Abstract
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.
Footnotes
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Send reprint requests to: Pierre Blier, M.D., Ph.D., Department of Psychiatry, University of Florida Brain Institute, P.O. Box 100256, Gainesville, FL 32610.
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This study was supported in part by a Medical Research Council of Canada (MRC) Grant no. 11014 and Scientist Award to P.B.; G.G. is a Ph.D. fellow from the Department of Neuroscience, “B. Brodie”, University of Cagliari (Italy), and a recipient of Royal Victoria Hospital, Wyeth Ayerst Canada, and MRC fellowships. K.-P.L. is supported by the Hermann and Lilly Schilling Foundation.
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The present work was presented at the 29th Annual meeting of the Society for Neuroscience in Miami, FL, October 1999 and at the 38th Annual meeting of the American College of Neuropsychopharmacology (ACNP) in Acapulco, Mexico, December 1999.
- Abbreviations:
- 5-HTT
- serotonin transporter
- 5-HT
- 5-hydroxytryptamine (serotonin)
- SSRI
- selective serotonin reuptake inhibitor
- 5-HTT −/−
- homozygous mice lacking the 5-HT transporter
- 5-HTT +/−
- heterozygous mice
- 5-HTT +/+
- wild-type mice
- 8-OH-DPAT
- 8-hydroxy-2-diproplyaminotetralin
- DRN
- dorsal raphe nucleus
- RT50
- recovery time 50
- Received August 22, 2000.
- Accepted November 27, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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