The 5-HT receptor 7 (Htr7) has a widespread distribution in the brain and plays important functional roles in thermoregulation, circadian rhythm, mood regulation, sleep, learning and memory. Studies from our group have shown that the expression of the Htr7 was increased in key areas of reward circuits of adult rats, chronically treated with the psycostimulant methylphenidate. The up-regulation of Htr7 was paralleled by structural modifications of synaptic contacts. To assess if a direct relationship between neuronal morphological alterations and Htr7 stimulation occurs, we are investigating the modifications of neuronal morphology and the signalling pathways activated by Htr7 in striatal and cortical primary cultures generated from rat embryos. Treatment of these cultures with Htr7 agonists induces MAPK-ERK phosphorylation and significant increase of the neurite length, when compared to untreated cultures. These effects are blocked by administration of a selective Htr7 antagonist, by administration of an ERK inhibitor, and by cycloheximide, an inhibitor of protein biosynthesis. Ongoing proteomic approaches will allow us to identify proteins involved in neurite outgrowth.

Our results show that selective stimulation of the Htr7 regulates ERK-dependent neuritic outgrowth in neuronal primary cultures, in a de novo protein synthesis-dependent fashion, suggesting a crucial role of Htr7 in the regulation of neuronal morphology and plastic changes of striatal circuits.