Cargando…

Initial Evaluations of the Microtubule-Based PET Radiotracer, [(11)C]MPC-6827 in a Rodent Model of Cocaine Abuse

PURPOSE: Microtubules (MTs) are structural units made of α and β tubulin subunits in the cytoskeleton responsible for axonal transport, information processing, and signaling mechanisms—critical for healthy brain function. Chronic cocaine exposure affects the function, organization, and stability of...

Descripción completa

Detalles Bibliográficos
Autores principales: Damuka, Naresh, Martin, Thomas J., Bansode, Avinash H., Krizan, Ivan, Martin, Conner W., Miller, Mack, Whitlow, Christopher T., Nader, Michael A., Solingapuram Sai, Kiran Kumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8918945/
https://www.ncbi.nlm.nih.gov/pubmed/35295607
http://dx.doi.org/10.3389/fmed.2022.817274
_version_ 1784668839811743744
author Damuka, Naresh
Martin, Thomas J.
Bansode, Avinash H.
Krizan, Ivan
Martin, Conner W.
Miller, Mack
Whitlow, Christopher T.
Nader, Michael A.
Solingapuram Sai, Kiran Kumar
author_facet Damuka, Naresh
Martin, Thomas J.
Bansode, Avinash H.
Krizan, Ivan
Martin, Conner W.
Miller, Mack
Whitlow, Christopher T.
Nader, Michael A.
Solingapuram Sai, Kiran Kumar
author_sort Damuka, Naresh
collection PubMed
description PURPOSE: Microtubules (MTs) are structural units made of α and β tubulin subunits in the cytoskeleton responsible for axonal transport, information processing, and signaling mechanisms—critical for healthy brain function. Chronic cocaine exposure affects the function, organization, and stability of MTs in the brain, thereby impairing overall neurochemical and cognitive processes. At present, we have no reliable, non-invasive methods to image MTs for cocaine use disorder (CUD). Recently we reported the effect of cocaine in patient-derived neuroblastoma SH-SY5Y cells. Here we report preliminary results of a potential imaging biomarker of CUD using the brain penetrant MT-based radiotracer, [(11)C]MPC-6827, in an established rodent model of cocaine self-administration (SA). METHODS: Cell uptake studies were performed with [(11)C]MPC-6827 in SH-SY5Y cells, treated with or without cocaine (n = 6/group) at 30 and 60 min incubations. MicroPET/CT brain scans were performed in rats at baseline and 35 days after cocaine self-administration and compared with saline-treated rats as controls (n = 4/sex). Whole-body post-PET biodistribution, plasma metabolite assay, and brain autoradiography were performed in the same rats from imaging. RESULTS: Cocaine-treated SH-SY5Y cells demonstrated a ∼26(±4)% decrease in radioactive uptake compared to non-treated controls. Both microPET/CT imaging and biodistribution results showed lower (∼35 ± 3%) [(11)C]MPC-6827 brain uptake in rats that had a history of cocaine self-administration compared to the saline-treated controls. Plasma metabolite assays demonstrate the stability (≥95%) of the radiotracer in both groups. In vitro autoradiography also demonstrated lower radioactive uptake in cocaine rats compared to the control rats. [(11)C]MPC-6827’s in vitro SH-SY5Y neuronal cell uptake, in vivo positron emission tomography (PET) imaging, ex vivo biodistribution, and in vitro autoradiography results corroborated well with each other, demonstrating decreased radioactive brain uptake in cocaine self-administered rats versus controls. There were no significant differences either in cocaine intake or in [(11)C]MPC-6827 uptake between the male and female rats. CONCLUSIONS: This project is the first to validate in vivo imaging of the MT-associations with CUD in a rodent model. Our initial observations suggest that [(11)C]MPC-6827 uptake decreases in cocaine self-administered rats and that it may selectively bind to destabilized tubulin units in the brain. Further longitudinal studies correlating cocaine intake with [(11)C]MPC-6827 PET brain measures could potentially establish the MT scaffold as an imaging biomarker for CUD, providing researchers and clinicians with a sensitive tool to better understand the biological underpinnings of CUD and tailor new treatments.
format Online
Article
Text
id pubmed-8918945
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-89189452022-03-15 Initial Evaluations of the Microtubule-Based PET Radiotracer, [(11)C]MPC-6827 in a Rodent Model of Cocaine Abuse Damuka, Naresh Martin, Thomas J. Bansode, Avinash H. Krizan, Ivan Martin, Conner W. Miller, Mack Whitlow, Christopher T. Nader, Michael A. Solingapuram Sai, Kiran Kumar Front Med (Lausanne) Medicine PURPOSE: Microtubules (MTs) are structural units made of α and β tubulin subunits in the cytoskeleton responsible for axonal transport, information processing, and signaling mechanisms—critical for healthy brain function. Chronic cocaine exposure affects the function, organization, and stability of MTs in the brain, thereby impairing overall neurochemical and cognitive processes. At