Neurochemical, behavioral, and physiological effects of pharmacologically enhanced serotonin levels in serotonin transporter (SERT)-deficient mice.

Abstract

RATIONALE:

Serotonin transporter (SERT) knockout (-/-) mice have an altered phenotype in adulthood, including high baseline anxiety and depressive-like behaviors, associated with increased baseline extracellular serotonin levels throughout life.

OBJECTIVES:

To examine the effects of increases in serotonin following the administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) in SERT wild-type (+/+), heterozygous (+/-), and -/- mice.

RESULTS:

5-HTP increased serotonin in all five brain areas examined with approximately 2- to 5-fold increases in SERT+/+ and +/- mice, and with greater 4.5- to 11.7-fold increases in SERT-/- mice. Behaviorally, 5-HTP induced exaggerated serotonin syndrome behaviors in SERT-/-, mice with similar effects in male and female mice. Studies suggest promiscuous serotonin uptake by the dopamine transporter (DAT) in SERT-/- mice, and here, the DAT blocker GBR 12909 enhanced 5-HTP-induced behaviors in SERT-/- mice. Physiologically, 5-HTP induced exaggerated temperature effects in SERT-deficient mice. The 5-HT1A antagonist WAY 100635 decreased 5-HTP-induced hypothermia in SERT+/+ and +/- mice with no effect in SERT-/- mice, whereas the 5-HT7 antagonist SB 269970 decreased this exaggerated response in SERT-/- mice only. WAY 100635 and SB 269970 together completely blocked 5-HTP-induced hypothermia in SERT+/- and -/- mice.

CONCLUSIONS:

These studies demonstrate that SERT-/- mice have exaggerated neurochemical, behavioral, and physiological responses to further increases in serotonin, and provide the first evidence of intact 5-HT7 receptor function in SERT-/- mice, with interesting interactions between 5-HT1A and 5-HT7 receptors. As roles for 5-HT7 receptors in anxiety and depression were recently established, the current findings have implications for understanding the high anxiety and depressive-like phenotype of SERT-deficient mice.

• Authors: Meredith A Fox, Catherine L Jensen, Helen T French, Alison R Stein, Su-Jan Huang, Teresa J Tolliver, Dennis L Murphy
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 201 Issue 2 Pg. 203-18 (Dec 2008) ISSN: 0033-3158 [Print] Germany
• PMID: 18712364 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Catecholamines
• Dopamine Uptake Inhibitors
• Monoamine Oxidase Inhibitors
• Phenols
• Piperazines
• Pyridines
• SB 269970
• Serotonin 5-HT1 Receptor Antagonists
• Serotonin Plasma Membrane Transport Proteins
• Serotonin Receptor Agonists
• Sulfonamides
• Serotonin
• Tranylcypromine
• Hydroxyindoleacetic Acid
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• 8-Hydroxy-2-(di-n-propylamino)tetralin
• vanoxerine
• 5-carboxamidotryptamine
• 5-Hydroxytryptophan
• Clorgyline

Topics

• 5-Hydroxytryptophan (pharmacology)
• 8-Hydroxy-2-(di-n-propylamino)tetralin (pharmacology)
• Animals
• Brain (anatomy & histology, drug effects, metabolism)
• Brain Chemistry (drug effects)
• Catecholamines (antagonists & inhibitors, classification)
• Clorgyline (pharmacology)
• Dopamine Uptake Inhibitors (pharmacology)
• Drug Synergism
• Drug Therapy, Combination
• Female
• Hydroxyindoleacetic Acid (analysis, metabolism)
• Hypothermia (chemically induced)
• Male
• Mice
• Mice, Knockout
• Monoamine Oxidase Inhibitors (pharmacology)
• Phenols (pharmacology)
• Piperazines (pharmacology, toxicity)
• Pyridines (pharmacology)
• Serotonin (analogs & derivatives, metabolism, pharmacology)
• Serotonin 5-HT1 Receptor Antagonists
• Serotonin Plasma Membrane Transport Proteins (deficiency, genetics)
• Serotonin Receptor Agonists (pharmacology)
• Serotonin Syndrome (chemically induced)
• Sulfonamides (pharmacology)
• Tranylcypromine (pharmacology)