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Fentanyl-induced changes in brain activity in awake nonhuman primates at 9.4 Tesla

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Abstract

Functional magnetic resonance imaging (fMRI) has been used to study the influence of opioids on neural circuitry implicated in opioid use disorder, such as the cortico-striatal-thalamo-cortical (CSTC) circuit. Given the increase in fentanyl-related deaths, this study was conducted to characterize the effects of fentanyl on patterns of brain activation in awake nonhuman primates. Four squirrel monkeys were acclimated to awake scanning procedures conducted at 9.4 Tesla. Subsequently, test sessions were conducted in which a dose of fentanyl that reliably maintains intravenous (IV) self-administration behavior in monkeys, 1 μg/kg, was administered and the effects on patterns of brain activity were assessed using: (1) a pharmacological regressor to elucidate fentanyl-induced patterns of neural activity, and (2) seed-based approaches targeting bilateral anterior cingulate, thalamus, or nucleus accumbens (NAc) to determine alterations in CSTC functional connectivity. Results showed a functional inhibition of BOLD signal in brain regions that mediate behavioral effects of opioid agonists, such as cingulate cortex, striatum and midbrain. Functional connectivity between each of the seed regions and areas involved in motoric, sensory and cognition-related behavior generally decreased. In contrast, NAc functional connectivity with other striatal regions increased. These results indicate that fentanyl produces changes within CSTC circuitry that may reflect key features of opioid use disorder (e.g. persistent drug-taking/seeking) and thereby contribute to long-term disruptions in behavior and addiction. They also indicate that fMRI in alert nonhuman primates can detect drug-induced changes in neural circuits and, in turn, may be useful for investigating the effectiveness of medications to reverse drug-induced dysregulation.

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Acknowledgments

The authors would like to thank Dr. Walid Yassine for his valuable input and thoughtful discussions during manuscript preparation.

Funding

This work was supported by a Pathways Research Awards® grant, an independent competitive grants program sponsored by Alkermes, Inc. and NIDA/NIH grants K01 DA039306, T32DA015036, and R01 DA047130.

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Authors and Affiliations

  1. Behavioral Biology Program, McLean Hospital - Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA

    Sarah L. Withey, Fernando B. de Moura, Jack Bergman & Stephen J. Kohut

  2. Behavioral Neuroimaging Laboratory, McLean Hospital - Harvard Medical School, Belmont, MA, USA

    Lei Cao, Fernando B. de Moura & Stephen J. Kohut

  3. McLean Imaging Center, McLean Hospital - Harvard Medical School, Belmont, MA, USA

    Lei Cao, Fernando B. de Moura, Kenroy R. Cayetano, Michael L. Rohan & Stephen J. Kohut

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Author contributions included conception and study design (SLW, JB and SJK), data collection or acquisition (SLW, FBM, KRC and MLR), statistical analysis (SLW, LC and SJK), interpretation of results.

(SLW and SJK), drafting the manuscript or revising it critically for important intellectual content (SLW, LC, FBM, JB and SJK) and approval of final version to be published and agreement to be accountable for the integrity and accuracy of all aspects of the work (All authors).

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Correspondence to Sarah L. Withey.

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The experimental protocol was approved by the Institutional Animal Care and Use Committee at McLean Hospital in a facility licensed by the US Department of Agriculture and in accordance with guidelines provided by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animals Resources, Commission on Life Sciences.

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Withey, S.L., Cao, L., de Moura, F.B. et al. Fentanyl-induced changes in brain activity in awake nonhuman primates at 9.4 Tesla. Brain Imaging and Behavior 16, 1684–1694 (2022). https://doi.org/10.1007/s11682-022-00639-4

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