). Pretreatment with Clozapine (CZP) can reverse the observed effects.
- AMPH increases activity in the Open Field test 10 minutes after treatment
- AMPH effect can be decreased by CZP
Figure 1: Open field behavior of amphetamine (AMPH)-treated Sprague Dawley rats. A: Distance traversed in cm/5 min over time; Two-way repeated measurements ANOVA with Bonferroni‘s post hoc test. Mean ± SEM. B: distance traversed in cm/5 min, 20 minutes after start of the analyses; One-way ANOVA with Bonferroni‘s post hoc test. Mean + SEM. CTRL = Control; CTRL, AMPH, AMPH+CZP: n = 8-10 per group;. *p<0.05; **p<0.01.
- PCP increases the startle response of Sprague Dawley rats in the prepulse inhibition test, effect can be prevented by CZP
- PCP decreases prepulse inhibition of Sprague Dawley rats in the prepulse inhibition test, effect can be reversed by CZP, effect of PCP depends on prepulse intensity
Figure 2: Startle response and Prepulse inhibition of PCP-treated Sprague Dawley rats. A: Startle amplitude in gram of PCP, PCP+CZP or CZP treated animals at 120 dB; One-way ANOVA with Bonferroni‘s post hoc test. B: Prepulse inhibition in percent of vehicle-, PCP- or PCP+CZP-treated animals using 4 different dB intensities; Two-way ANOVA with Bonferroni‘s post hoc test. A,B: n = 10; Mean + SEM; **p<0.01;***p<0.001.