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Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study.
J Pharmacol Exp Ther. 2001 Mar; 296(3):987-95.JP

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-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.

Authors+Show Affiliations

Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Canada.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11181933

Citation

Gobbi, G, et al. "Modifications of the Serotonergic System in Mice Lacking Serotonin Transporters: an in Vivo Electrophysiological Study." The Journal of Pharmacology and Experimental Therapeutics, vol. 296, no. 3, 2001, pp. 987-95.
Gobbi G, Murphy DL, Lesch K, et al. Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. J Pharmacol Exp Ther. 2001;296(3):987-95.
Gobbi, G., Murphy, D. L., Lesch, K., & Blier, P. (2001). Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. The Journal of Pharmacology and Experimental Therapeutics, 296(3), 987-95.
Gobbi G, et al. Modifications of the Serotonergic System in Mice Lacking Serotonin Transporters: an in Vivo Electrophysiological Study. J Pharmacol Exp Ther. 2001;296(3):987-95. PubMed PMID: 11181933.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. AU - Gobbi,G, AU - Murphy,D L, AU - Lesch,K, AU - Blier,P, PY - 2001/2/22/pubmed PY - 2001/3/17/medline PY - 2001/2/22/entrez SP - 987 EP - 95 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 296 IS - 3 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11181933/Modifications_of_the_serotonergic_system_in_mice_lacking_serotonin_transporters:_an_in_vivo_electrophysiological_study_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11181933 DB - PRIME DP - Unbound Medicine ER -