Journal
MOLECULAR PSYCHIATRY
Volume 27, Issue 4, Pages 2136-2145Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-022-01448-3
Keywords
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Funding
- National Institutes of Health National Institute on Drug Abuse [R21DA040777, R01DA047967, T32GM108554]
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The study demonstrates that TAAR1 regulates drug-induced reinstatement of cocaine-seeking by negatively regulating CaMKII alpha activity in the NAc, providing further confirmation of TAAR1 as a potential target for the treatment of cocaine relapse.
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 CaMKII alpha activity in the NAc shell. Activation of TAAR1 dampened the CaMKII alpha/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 CaMKII alpha activity in the NAc shell. Furthermore, viral-mediated expression of CaMKII alpha 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 CaMKII alpha 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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