Serotonin 5-HT receptor overexpression in the raphe nuclei area produces antidepressive effect and affects brain serotonin system in male mice.

Heterodimerization between 5-HT and 5-HT receptors seems to play an important role in the mechanism of depression and antidepressant drug action. It was suggested that the shift of the ratio between 5-HT /5-HT hetero- and 5-HT /5-HT homodimers in presynaptic neurons toward 5-HT /5-HT homodimers is one of the reasons of depression. Consequently, the artificial elevation of 5-HT receptor number in presynaptic terminals might restore physiological homo-/heterodimer ratio resulting in antidepressive effect. Here we showed that adeno-associated virus (AAV)-based 5-HT receptor overexpression in the midbrain raphe nuclei area produced antidepressive effect in male mice of both C57Bl/6J and genetically predisposed to depressive-like behavior ASC (antidepressant sensitive cataleptics) strains. These changes were accompanied by the elevation of 5-HT receptor mRNA level in the frontal cortex of C57Bl/6J and its reduction in the hippocampus of ASC mice. The presence of engineered 5-HT receptor in the midbrain of both mouse strains was further demonstrated. Importantly that 5-HT receptor overexpression resulted in the reduction of 5-HT receptor level in the membrane protein fraction from the midbrain samples of C57Bl/6J, but not ASC, mice. 5-HT receptor overexpression caused an increase of 5-HIAA/5-HT ratio in the midbrain and the frontal cortex of C57Bl/6J and in all investigated brain structures of ASC mice. Thus, 5-HT receptor overexpression in the raphe nuclei area affects brain 5-HT system and causes antidepressive effect both in C57Bl/6J and in "depressive" ASC male mice. Obtained results indicate the involvement of 5-HT receptor in the mechanisms underlying depressive behavior.