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Unpleasant Sound Elicits Negative Emotion and Reinstates Drug Seeking

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Although previous studies have suggested an association between unpleasant sounds and the use of drugs, scientific evidence supporting this is lacking. This study investigated in rats (male Sprague-Dawley rats) if aversive sounds modulate dopamine (DA) transmission in the mesolimbic reward system and cocaine reinforcement. For sound stimulation, we used artificial low-frequency ultrasound (ALFUS) in the frequency ranges (22–38 kHz) which produces an aversive response in rats. Rats displayed increased anxiety-like behaviors, 22-kHz ultrasonic vocalizations (USVs), and stress responses with ALFUS. In vivo extracellular recording and immunohistochemistry revealed that ALFUS stimulation activated central amygdalar neurons and amygdalar GABAergic neurons. Amygdalar lesions prevented an increase of 22-kHz USVs by ALFUS. Dopamine levels in NAc decreased during ALFUS stimulation. In rats self-administering cocaine, ALFUS caused reinstatement of cocaine seeking after a period of extinction. Thus, ALFUS stimulation induced negative emotional states in association with a decrease in mesolimbic DA function and reinstatement of cocaine-seeking behaviors, suggesting that exposure to unpleasant sounds enhances negative emotional states and may induce relapse in addicts.

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General: SC and HYK designed the experiment. SC, YF, JHS, YR, SCS, HKK, JMK, MSK, BHL, and EYJ performed the experiments and analyzed the data. SC, CHY, and HYK drafted the manuscript. HYK was responsible for the overall direction of the project and for the edits to the manuscript.


This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2018R1A5A2025272, 2018R1E1A2A02086499, and 2018R1A6A3A01013294), the KBRI basic research program through the Korea Brain Research Institute funded by the Ministry of Science and ICT (19-BR-03-01), and the Korea Institute of Oriental Medicine (KIOM) (KSN1812181).

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Correspondence to Hee Young Kim.

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Chang, S., Fan, Y., Shin, J.H. et al. Unpleasant Sound Elicits Negative Emotion and Reinstates Drug Seeking. Mol Neurobiol 56, 7594–7607 (2019).

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  • Unpleasant sound
  • Negative emotion
  • Drug seeking
  • Cocaine
  • Anxiety
  • Stress