The Chronic Treatment With 5-HT_2A Receptor Agonists Affects the Behavior and the BDNF System in Mice

Serotonin 5-HT_2A receptors and the brain-derived neurotrophic factor (BDNF) are involved in the pathophysiology and treatment of many psychiatric diseases. However, the interaction between 5-HT_2A and BDNF is still poorly understood. In the present paper, the effects of chronic treatment with mixed 5-HT_2A/2C receptor agonist DOI, highly selective 5-HT_2A agonists TCB-2 and 25CN-NBOH on behavior and the BDNF system have been investigated. Chronic treatment of males of C57Bl/6 mice with DOI, TCB-2 and 25CN-NBOH (1 mg/kg, i.p., 14 days) resulted in desensitization of 5-HT_2A receptors. Treatment with 25CN-NBOH significantly increased startle amplitude. At the same time all used drugs failed to affect anxiety, exploratory and stereotyped behavior as well as spatial memory and learning. TCB-2 and 25CN-NBOH increased the BDNF mRNA level. All 5-HT_2A agonists increased the proBDNF level but failed to alter the mature BDNF protein level. TrkB and p75^NTR mRNA levels were affected by all utilized agonists. All drugs decreased the total level as well as membrane TrkB protein one indicating downregulation of TrkB receptors. All agonists decreased the membrane p75^NTR protein level. Thus, we have shown for the first time that the chronic activation of the 5-HT_2A receptor with agonists has affected the BDNF system almost on all levels-transcription, proBDNF production, TrkB and p75^NTR receptors' level. The obtained data suggested possible suppression in BDNF-TrkB signaling under chronic treatment with 5-HT_2A agonists.