5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex

A hallucinogenic 5-HT2A/2C receptor agonist, but not a 5-HT1A receptor agonist, differentially regulated BDNF mRNA levels in rat brain. In the hippocampus, it decreased BDNF mRNA in the dentate gyrus granule cell layer without affecting CA subfields. In neocortical areas (but not piriform cortex), it dramatically increased BDNF mRNA. These effects were blocked by a selective 5-HT2A, but not 5-HT2C, receptor antagonist. Stress-induced downregulation of BDNF mRNA in hippocampus was blocked by pretreatment with ketanserin, a 5-HT2A/2C antagonist, suggesting 5-HT2A receptors mediate that effect. The findings suggest hallucinogenic 5-HT2A agonists may alter synaptic strength in hippocampus and neocortex, potentially mediating behavioral effects.

Study at a glance

Abstract

The influence of 5-HT receptor agonists on the expression of BDNF in brain was determined. Administration of a hallucinogenic 5-HT2A /2C receptor agonist, but not a 5-HT1A receptor agonist, resulted in a significant but differential regulation of BDNF mRNA levels in hippocampus and neocortex. In the hippocampus, the 5-HT2A /2C receptor agonist significantly decreased BDNF mRNA expression in the dentate gyrus granule cell layer but did not influence expression of the neurotrophin in the CA subfields. In parietal cortex and other neocortical areas, but not piriform cortex, the 5-HT2A /2C receptor agonist dramatically increased the expression of BDNF mRNA. The effect of the 5-HT2A /2C receptor agonist on BDNF mRNA in both the hippocampus and the neocortex was blocked by pretreatment with a selective 5-HT2A, but not 5-HT2C, receptor antagonist. The expression of BDNF mRNA in the hippocampus is reported to be decreased by stress, raising the possibility that the 5-HT2A receptor mediates this effect. Pretreatment with ketanserin, a 5-HT2A /2C receptor antagonist, significantly blocked the stress-induced downregulation of BDNF mRNA in hippocampus, in support of this hypothesis. The results of this study raise the possibility that regulation of BDNF expression by hallucinogenic 5-HT2A receptor agonists leads to adaptations of synaptic strength in the hippocampus and the neocortex that may mediate some of the acute and long-term behavioral effects of these agents.