title: Antipsychotic drugs up-regulate tryptophan hydroxylase in ADF neurons of Caenorhabditis elegans: role of calcium-calmodulin-dependent protein kinase II and transient receptor potential vanilloid channel.
abstract: Antipsychotic drugs produce acute behavioral effects through antagonism of dopamine and serotonin receptors, and long-term adaptive responses that are not well understood. The goal of the study presented here was to use Caenorhabditis elegans to investigate the molecular mechanism or mechanisms that contribute to adaptive responses produced by antipsychotic drugs. First-generation antipsychotics, trifluoperazine and fluphenazine, and second-generation drugs, clozapine and olanzapine, increased the expression of tryptophan hydroxylase-1::green fluorescent protein (TPH-1::GFP) and serotonin in the ADF neurons of C. elegans. This response was absent or diminished in mutant strains lacking the transient receptor potential vanilloid channel (TRPV; osm-9) or calcium/calmodulin-dependent protein kinase II (CaMKII; unc-43). The role of calcium signaling was further implicated by the finding that a selective antagonist of calmodulin and a calcineurin inhibitor also enhanced TPH-1::GFP expression. The ADF neurons modulate foraging behavior (turns/reversals off food) through serotonin production. We found that short-term exposure to the antipsychotic drugs altered the frequency of turns/reversals off food. This response was mediated through dopamine and serotonin receptors and was abolished in serotonin-deficient mutants (tph-1) and strains lacking the SER-1 and MOD-1 serotonin receptors. Consistent with the increase in serotonin in the ADF neurons induced by the drugs, drug withdrawal after 24-hr treatment was accompanied by a rebound in the number of turns/reversals, which demonstrates behavioral adaptation in serotonergic systems. Characterization of the cellular, molecular, and behavioral adaptations to continuous exposure to antipsychotic drugs may provide insight into the long-term clinical effects of these medications.
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana 71130, USA.
authors.forename: Dallas R
authors.initials: DR
authors.lastname: Donohoe
authors.forename: Thang
authors.initials: T
authors.lastname: Phan
authors.forename: Kathrine
authors.initials: K
authors.lastname: Weeks
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Aamodt
authors.forename: Donard S
authors.initials: DS
authors.lastname: Dwyer
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D030801:Animals, Genetically Modified; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000187:drug effects / Q000378:metabolism*; D018118:Chloride Channels / Q000096:biosynthesis / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology; D005476:Fluphenazine / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D000077152:Olanzapine; D044348:Receptors, Serotonin, 5-HT2 / Q000096:biosynthesis / Q000187:drug effects; D012701:Serotonin / Q000096:biosynthesis; D050916:TRPV Cation Channels / Q000187:drug effects / Q000378:metabolism*; D014268:Trifluoperazine / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000096:biosynthesis / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D014150:Antipsychotic Agents; D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels; C417030:MOD-1 protein, C elegans; D044348:Receptors, Serotonin, 5-HT2; C515315:SER-1 protein, C elegans; D050916:TRPV Cation Channels; D001569:Benzodiazepines; D014268:Trifluoperazine; D012701:Serotonin; D014365:Tryptophan Hydroxylase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003024:Clozapine; D000077152:Olanzapine; D005476:Fluphenazine