Биохимия и фармакология: открытый доступ
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Is Brain-derived Neurotrophic Factor a Possible Mechanism Underlying Risperidone Sensitization in Adolescent Rats?

Qing Shu, Gang Hu, and Ming Li

Risperidone is one of the most widely used atypical antipsychotic drugs and is approved for the treatment of mental disorders (eg. schizophrenia, autism) in children and adolescents. The present study investigated the repeated treatment effect of risperidone and associated neurotropic mechanism in the phencyclidine (PCP)-induced hyperlocomotion model in adolescent rats. We examined whether repeated risperidone treatment would cause a sensitized inhibition of PCP-induced hyperlocomotion in adolescent rats, and whether such a sensitization effect was mediated by risperidone-induced alterations in Brain-Derived Neurotrophic Factor (BDNF), an important biomarker which plays a role in neuropathology of schizophrenia and action of antipsychotic medications. Male adolescent Sprague-Dawley rats (postnatal days [P] 44-48) were first treated with risperidone (0.5 or 1.0 mg/kg, sc) or vehicle and tested in the PCP (3.2 mg/kg, sc)-induced hyperlocomotion model for 5 consecutive days. Three days later, all rats were then challenged with risperidone (0.5 mg/kg) and PCP on ~P 51 to assess the potential sensitization effect. They were then sacrificed 1 day later and BDNF levels in the prefrontal cortex (PFC), striatum and hippocampus were examined using Western blotting. Behaviorally, repeated risperidone treatment progressively increased its inhibition of PCP-induced hyperlocomotion across the 5 test days. In the subsequent challenge test, rats previously treated with risperidone 1.0 mg/kg showed a stronger inhibition of the PCP-induced hyperlocomotion than those previously treated with vehicle, indicating a robust risperidone sensitization. However, no such group differences in the BDNF and its precursor proteins in any of the three brain regions were found. Therefore, although repeated adolescent risperidone administration induced a sensitization effect in the PCP-induced hyperlocomotion model in a dose-dependent fashion, whether BDNF is critically involved in this effect is still unsettled. Future work that directly manipulates BDNF systems is needed to further investigate this issue.