Assessment of transient dopamine responses to smoked cannabis

Katina C Calakos; Heather Liu; Yihuan Lu; Jon Mikael Anderson; David Matuskey; Nabeel Nabulsi; Yunpeng Ye; Patrick D Skosnik; Deepak Cyril D'Souza; Evan D Morris; Kelly P Cosgrove; Ansel T Hillmer

doi:10.1016/j.drugalcdep.2021.108920

Assessment of transient dopamine responses to smoked cannabis

Drug Alcohol Depend. 2021 Oct 1:227:108920. doi: 10.1016/j.drugalcdep.2021.108920. Epub 2021 Jul 29.

Authors

Affiliations

¹ Department of Psychiatry, Yale School of Medicine, 300 George Street, New Haven, CT, 06511, United States; Interdepartmental Neuroscience Program, Yale University, 333 Cedar Street, New Haven, CT, 06510, United States. Electronic address: katina.calakos@yale.edu.
² Department of Biomedical Engineering, Yale University, 17 Hillhouse Avenue, New Haven, CT, 06511, United States. Electronic address: heather.liu@yale.edu.
³ Department of Radiology and Biomedical Imaging, Yale School of Medicine, 330 Cedar Street, New Haven, CT, 06519, United States; Yale PET Center, Yale University, 801 Howard Avenue, New Haven, CT, 06510, United States. Electronic address: yihuan.lu@yale.edu.
⁴ Department of Psychiatry, Yale School of Medicine, 300 George Street, New Haven, CT, 06511, United States. Electronic address: jonmikael.anderson@yale.edu.
⁵ Department of Psychiatry, Yale School of Medicine, 300 George Street, New Haven, CT, 06511, United States; Department of Radiology and Biomedical Imaging, Yale School of Medicine, 330 Cedar Street, New Haven, CT, 06519, United States; Yale PET Center, Yale University, 801 Howard Avenue, New Haven, CT, 06510, United States; Department of Neurology, Yale School of Medicine, 800 Howard Avenue, New Haven, CT, 06519, United States. Electronic address: david.matuskey@yale.edu.
⁶ Department of Radiology and Biomedical Imaging, Yale School of Medicine, 330 Cedar Street, New Haven, CT, 06519, United States; Yale PET Center, Yale University, 801 Howard Avenue, New Haven, CT, 06510, United States. Electronic address: nabeel.nabulsi@yale.edu.
⁷ Department of Radiology and Biomedical Imaging, Yale School of Medicine, 330 Cedar Street, New Haven, CT, 06519, United States; Yale PET Center, Yale University, 801 Howard Avenue, New Haven, CT, 06510, United States. Electronic address: yunpeng.ye@yale.edu.
⁸ Department of Psychiatry, Yale School of Medicine, 300 George Street, New Haven, CT, 06511, United States; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, United States. Electronic address: patrick.skosnik@yale.edu.
⁹ Department of Psychiatry, Yale School of Medicine, 300 George Street, New Haven, CT, 06511, United States; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, 34 Park Street, New Haven, CT, 06519, United States. Electronic address: deepak.dsouza@yale.edu.
¹⁰ Department of Psychiatry, Yale School of Medicine, 300 George Street, New Haven, CT, 06511, United States; Interdepartmental Neuroscience Program, Yale University, 333 Cedar Street, New Haven, CT, 06510, United States; Department of Biomedical Engineering, Yale University, 17 Hillhouse Avenue, New Haven, CT, 06511, United States; Department of Radiology and Biomedical Imaging, Yale School of Medicine, 330 Cedar Street, New Haven, CT, 06519, United States; Yale PET Center, Yale University, 801 Howard Avenue, New Haven, CT, 06510, United States. Electronic address: evan.morris@yale.edu.
¹¹ Department of Psychiatry, Yale School of Medicine, 300 George Street, New Haven, CT, 06511, United States; Interdepartmental Neuroscience Program, Yale University, 333 Cedar Street, New Haven, CT, 06510, United States; Department of Radiology and Biomedical Imaging, Yale School of Medicine, 330 Cedar Street, New Haven, CT, 06519, United States; Department of Neuroscience, Yale University, 333 Cedar Street, New Haven, CT, 06510, United States. Electronic address: kelly.cosgrove@yale.edu.
¹² Department of Psychiatry, Yale School of Medicine, 300 George Street, New Haven, CT, 06511, United States; Department of Biomedical Engineering, Yale University, 17 Hillhouse Avenue, New Haven, CT, 06511, United States; Department of Radiology and Biomedical Imaging, Yale School of Medicine, 330 Cedar Street, New Haven, CT, 06519, United States; Yale PET Center, Yale University, 801 Howard Avenue, New Haven, CT, 06510, United States. Electronic address: ansel.hillmer@yale.edu.

Abstract

Background: Dopaminergic mechanisms that may underlie cannabis' reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the dopamine D_2/3 receptor antagonist [¹¹C]raclopride and kinetic modelling testing for transient changes in radiotracer uptake to assess the striatal dopamine response to smoked cannabis in a preliminary sample.

Methods: PET emission data were acquired from regular cannabis users (n = 14; 7 M/7 F; 19-32 years old) over 90 min immediately after [¹¹C]raclopride administration (584 ± 95 MBq) as bolus followed by constant infusion (K_bol = 105 min). Participants smoked a cannabis cigarette, using a paced puff protocol, 35 min after scan start. Plasma concentrations of Δ⁹-THC and metabolites and ratings of subjective "high" were collected during imaging. Striatal dopamine responses were assessed voxelwise with a kinetic model testing for transient reductions in [¹¹C]raclopride binding, linear-parametric neurotransmitter PET (lp-ntPET) (cerebellum as a reference region).

Results: Cannabis smoking increased plasma Δ⁹-THC levels (peak: 0-10 min) and subjective high (peak: 0-30 min). Significant clusters (>16 voxels) modeled by transient reductions in [¹¹C]raclopride binding were identified for all 12 analyzed scans. In total, 26 clusters of significant responses to cannabis were detected, of which 16 were located in the ventral striatum, including at least one ventral striatum cluster in 11 of the 12 analyzed scans.

Conclusions: These preliminary data support the sensitivity of [¹¹C]raclopride PET with analysis of transient changes in radiotracer uptake to detect cannabis smoking-induced dopamine responses. This approach shows future promise to further elucidate roles of mesolimbic dopaminergic signaling in chronic cannabis use. ClinicalTrials.gov Identifier: NCT02817698.

Keywords: Cannabis; Dopamine; PET; [(11)C]raclopride.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Cannabis*
Corpus Striatum / diagnostic imaging
Dopamine
Humans
Marijuana Smoking*
Positron-Emission Tomography
Raclopride
Ventral Striatum*
Young Adult

Assessment of transient dopamine responses to smoked cannabis

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