In This Issue pubs.acs.org/chemneuro
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OLD DRUGS, NEW TRICKS
target interactions, as well as biodistribution in vivo. Traditionally, this has been best accomplished through the employment of positron emission tomography (PET) radioligands, wherein positron emitting nuclides such as [11C] or [18F] are employed to enable measurement of ligand−receptor engagement. Here, Wager and co-workers (DOI: 10.1021/acschemneuro.7b00155) detail efforts to rationally design a CNS radioligand for engagement of the casein kinase 1 delta/epsilon (CK1δ/ε). The authors employ a set of stringent physicochemical properties in the target molecule imposing criteria determined from previous multiparameter optimization and PET ligand studies. Starting with known CK1δ/ε inhibitor hits as lead compounds, the authors develop a tritiated tool ligand that meets most of their preset criteria for CNS PET compounds.
Major depressive disorder (MDD) is a common neuropsychiatric disorder affecting nearly 7% of the population. It is hypothesized that deregulation of neural plasticity, which contributes to the generation of new neurons in the adult hippocampus that modulate mood and stress response, is one of the underlying causes of MDD. Antidepressant drugs can increase hippocampal neurogenesis in rodents and primates, which may contribute to their therapeutic effects. However, as various antidepressants interact with different receptors, the underlying mechanisms of how these interactions mediate hippocampal neurogenesis is not well-known. In this issue, Bortolotto et al. (DOI: 10.1021/acschemneuro.7b00175) explore the effects of the antidepressant trazodone on both murine and human neural progenitor cells (NPCs). Trazodone is distinctive from other classes of antidepressants in that it simultaneously interacts with multiple serotoninergic receptors, including 5-HT2a, 5-HT2c, 5-HT1a, and 5-HTT, as well as the α1- and α2-adrenergic receptors. The authors discovered that trazodone has significant proneurogenic effects that rely on its antagonism at 5-HT2 receptors. Moreover, trazodone antagonism of different serotoninergic receptors produced different effects in rodent versus human NPCs. In summary, a new pharmacological activity has been identified for this decadesold therapeutic.
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Zebrafish have recently gained prominence as a valuable model organism for studying neuronal function. Zebrafish more accurately mirror the human CNS than invertebrates yet are easier to work with than rodents. Specifically, zebrafish are beginning to emerge as useful model organisms for performing fast-scan cyclic voltammetry (FSCV) measurements of release and uptake of neurotransmitters. Previously, these measurements were conducted with brain slices harvested from zebrafish, which can be limited by potential cellular damage induced at the surface of the slice as well as incomplete neuronal pathways. In this issue, Shin and co-workers (DOI: 10.1021/acschemneuro.7b00022) use whole, intact zebrafish brains to measure dopamine uptake and release ex vivo using FSCV. These measurements supported previous data on dopamine release from slices, validating the use of whole brains for measurements. Moreover, whole brain measurements also revealed important differences from previous data collected from slices: the effects of stimulation frequency on dopamine release are markedly different between the two sample types, as are the responses of D2 dopamine autoreceptors to anatagonist treatment. Importantly, the authors have expanded the use of the zebrafish model organism to allow for in-depth analysis of neurotransmitter release.
CRITERIA FOR DEVELOPMENT OF NOVEL PET LIGANDS
In the development of new pharmacological ligands for CNS targets, it is crucial to effectively measure target engagement to determine binding affinity, selectivity, and nonspecific or off© 2017 American Chemical Society
ZEBRAFISH MODEL ORGANISMS: NEW INFO FROM WHOLE BRAINS
Published: September 20, 2017 1814
DOI: 10.1021/acschemneuro.7b00339 ACS Chem. Neurosci. 2017, 8, 1814−1814