present, we have no reliable, non-invasive methods to image MTs for cocaine use disorder (CUD). Recently we reported the effect of cocaine in patient-derived neuroblastoma SH-SY5Y cells. Here we report preliminary results of a potential imaging biomarker of CUD using the brain penetrant MT-based radiotracer, [(11)C]MPC-6827, in an established rodent model of cocaine self-administration (SA). METHODS: Cell uptake studies were performed with [(11)C]MPC-6827 in SH-SY5Y cells, treated with or without cocaine (n = 6/group) at 30 and 60 min incubations. MicroPET/CT brain scans were performed in rats at baseline and 35 days after cocaine self-administration and compared with saline-treated rats as controls (n = 4/sex). Whole-body post-PET biodistribution, plasma metabolite assay, and brain autoradiography were performed in the same rats from imaging. RESULTS: Cocaine-treated SH-SY5Y cells demonstrated a ∼26(±4)% decrease in radioactive uptake compared to non-treated controls. Both microPET/CT imaging and biodistribution results showed lower (∼35 ± 3%) [(11)C]MPC-6827 brain uptake in rats that had a history of cocaine self-administration compared to the saline-treated controls. Plasma metabolite assays demonstrate the stability (≥95%) of the radiotracer in both groups. In vitro autoradiography also demonstrated lower radioactive uptake in cocaine rats compared to the control rats. [(11)C]MPC-6827’s in vitro SH-SY5Y neuronal cell uptake, in vivo positron emission tomography (PET) imaging, ex vivo biodistribution, and in vitro autoradiography results corroborated well with each other, demonstrating decreased radioactive brain uptake in cocaine self-administered rats versus controls. There were no significant differences either in cocaine intake or in [(11)C]MPC-6827 uptake between the male and female rats. CONCLUSIONS: This project is the first to validate in vivo imaging of the MT-associations with CUD in a rodent model. Our initial observations suggest that [(11)C]MPC-6827 uptake decreases in cocaine self-administered rats and that it may selectively bind to destabilized tubulin units in the brain. Further longitudinal studies correlating cocaine intake with [(11)C]MPC-6827 PET brain measures could potentially establish the MT scaffold as an imaging biomarker for CUD, providing researchers and clinicians with a sensitive tool to better understand the biological underpinnings of CUD and tailor new treatments. Frontiers Media S.A. 2022-02-28 /pmc/articles/PMC8918945/ /pubmed/35295607 http://dx.doi.org/10.3389/fmed.2022.817274 Text en Copyright © 2022 Damuka, Martin, Bansode, Krizan, Martin, Miller, Whitlow, Nader and Solingapuram Sai. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Damuka, Naresh
Martin, Thomas J.
Bansode, Avinash H.
Krizan, Ivan
Martin, Conner W.
Miller, Mack
Whitlow, Christopher T.
Nader, Michael A.
Solingapuram Sai, Kiran Kumar
Initial Evaluations of the Microtubule-Based PET Radiotracer, [(11)C]MPC-6827 in a Rodent Model of Cocaine Abuse
title Initial Evaluations of the Microtubule-Based PET Radiotracer, [(11)C]MPC-6827 in a Rodent Model of Cocaine Abuse
title_full Initial Evaluations of the Microtubule-Based PET Radiotracer, [(11)C]MPC-6827 in a Rodent Model of Cocaine Abuse
title_fullStr Initial Evaluations of the Microtubule-Based PET Radiotracer, [(11)C]MPC-6827 in a Rodent Model of Cocaine Abuse
title_full_unstemmed Initial Evaluations of the Microtubule-Based PET Radiotracer, [(11)C]MPC-6827 in a Rodent Model of Cocaine Abuse
title_short Initial Evaluations of the Microtubule-Based PET Radiotracer, [(11)C]MPC-6827 in a Rodent Model of Cocaine Abuse
title_sort initial evaluations of the microtubule-based pet radiotracer, [(11)c]mpc-6827 in a rodent model of cocaine abuse
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8918945/
https://www.ncbi.nlm.nih.gov/pubmed/35295607
http://dx.doi.org/10.3389/fmed.2022.817274
work_keys_str_mv AT damukanaresh initialevaluationsofthemicrotubulebasedpetradiotracer11cmpc6827inarodentmodelofcocaineabuse
AT martinthomasj initialevaluationsofthemicrotubulebasedpetradiotracer11cmpc6827inarodentmodelofcocaineabuse
AT bansodeavinashh initialevaluationsofthemicrotubulebasedpetradiotracer11cmpc6827inarodentmodelofcocaineabuse
AT krizanivan initialevaluationsofthemicrotubulebasedpetradiotracer11cmpc6827inarodentmodelofcocaineabuse
AT martinconnerw initialevaluationsofthemicrotubulebasedpetradiotracer11cmpc6827inarodentmodelofcocaineabuse
AT millermack initialevaluationsofthemicrotubulebasedpetradiotracer11cmpc6827inarodentmodelofcocaineabuse
AT whitlowchristophert initialevaluationsofthemicrotubulebasedpetradiotracer11cmpc6827inarodentmodelofcocaineabuse
AT nadermichaela initialevaluationsofthemicrotubulebasedpetradiotracer11cmpc6827inarodentmodelofcocaineabuse
AT solingapuramsaikirankumar initialevaluationsofthemicrotubulebasedpetradiotracer11cmpc6827inarodentmodelofcocaineabuse