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 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-HT(1A) 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-HT(1A) receptors. Nevertheless, the cell body 5-HT(1A) autoreceptors were desensitized in both 5-HTT -/- and 5-HTT +/- mice. At the postsynaptic level, the recovery time (RT(50)) of the firing rate of hippocampus CA(3) 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 RT(50) 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-HT(1A) 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-HT(1A) 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.
Gobbi
G
G
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Canada.
Murphy
D L
DL
Lesch
K
K
Blier
P
P
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007262:Infusions, Intravenous; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017374:Paroxetine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011712:Pyramidal Tracts / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013997:Time Factors
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017374:Paroxetine; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide