title: Reversal of pentylenetetrazole-altered swimming and neural activity-regulated gene expression in zebrafish larvae by valproic acid and valerian extract.
abstract: Ethnopharmacology has documented hundreds of psychoactive plants awaiting exploitation for drug discovery. A robust and inexpensive in vivo system allowing systematic screening would be critical to exploiting this knowledge.
  
  
  
  The objective of this study was to establish a cheap and accurate screening method which can be used for testing psychoactive efficacy of complex mixtures of unknown composition, like plant crude extracts.
  
  
  
  We used automated recording of zebrafish larval swimming behavior during light vs. dark periods which we reproducibly altered with an anxiogenic compound, pentylenetetrazole (PTZ). First, we reversed this PTZ-altered swimming by co-treatment with a well-defined synthetic anxiolytic drug, valproic acid (VPA). Next, we aimed at reversing it by adding crude root extracts of Valeriana officinalis (Val) from which VPA was originally derived. Finally, we assessed how expression of neural activity-regulated genes (c-fos, npas4a, and bdnf) known to be upregulated by PTZ treatment was affected in the presence of Val.
  
  
  
  Both VPA and Val significantly reversed the PTZ-altered swimming behaviors. Noticeably, Val at higher doses was affecting swimming independently of the presence of PTZ. A strong regulation of all three neural-activity genes was observed in Val-treated larvae which fully supported the behavioral results.
  
  
  
  We demonstrated in a combined behavioral-molecular approach the strong psychoactivity of a natural extract of unknown composition made from V. officinalis. Our results highlight the efficacy and sensitivity of such an approach, therefore offering a novel in vivo screening system amenable to high-throughput testing of promising ethnobotanical candidates.
authors.affiliation: School of Medicine, Department of Pharmacology and Toxicology, Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA.
authors.forename: Bianca A
authors.initials: BA
authors.lastname: Torres-Hernández
authors.affiliation: School of Medicine, Department of Anatomy and Neurobiology, Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA.
authors.forename: Luis R
authors.initials: LR
authors.lastname: Colón
authors.affiliation: School of Medicine, Department of Pharmacology and Toxicology, Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA.
authors.forename: Coral
authors.initials: C
authors.lastname: Rosa-Falero
authors.affiliation: School of Medicine, Department of Anatomy and Neurobiology, Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA.
authors.forename: Aranza
authors.initials: A
authors.lastname: Torrado
authors.affiliation: School of Medicine, Department of Anatomy and Neurobiology, Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA.
authors.forename: Nahira
authors.initials: N
authors.lastname: Miscalichi
authors.affiliation: School of Medicine, Department of Pharmacology and Toxicology, Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA.
authors.forename: José G
authors.initials: JG
authors.lastname: Ortíz
authors.affiliation: Puerto Rico Clinical and Translational Research Consortium (PRCTRC), Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA.
authors.forename: Lorena
authors.initials: L
authors.lastname: González-Sepúlveda
authors.affiliation: Puerto Rico Clinical and Translational Research Consortium (PRCTRC), Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA.
authors.forename: Naydi
authors.initials: N
authors.lastname: Pérez-Ríos
authors.affiliation: Puerto Rico Clinical and Translational Research Consortium (PRCTRC), Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA.
authors.forename: Erick
authors.initials: E
authors.lastname: Suárez-Pérez
authors.affiliation: School of Medicine, Department of Anatomy and Neurobiology, Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Bradsher
authors.affiliation: School of Medicine, Department of Anatomy and Neurobiology, Medical Science Campus of the University of Puerto Rico (MCS-UPR), San Juan, PR, USA. martine.behra@upr.edu.
authors.forename: Martine
authors.initials: M
authors.lastname: Behra
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D018692:Antimanic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007814:Larva; D010433:Pentylenetetrazole / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013550:Swimming / Q000502:physiology*; D014632:Valerian; D014635:Valproic Acid / Q000494:pharmacology*; D015027:Zebrafish / Q000502:physiology
chemical_list: D014151:Anti-Anxiety Agents; D018692:Antimanic Agents; D015415:Biomarkers; D006993:Hypnotics and Sedatives; D010936:Plant Extracts; D016760:Proto-Oncogene Proteins c-fos; D014635:Valproic Acid; D010433:Pentylenetetrazole
keywords: Crude extracts; Ethnobotany; In vivo high-throughput psychoactivity screening; Psychoactive plants; Valerian; Zebrafish larva behavior; bdnf; c-fos; npas4a