Modifications of the serotonergic system in mice lacking serotonin transporters: An in vivo electrophysiological study

The serotonin transporter (5-HTT) plays a key role in the regulation of ser otonin (5-hydroxytryptamine, 5-HT) transmission in the pathophysiology and therapeutics of several psychiatric disorders. The mean spontaneous firing rate of midbrain dorsal raphe 5-HT neurons was recorded in chloral hydrate- anesthetized mice. The serotonin transporter (5-HTT), which plays a key rol e in the regulation of serotonin was significantly decreased in homozygous mice lacking the 5-HT transporter (5-HTT-/-) by 66% and in heterozygous (5- HTT +/-) mice by 36% compared with their normal littermates (5-HTT +/-). Sy stemic injection of the selective 5-HT1A receptor antagonist WAY 100635 enh anced 5-HT neuronal firing by 127% in 5-HT -/- mice, thus indicating an enh anced synaptic availability of 5-HT at inhibitory 5-HT1A receptors. Neverth eless, the cell body 5-HT1A autoreceptors were desensitized in both 5-HTT - /- and 5-HTT +/- mice. At the postsynaptic level, the recovery time (RT50)o f the firing rate of hippocampus CA(3) pyramidal neurons following iontopho retic applications of 5-HT was significantly prolonged only in 5-HTT -/- mi ce. The selective 5-HT reuptake inhibitor paroxetine significantly prolonge d the RT50 in 5-HTT +/+ and 5-HTT +/- mice, without altering the maximal in hibitory effect of 5-HT. These neurons in 5-HTT -/- mice showed an attenuat ed response to the 5-HT1A agonist 8-hydroxy-2-diproplyaminotetralin, but no t to 5-HT itself. These results establish that the lack of 5-HTT causes a p rolonged recovery of firing activity following 5-HT applications. The genet ic deletion of the 5-HTT plays a key role on 5-HT1A receptor adaptation: a desensitization at pre- and postsynaptic levels in 5-HTT -/- mice, but to a different extent, and only at the presynaptic level in the 5-HTT +/- group .