Journal Article

Drosophila modifier screens to identify novel neuropsychiatric drugs including aminergic agents for the possible treatment of Parkinson’s disease and depression

Lawless, G M, Maidment, N T, Lam, H A, Shahi, V, Chou, M-T, Huang, B, Jang, J, Hadi, R, Biedermann, T, Krantz, D E, Terrell, A, Lawal, H O, Roberts, L, Djapri, C

2014

Overview

Small molecules that increase the presynaptic function of aminergic cells may provide neuroprotection in Parkinson’s disease (PD) as well as treatments for attention deficit hyperactivity disorder (ADHD) and depression. Model genetic organisms such as Drosophila melanogaster may enhance the detection of new drugs via modifier or ‘enhancer/suppressor’ screens, but this technique has not been applied to processes relevant to psychiatry. To identify new aminergic drugs in vivo , we used a mutation in the Drosophila vesicular monoamine transporter ( dVMAT ) as a sensitized genetic background and performed a suppressor screen. We fed dVMAT mutant larvae ∼1000 known drugs and quantitated rescue (suppression) of an amine-dependent locomotor deficit in the larva. To determine which drugs might specifically potentiate neurotransmitter release, we performed an additional secondary screen for drugs that require presynaptic amine storage to rescue larval locomotion. Using additional larval locomotion and adult fertility assays, we validated that at least one compound previously used clinically as an antineoplastic agent potentiates the presynaptic function of aminergic circuits. We suggest that structurally similar agents might be used to development treatments for PD, depression and ADHD, and that modifier screens in Drosophila provide a new strategy to screen for neuropsychiatric drugs. More generally, our findings demonstrate the power of physiologically based screens for identifying bioactive agents for select neurotransmitter systems.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/1435 / 631/92/609 / 692/699/375/365/1718 / 692/699/476/1414 / Adult and adolescent clinical studies / Animals / Animals, Genetically Modified / Antiparkinson Agents - pharmacology / Antipsychotic drugs / Attention deficit disorders. Hyperactivity / Attention deficit hyperactivity disorder / Behavioral Sciences / Biological and medical sciences / Biological Psychology / Child clinical studies / Dacarbazine - pharmacology / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Depression, Mental / Disease / Drosophila / Drosophila melanogaster / Drosophila Proteins - genetics / Drosophila Proteins - metabolism / Drug Evaluation, Preclinical - methods / Drug therapy / Drugs / Female / Fertility / Fertility - drug effects / Food / General aspects / Insects / Larva - drug effects / Larva - physiology / Locomotion / Locomotion - drug effects / Locomotion - physiology / Male / Medical sciences / Medicine / Medicine & Public Health / Mental depression / Movement disorders / Mutation / Neurodegenerative diseases / Neurology / Neuroprotection / Neurosciences / Neurotoxicity / Neurotransmitter release / Organic mental disorders. Neuropsychology / original-article / Parkinson Disease - drug therapy / Parkinson's disease / Pergolide - pharmacology / Pharmaceutical research / Pharmacotherapy / Proteins / Psychiatry / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Psychotropic drugs / Synapses - drug effects / Syrups & sweeteners / Vesicular Monoamine Transport Proteins - genetics / Vesicular Monoamine Transport Proteins - metabolism / Vesicular monoamine transporter