Effects of nitric oxide-related compounds in the acute ketamine animal model of schizophrenia

Abstract

Background: Better treatments for schizophrenia are urgently needed. The therapeutic use of the nitric oxide (NO)-donor sodium nitroprusside (SNP) in patients with schizophrenia has shown promising results. The role of NO in schizophrenia is still unclear, and NO modulation is unexplored in ketamine (KET) animal models to date. In the present study, we compared the behavioral effects of pre- and post-treatment with SNP, glyceryl trinitrate (GTN), and methylene blue (MB) in the acute KET animal model of schizophrenia. The present study was designed to test whether acute SNP, GTN, and MB treatment taken after (therapeutic effect) or before (preventive effect) a single KET injection would influence the behavior of rats in the sucrose preference test, object recognition task and open field.

Results: The results showed that KET induced cognitive deficits and hyperlocomotion. Long- term memory improvement was seen with the therapeutic GTN and SNP treatment, but not with the preventive one. MB pretreatment resulted in long-term memory recovery. GTN pre-, but not post-treatment, tended to increase vertical and horizontal activity in the KET model. Therapeutic and preventive SNP treatment consistently decreased KET-induced hyperlocomotion.

Conclusion: NO donors - especially SNP - are promising new pharmacological candidates in the treatment of schizophrenia. In addition, we showed that the potential impact of NO-related compounds on KET-induced behavioral changes may depend on the temporal window of drug administration.

Figure 1

Timeline of the experimental procedures. Times depicted represent the beginning of each event with regard to time 0.

Figure 2

Percentage of sucrose solution consumption over a 72 hours period. There was an increase in sucrose consumption in SAL + GTN compared to SAL + MB (€: p < 0.05) in the first 24 h in control animals (A). In the KET model, therapeutic treatment (B) with GTN (¥: p < 0.05) and MB (¢: p < 0.05) resulted in anhedonia in the first 24 h. Preventive treatment (C) did not result in significant anhedonia. Values presented as mean ± standard error of mean. N = 12 to 14 on each group.

Figure 3

Object recognition memory. Test phase (30 min after first object exposition) and late test phase (24 hours after first object exposure) refers respectively to equivalents of short term (A, B and C) and long term memory (D, E and F). SAL+ SNP and SAL + MB showed impaired short term object recognition memory. KET + SAL and SAL + KET animals showed impaired short and long term memory when compared to SAL + SAL (#: p < 0.05). Long term memory improvement was seen in KET animals post-treated with GTN and with SNP, but not on those pretreated. Long term memory improvement was seen in KET animals pretreated with MB, but not on those post-treated. *: p < 0.05; **: p < 0.01; tr: p = 0.05. Values presented as mean ± standard error of mean. N = 12 to 14 on each group.

Figure 4

Behaviors in the open field test. GTN, SNP or MB did not show anxiolytic effects in control animals regarding the proportion of their trajectory spent in the center (A). KET + SAL (B) and SAL + KET (C) were more frequently in the center than SAL + SAL (#: p < 0.04). Decreased vertical activity was seen in control animals treated with SNP (D) and in KET animals post-treated with SNP (E). Pretreatment did not result in significant differences in vertical activity (F). *: p < 0.05. Horizontal activity was decreased in control animals treated with SNP (G) during the first 4 min of the open field test (§: p < 0.05). KET + SAL (H) and SAL + KET (I) animals presented with hyperlocomotion during all time points of the open field test when compared to SAL + SAL (#: p < 0.003). Therapeutic treatment with SNP was able to revert KET-induced hyperlocomotion (£: p < 0.04 in H). KET + MB showed increased horizontal activity when compared to KET + SNP (¢: p = 0.001). Preventive treatment with SNP prevented KET-induced hyperlocomotion (£: p < 0.02 in I). GTN + KET ($: p < 0.001) and MB + KET (¢: p < 0.009) showed increased horizontal activity when compared to SNP + KET. GTN + KET showed increased horizontal activity when compared to MB + KET (€: p = 0.03). Values presented as mean ± standard error of mean. N = 12 to 14 on each group.