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Robust aversive effects of trace amine-associated receptor 1 activation in mice

Neuropsychopharmacology volume 48, pages 1446–1454 (2023)Cite this article

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Abstract

Drugs that stimulate the trace amine-associated receptor 1 (TAAR1) are under clinical investigation as treatments for several neuropsychiatric disorders. Previous studies in a genetic mouse model of voluntary methamphetamine intake identified TAAR1, expressed by the Taar1 gene, as a critical mediator of aversive methamphetamine effects. Methamphetamine is a TAAR1 agonist, but also has actions at monoamine transporters. Whether exclusive activation of TAAR1 has aversive effects was not known at the time we conducted our studies. Mice were tested for aversive effects of the selective TAAR1 agonist, RO5256390, using taste and place conditioning procedures. Hypothermic and locomotor effects were also examined, based on prior evidence of TAAR1 mediation. Male and female mice of several genetic models were used, including lines selectively bred for high and low methamphetamine drinking, a knock-in line in which a mutant form of Taar1 that codes for a non-functional TAAR1 was replaced by the reference Taar1 allele that codes for functional TAAR1, and their matched control line. RO5256390 had robust aversive, hypothermic and locomotor suppressing effects that were found only in mice with functional TAAR1. Knock-in of the reference Taar1 allele rescued these phenotypes in a genetic model that normally lacks TAAR1 function. Our study provides important data on TAAR1 function in aversive, locomotor, and thermoregulatory effects that are important to consider when developing TAAR1 agonists as therapeutic drugs. Because other drugs can have similar consequences, potential additive effects should be carefully considered as these treatment agents are being developed.

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Fig. 1: The TAAR1 agonist, RO5256390, induces robust conditioned taste aversion in MALDR mice.
Fig. 2: RO5256390 induces robust conditioned place aversion in MALDR mice.
Fig. 3: RO5256390 induces robust hypothermia in MALDR mice.
Fig. 4: Sensitivity to RO5256390-induced conditioned place aversion and hypothermia is reinstated by excision of the Taar1m1J mutation and knock-in of the wild-type Taar1+ allele.
Fig. 5: Sensitivity to the hypothermic effect of RO5256390 is dependent on Taar1 genotype.

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Acknowledgements

We thank Jason Erk for assistance with maintenance of the mouse colonies contributing to this research. We also thank GVSU students who contributed to completing the experiment at GVSU, as follows: Adam Eger, Kevin Frost, Ethan Dunn, Adara Dawson and Jaysen Holly. This work was supported by Department of Veterans Affairs grants I01BX002106 (TJP) and 15F-RCS-009 (TJP), NIDA grants P50DA018165 (TJP), R01DA046081 (TJP), and U01DA041579 (TJP), and Institutional Development Award NIH NIGMS P20GM103442 (SS).

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  1. Shkelzen Shabani

    Present address: Biomedical Sciences at Grand Valley State University, Allendale, MI, USA

Authors and Affiliations

  1. Department of Biomedical Sciences, Grand Valley State University, Allendale, MI, USA

    Shkelzen Shabani & Derek Tonello

  2. Department of Biology, Minot State University, Minot, ND, USA

    Shkelzen Shabani, Sydney Houlton & Bikalpa Ghimire

  3. Department of Behavioral Neuroscience and Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, USA

    Cheryl Reed, Harue Baba, Sara Aldrich & Tamara J. Phillips

  4. VA Portland Health Care System, Portland, OR, USA

    Tamara J. Phillips

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Contributions

Substantial contributions to the conception or design of the work—SS, CR, TJP; Acquisition, analysis, or interpretation of data for the work—SS, SH, BG, DT, CR, HB, SA, TJP; Drafting the work or revising it critically for important intellectual content—SS, TJP; Final approval of the version to be published—SS, SH, BG, DT, CR, HB, SA, TJP; Agreement to be accountable for all aspects of the work in ensuring accuracy and integrity—SS, TJP.

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Correspondence to Tamara J. Phillips.

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Shabani, S., Houlton, S., Ghimire, B. et al. Robust aversive effects of trace amine-associated receptor 1 activation in mice. Neuropsychopharmacol. 48, 1446–1454 (2023). https://doi.org/10.1038/s41386-023-01578-4

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