Psychostimulants differentially regulate serotonin transporter expression in thalamocortical neurons.
5-HT transporters (SERTs) are transiently expressed in thalamocortical neurons during development, permitting these glutamatergic neurons to co-release 5-HT as a "borrowed" transmitter. The high level of SERT expression in these neurons is likely important in the serotonergic modulation of neocortical circuits and provides a system for examining endogenous SERT regulation. We tested the hypothesis that developmental expression of SERT in thalamocortical neurons is regulated by psychostimulants that are agonists and antagonists of SERT. Cultured thalamocortical neurons from embryonic day 18 rats were examined for SERT expression until P15. In untreated cultures, SERT protein levels peaked at postnatal day 3 (P3) and were absent by P10. Chronic treatment with SERT substrates (5-HT, 3,4-methylenedioxymethamphetamine) increased both peak SERT protein levels (fourfold) and the time course of SERT expression. SERT substrates also shifted the relative functional expression of SERT by redistributing intracellular SERT protein to the plasma membrane. The subcellular redistribution was prevented by PKC activators. SERT antagonists (e.g., fluoxetine, cocaine) reduced total SERT expression levels and the time course of SERT expression. These data (1) show that endogenous SERT is differentially regulated by 5-HT and psychostimulants, (2) indicate that SERT modulation occurs via changes in both total SERT protein levels and subcellular redistribution of the transporter, and (3) suggest that some of the actions of drugs of abuse in neocortical development may be attributable to alterations in SERT expression and concomitant changes in 5-HT signaling.
Whitworth
Terri L
TL
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Herndon
Laura C
LC
Quick
Michael W
MW
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006213:Hallucinogens / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008856:Microscopy, Fluorescence; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013788:Thalamus / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D013997:Time Factors
D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D020536:Enzyme Activators; D006213:Hallucinogens; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; C493232:Slc6a4 protein, rat; D012701:Serotonin; D018817:N-Methyl-3,4-methylenedioxyamphetamine