Molecular genetic responses to lysergic acid diethylamide include transcriptional activation of MAP kinase phosphatase-1, C/EBP-beta and ILAD-1, a novel gene with homology to arrestins.
We recently demonstrated that the potent hallucinogenic drug lysergic acid diethylamide (LSD) dynamically influences the expression of a small collection of genes within the mammalian prefrontal cortex. Towards generating a greater understanding of the molecular genetic effects of hallucinogens and how they may relate to alterations in behavior, we have identified and characterized expression patterns of a new collection of three genes increased in expression by acute LSD administration. These genes were identified through additional screens of Affymetrix DNA microarrays and examined in experiments to assess dose-response, time course and the receptor mediating the expression changes. The first induced gene, C/EBP-beta, is a transcription factor. The second gene, MKP-1, suggests that LSD activates the MAP (mitogen activated protein) kinase pathway. The third gene, ILAD-1, demonstrates sequence similarity to the arrestins. The increase in expression of each gene was partially mediated through LSD interactions at 5-HT2A (serotonin) receptors. There is evidence of alternative splicing at the ILAD-1 locus. Furthermore, data suggests that various splice isoforms of ILAD-1 respond differently at the transcriptional level to LSD. The genes thus far found to be responsive to LSD are beginning to give a more complete picture of the complex intracellular events initiated by hallucinogens.
Nichols
Charles D
CD
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. Charles.Nicols@vanderbilt.edu
Sanders-Bush
Elaine
E
D000818:Animals; D019390:Arrestins / Q000235:genetics*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics*; D018797:Cell Cycle Proteins; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006213:Hallucinogens / Q000494:pharmacology*; D017874:Immediate-Early Proteins / Q000235:genetics*; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010749:Phosphoprotein Phosphatases; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics
C489250:Arrdc2 protein, rat; D019390:Arrestins; D022782:CCAAT-Enhancer-Binding Protein-beta; D018797:Cell Cycle Proteins; D006213:Hallucinogens; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D008238:Lysergic Acid Diethylamide; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases