Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration

Apart from their differential propensities to block dopamine D2 and serotonin 5-HT2 receptors, the molecular mechanisms underlying the clinical efficacy of typical and atypical antipsychotics in schizophrenia are largely unknown. Given recent interest in the effects of antipsychotics on neurotrophic and other growth related factors, the effects of antipsychotics on brain-derived neurotrophic factor (BDNF), a neurotrophin crucial to the structural integrity of adult neurons, were investigated in male Wistar rats. Chronic (19 day) but not acute (45 min) antipsychotic administration significantly altered levels of hippocampal BDNF mRNA. In addition, whereas chronic treatment with the strong D2 receptor-blocker haloperidol significantly downregulated hippocampal BDNF mRNA, the selective 5-HT2 receptor-blocker ritanserin significantly upregulated CA1 hippocampal BDNF mRNA in comparison to controls. Since high doses of risperidone and clozapine produce potent inhibition of both 5-HT2 and D2 receptors, while lower doses produce significantly greater 5-HT2 vs. D2 receptor blockade, a dose-response study was employed to determine whether low doses of these atypical antipsychotics would also upregulate hippocampal BDNF mRNA in the absence of significant D2 receptor blockade. Whereas chronic haloperidol and high-dose risperidone significantly downregulated hippocampal BDNF mRNA, intermediate and lower doses of risperidone and clozapine were, unlike ritanserin, without effect when compared to controls. Thus, although the long-term downregulation of hippocampal BDNF mRNA may underlie the different clinical profiles of certain antipsychotics, this effect seems to be associated with antipsychotic doses that not only cause significant D2 receptor inhibition, but are usually associated with side effects rather than therapeutic efficacies.