Impaired performance on touchscreen object-location paired associates learning by acute systemic MK-801 is reversed by L-govadine but not D-govadine or CDPPB
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Schizophrenia is a serious psychiatric disorder that affects 1% of the population. Current theories implicate NMDA receptor hypofunction as a contributor to the symptomology and pathological alterations in schizophrenia. Cognitive impairments are increasingly recognized as not only fundamental to schizophrenia, but the strongest predictor of patient functional outcomes. Current antipsychotics do not improve the cognitive symptoms of the disorder; however, recent efforts have resulted in the identification of novel drug targets. One target is metabotropic glutamate receptors as they interact with and modulate NMDA receptors. Another approach focuses on dopamine, the neurotransmitter system targeted by traditional antipsychotics. Tetrahydroprotoberberines, such as D- and L-govadine, are synthetic compounds derived from traditional medicine that have demonstrated efficacy in treating schizophrenic symptoms. The present study assessed the effects of CDPPB (a metabotropic glutamate receptor 5 positive allosteric modulator), D- and L-govadine, and the typical antipsychotic haloperidol on the Paired Associates Learning (PAL) task in rats. The PAL task is impaired in patients with schizophrenia, has been adapted for use with rodents using touchscreen-equipped operant chambers, and has been promoted by MATRICS as a promising behavioural task with the potential to further translational health research in schizophrenia. The objectives of this study were: 1) examine the effects of acute NMDA receptor antagonism with MK-801 as a model for schizophrenia on performance of the PAL task; 2) test the effects of the putative antipsychotics, CDPPB and D- and L-govadine on reversing the effects of NMDA receptor antagonism on the task; and 3) to compare these novel therapeutics to a classic antipsychotic. Two squads of male Long-Evans rats were trained to perform the PAL task in touchscreen-equipped operant chambers. After the rats reached criterion the following treatment schedules were divided between the two squads: 1) vehicle (10% cyclodextrin; i.p.), and CDPPB (1.0, 3.0, and 10.0 mg/kg, i.p.); or 2) vehicle (10% cyclodextrin; i.p.), CDPPB (3.0 mg/kg, i.p.), the NMDA receptor antagonist MK-801 (0.15 mg/kg, i.p.), and CDPPB with MK-801; or 3) vehicle (50% DMSO; s.c.), MK-801, D-govadine (1.0 mg/kg; s.c.), L-govadine (1.0 mg/kg; s.c.) and MK-801 with each isomer of govadine; or 4) vehicle (sodium acetate and acetic acid, pH 5.0, s.c.), and haloperidol (0.05 and 0.1 mg/kg, s.c.). Acute MK-801 significantly reduced the number of trials completed, impaired accuracy, and increased the number of errors in the PAL task. CDPPB had no effect on the PAL task and did not improve the MK-801 induced impairments. Administration of L-govadine, but not D-govadine, prior to MK-801 improved accuracy and reduced errors compared to MK-801 alone. L-govadine alone, but not D-govadine, reduced total responding compared to vehicle. Haloperidol caused a dose-dependent decrease in all activity in the task confounding interpretation of the results in regard to cognition. These data establish disruptive effects of acute MK-801 treatment on PAL task performance and demonstrate that L-govadine is capable of cognitive enhancement in a rodent model of schizophrenia.
DegreeMaster of Science (M.Sc.)
SupervisorHowland, John G.
CommitteeLee, Paul; Campanucci, Veronica; West, Nigel
Copyright DateJuly 2014
metabotropic glutamate receptors