Receptor mediation of exaggerated responses to serotonin-enhancing drugs in serotonin transporter (SERT)-deficient mice.
Administration of serotonin-enhancing drugs induces a distinctive behavioral syndrome in rodents. We previously reported that mice with a targeted disruption of the serotonin transporter (SERT) display some of these behaviors spontaneously, in the absence of drug. In the current studies, we assessed the drug-induced serotonin syndrome in SERT wildtype (+/+), heterozygous (+/-) and knockout (-/-) mice. In SERT -/- mice, the monoamine oxidase inhibitor (MAOI) tranylcypromine (1mg/kg) or the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP; 80 mg/kg) led to markedly exaggerated serotonin syndrome behaviors relative to SERT +/+ mice, with an intermediate phenotype in SERT +/- mice. SERT +/+ mice developed significant serotonin syndrome behaviors only with the combination of the MAO-A/B inhibitor tranylcypromine (0.5 or 1 mg/kg) or the MAO-A-selective inhibitor clorgyline (1.2 mg/kg) plus 5-HTP. In evaluations of underlying mechanisms, pretreatment with the Htr1a receptor antagonist WAY 100635 (1 mg/kg), but not the Htr7 antagonist SB 269970 (3 mg/kg) or the Htr2a antagonist MDL 11,939 (5 mg/kg), markedly decreased the exaggerated 5-HTP-induced behaviors in SERT -/- mice. Subsequent experiments showed that the Htr1a agonist 8-OH-DPAT (1 or 2 mg/kg) elicited serotonin syndrome behaviors in a dose-dependent manner, blocked by WAY 100635 (1 mg/kg), in mice of all three genotypes, confirming the role of Htr1a receptors. The current data document markedly enhanced behavioral sensitivity to serotonin-enhancing drugs in SERT-deficient mice. These studies also show that the exaggerated behavioral responses observed in SERT +/- and -/- mice are mediated by postsynaptic Htr1a receptors, and suggest intact postsynaptic Htr1a function in SERT -/- mice.
Fox
Meredith A
MA
Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. mfox@mail.nih.gov
Jensen
Catherine L
CL
Gallagher
Pamela S
PS
Murphy
Dennis L
DL
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D020230:Serotonin Syndrome / Q000523:psychology; D014191:Tranylcypromine / Q000494:pharmacology
D008996:Monoamine Oxidase Inhibitors; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; C066169:alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol; D014191:Tranylcypromine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006916:5-Hydroxytryptophan