Neurochemical changes underlying schizophrenia-related behavior in a modified forced swim test in mice

Abstract The modified forced swim test (MFST) has excellent predictive validity for investigating the antipsychotic activity of drugs, with particular emphasis on their activity toward negative symptoms of schizophrenia. However, its face and construct validity are less understood. Therefore, in the present study, some biochemical changes within GABAergic and serotonergic neurotransmission that could be related to observed MK-801-induced disturbances and the activity of compounds active at those neurotransmitters were investigated. In biochemical experiments, mice were treated acutely or chronically with MK-801 (13 days, 0.4 mg/kg). Their brains were dissected and frontal cortices and hippocampi were taken for further analysis. The levels of neurotransmitters were investigated with HPLC, and the expression of surrogate markers of schizophrenia (5-HT 1A receptors, GAD 65 , and GAD 67 , at both protein and mRNA levels) was measured via western blotting and q RT-PCR. The modified forced swim test and locomotor activity were used to assess the activity of GABA B and 5-HT 1A -related compounds. Repeated MK-801 treatment (13 days, 0.4 mg/kg dose) led to decreases in the DOPAC/DA, 3MT/DA and HVA/DA metabolic ratios. Increased 5-HT 1A protein expression and decreased GAD 65 and GAD 67 protein expression was observed in both the cortex and hippocampus. mRNA levels for all proteins were decreased. The increased immobility in the forced swim test was reversed both by a GABA B agonist (SKF97541, 0.025 or 0.05 mg/kg), a positive allosteric modulator of GABA B receptor (racBHFF, 5 or 10 mg/kg) and by a 5-HT 1A agonist (( R )-(+)-8-OH-DPAT 0.01 or 0.025 mg/kg). Our research supports the hypothesis that changes in the levels of GABA and/or 5-HT 1A receptors may contribute to the schizophrenia-like phenotype, and GABAergic and serotonergic agents may be good candidates for treating negative symptoms of schizophrenia.