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TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc

Molecular Psychiatry volume 27, pages 2136–2145 (2022)Cite this article

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Abstract

Relapse remains a major challenge to the treatment of cocaine addiction. Recent studies suggested that the trace amine-associated receptor 1 (TAAR1) could be a promising target to treat cocaine addiction and relapse; however, the underlying mechanism remains unclear. Here, we aimed to investigate the neural mechanism underlying the role of TAAR1 in the drug priming-induced reinstatement of cocaine-seeking behavior in rats, an animal model of cocaine relapse. We focused on the shell subregion of nucleus accumbens (NAc), a key brain region of the brain reward system. We found that activation of TAAR1 by systemic and intra-NAc shell administration of the selective TAAR1 agonist RO5166017 attenuated drug-induced reinstatement of cocaine-seeking and prevented drug priming-induced CaMKIIα activity in the NAc shell. Activation of TAAR1 dampened the CaMKIIα/GluR1 signaling pathway in the NAc shell and reduced AMPAR-EPSCs on the NAc slice. Microinjection of the selective TAAR1 antagonist EPPTB into the NAc shell enhanced drug-induced reinstatement as well as potentiated CaMKIIα activity in the NAc shell. Furthermore, viral-mediated expression of CaMKIIα in the NAc shell prevented the behavioral effects of TAAR1 activation. Taken together, our findings indicate that TAAR1 regulates drug-induced reinstatement of cocaine-seeking by negatively regulating CaMKIIα activity in the NAc. Our findings elucidate a novel mechanism of TAAR1 in regulating drug-induced reinstatement of cocaine-seeking and further suggests that TAAR1 is a promising target for the treatment of cocaine relapse.

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Fig. 1: TAAR1 activation reduced cocaine relapse but not locomotor activity or food self-administration.
Fig. 2: Activation of TAAR1 attenuated cocaine priming-induced reinstatement of cocaine-seeking and activation of CaMKIIα in the NAc.
Fig. 3: Activation of TAAR1 dampened CaMKIIα activity and AMPAR-mediated EPSCs in the NAc.
Fig. 4: Local inhibition of TAAR1 in the NAc promoted cocaine priming-induced reinstatement of cocaine-seeking and activation of CaMKIIα.
Fig. 5: Virus-mediated expression of CaMKIIα in the NAc prevented the inhibitory effects of TAAR1 activation.

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Acknowledgements

We thank Dr. Marius C. Hoener at F. Hoffmann-La Roche Ltd (Basel, Switzerland) for providing with us the breeding pairs of TAAR1 KO rats. This work was supported by the National Institutes of Health National Institute on Drug Abuse (Grants R21DA040777 and R01DA047967 to J-X.L.). Kevin was supported by T32GM108554 (Training in Perioperative Science). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. These authors contributed equally: Jianfeng Liu, Ruyan Wu.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA

    Jianfeng Liu, Ruyan Wu, Robert Seaman Jr., Bernard Johnson, Jimmy Vu, Yufei Huang, David Dietz & Jun-Xu Li

  2. Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, Hubei, China

    Jianfeng Liu

  3. Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA

    Kevin M. Manz & Brad A. Grueter

  4. Research Triangle Institute, Research Triangle Park, NC, USA

    Yanan Zhang

  5. Department of Physiology, Michigan State University, East Lansing, MI, USA

    Alfred J. Robison

  6. Neuroscience Program, Michigan State University, East Lansing, MI, USA

    Alfred J. Robison

  7. Gene Delivery Technology Core, Massachusetts General Hospital, Cambridge, MA, USA

    Rachael Neve

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Contributions

JL and J-XL designed the study; JL, RW, RS, BJ, KM, JV, and YH conducted the experiments; YZ provided the TAAR1 agonists; AR and RN provided the viruses used in this study; JL, J-XL, BG, and DM prepared the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Jun-Xu Li.

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Liu, J., Wu, R., Seaman, R. et al. TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc. Mol Psychiatry 27, 2136–2145 (2022). https://doi.org/10.1038/s41380-022-01448-3

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