RT Journal Article
SR Electronic
T1 Modifications of the Serotonergic System in Mice Lacking Serotonin Transporters: An in Vivo Electrophysiological Study
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 987
OP 995
VO 296
IS 3
A1 Gabriella Gobbi
A1 Dennis L. Murphy
A1 Klaus-Peter Lesch
A1 Pierre Blier
YR 2001
UL http://jpet.aspetjournals.org/content/296/3/987.abstract
AB The serotonin transporter (5-HTT) plays a key role in the regulation of serotonin (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 role 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 +/+). Systemic injection of the selective 5-HT1A receptor antagonist WAY 100635 enhanced 5-HT neuronal firing by 127% in 5-HT −/− mice, thus indicating an enhanced synaptic availability of 5-HT at inhibitory 5-HT1A receptors. Nevertheless, the cell body 5-HT1A autoreceptors were desensitized in both 5-HTT −/− and 5-HTT +/− mice. At the postsynaptic level, the recovery time (RT50) of the firing rate of hippocampus CA3pyramidal neurons following iontophoretic applications of 5-HT was significantly prolonged only in 5-HTT −/− mice. The selective 5-HT reuptake inhibitor paroxetine significantly prolonged the RT50 in 5-HTT +/+ and 5-HTT +/− mice, without altering the maximal inhibitory effect of 5-HT. These neurons in 5-HTT −/− mice showed an attenuated response to the 5-HT1A agonist 8-hydroxy-2-diproplyaminotetralin, but not to 5-HT itself. These results establish that the lack of 5-HTT causes a prolonged recovery of firing activity following 5-HT applications. The genetic 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. The American Society for Pharmacology and Experimental Therapeutics