Effect of acute administration of different ketamine doses on anxiety and metabolic activity of the amygdala in rats

Anxiety has been described in the initial stages of schizophrenia, and affective flattening in the chronic illness. The etiology remains unknown. Ketamine, a noncompetitive N-Methyl-D-amino-aspartate acid (NMDA) receptor antagonist, is used in rats as a translational model of schizophrenia. A glutamate deficit within Nucleus Accumbens Septi (NAS) afferent projections has been proposed to be involved in schizophrenia. The amygdala is related to memory, fear and anxiety, and is closely linked to the NAS. Here, we studied anxiety in male rats using the elevated plus-maze (EPM) after receiving acute administration of different subanesthetic doses of ketamine. The metabolic state of the amygdala was measured after ketamine treatment. The main aim of the present study is to compare the effect of different doses as emulating progressive stages of schizophrenia. Classical anxiety parameters were observed during elevated plus maze (EPM) experiments in rats with the low doses of ketamine. After this, amygdalas were randomly extracted and submitted to a test of redox cellular metabolic activity with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Low doses (1.25 and 2.5 mg/kg) significantly decreased time spent in the open arm, time per entry and open arm entries, and increased time in the closed arms and grooming. These doses also decreased metabolic activity. We conclude that the administration of subanesthetic doses of ketamine exert an acute anxiogenic effect in the plus maze test at the lower doses, accompanied by a decrease in amygdala metabolic activity, suggesting metabolic exhaustion. The higher doses reversed the anxiety parameters, suggesting an explanation of the opposite symptoms in schizophrenia progression.