Antidepressants are known to increase brain derived neurotrophic factor (BDNF) mRNA in the adult rat brain. The BDNF gene has four differentially regulated promoters that generate four transcript forms, each containing a unique non-coding 5' exon (exon I-IV) and a common 3' coding exon. Using in situ hybridization with exon-specific riboprobes, we have examined whether diverse classes of antidepressants recruit a single or multiple BDNF promoters to regulate BDNF mRNAs. The antidepressants tested were electroconvulsive seizure (ECS) and the pharmacological antidepressants tranylcypromine, desipramine and fluoxetine. The effects of both acute and chronic ECS were the most prominent on exon I and II containing BDNF mRNAs in hippocampal and cortical subfields. Chronic ECS enhanced the acute induction of exon I, II and IV mRNAs but did not influence the acute upregulation of exon III mRNAs. Acute pharmacological antidepressants resulted in region-specific decreases in distinct exon-specific BDNF transcripts. In contrast, chronic administration with tranylcypromine and desipramine enhanced exon II and exon III mRNAs, respectively, in discrete hippocampal and cortical subfields. Chronic fluoxetine treatment did not have a significant effect on the exon-specific BDNF transcripts. The results indicate that distinct antidepressants differentially regulate BDNF mRNAs through a region-specific recruitment of the four BDNF promoters and suggest that diverse signaling mechanisms may be recruited to regulate BDNF transcripts.