Visiting Investigators

Permanent URI for this collection

https://hdl.handle.net/1912/116

Scores of distinguished biologists from around the world come to the MBL to collaborate and conduct research. They use marine and other organisms as model systems for their research.

These researchers participate in a number of established MBL groups including but not limited to:

  • MBL Summer Research Fellows
  • Dart Scholars
  • Grass Faculty Awardees
  • NeuroImaging Cluster
  • Grass Fellows
  • Whitman Center

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Browsing Visiting Investigators by Subject "Addiction"
  • Article
    Evaluation of an image-derived input function for kinetic modeling of nicotinic acetylcholine receptor-binding PET ligands in mice
    (MDPI, 2023-10-24) Zammit, Matthew ; Kao, Chien-Min ; Zhang, Hannah J. ; Tsai, Hsiu-Ming ; Holderman, Nathanial ; Mitchell, Samuel ; Tanios, Eve ; Bhuiyan, Mohammed ; Freifelder, Richard ; Kucharski, Anna ; Green, William N. ; Mukherjee, Jogeshwar ; Chen, Chin-Tu
    Positron emission tomography (PET) radioligands that bind with high-affinity to α4β2-type nicotinic receptors (α4β2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and the cerebellum for kinetic analysis of radioligand binding in mice. Two radioligands were explored: 2-[18F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [18F]Nifene, displaying similar pKa and binding affinity to nicotine. Time–activity curves of the left ventricle of the heart displayed similar distribution across wild type mice, mice lacking the β2-subunit for ligand binding, and acute nicotine-treated mice, whereas reference tissue binding displayed high variation between groups. Binding potential estimated from a two-tissue compartment model fit of the data with the image-derived input function were higher than estimates from reference tissue-based estimations. Rate constants of radioligand dissociation were very slow for 2-FA and very fast for Nifene. We conclude that using an image-derived input function for kinetic modeling of nicotinic PET ligands provides suitable results compared to reference tissue-based methods and that the chemical properties of 2-FA and Nifene are suitable to study receptor response to nicotine addiction and smoking cessation therapies.
  • Article
    Trapping of nicotinic acetylcholine receptor ligands assayed by in vitro cellular studies and in vivo PET imaging
    (Society for Neuroscience, 2023-01-04) Zhang, Hannah J. ; Zammit, Matthew ; Kao, Chien-Min ; Govind, Anitha P. ; Mitchell, Samuel J. ; Holderman, Nathanial ; Bhuiyan, Mohammed ; Freifelder, Richard ; Kucharski, Anna ; Zhuang, Xiaoxi ; Mukherjee, Jogeshwar ; Chen, Chin-Tu ; Green, William N.
    A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in brain. Ligands, like varenicline, with high pKa and high affinity for α4β2-type nicotinic receptors (α4β2Rs) are trapped in intracellular acidic vesicles containing α4β2Rs in vitro. Nicotine, with lower pKa and α4β2R affinity, is not trapped. Here, we extend our results by imaging nicotinic PET ligands in vivo in male and female mouse brain and identifying the trapping brain organelle in vitro as Golgi satellites (GSats). Two PET 18F-labeled imaging ligands were chosen: [18F]2-FA85380 (2-FA) with varenicline-like pKa and affinity and [18F]Nifene with nicotine-like pKa and affinity. [18F]2-FA PET-imaging kinetics were very slow consistent with 2-FA trapping in α4β2R-containing GSats. In contrast, [18F]Nifene kinetics were rapid, consistent with its binding to α4β2Rs but no trapping. Specific [18F]2-FA and [18F]Nifene signals were eliminated in β2 subunit knock-out (KO) mice or by acute nicotine (AN) injections demonstrating binding to sites on β2-containing receptors. Chloroquine (CQ), which dissipates GSat pH gradients, reduced [18F]2-FA distributions while having little effect on [18F]Nifene distributions in vivo consistent with only [18F]2-FA trapping in GSats. These results are further supported by in vitro findings where dissipation of GSat pH gradients blocks 2-FA trapping in GSats without affecting Nifene. By combining in vitro and in vivo imaging, we mapped both the brain-wide and subcellular distributions of weak-base nicotinic receptor ligands. We conclude that ligands, such as varenicline, are trapped in neurons in α4β2R-containing GSats, which results in very slow release long after nicotine is gone after smoking.