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Vol. 296, Issue 3, 987-995, March 2001
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill
University, Montreal, Canada (G.G.); Laboratory of Clinical Science,
National Institute of Mental Health, Bethesda, Maryland (D.L.M);
Department of Psychiatry, University of Wurzburg, Würzburg,
Germany (K.-P.L.); and Department of Psychiatry, University of Florida
Brain Institute, Gainesville, Florida (P.B.)
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 CA3
pyramidal 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.
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