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Int J Neuropsychopharmacol. 2017 May 1;20(5):403-409. doi: 10.1093/ijnp/pyw113.

Distinct Roles of Opioid and Dopamine Systems in Lateral Hypothalamic Intracranial Self-Stimulation.

Author information

Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
The Basic Technology Research Center, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Branch of Molecular Neurobiology, National Institute on Drug Abuse, Baltimore, Maryland, USA.
Research Service, New Mexico VA Health Care System, Albuquerque, New Mexico, USA.
Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan.



Opioid and dopamine systems play crucial roles in reward. Similarities and differences in the neural mechanisms of reward that are mediated by these 2 systems have remained largely unknown. Thus, in the present study, we investigated the differences in reward function in both µ-opioid receptor knockout mice and dopamine transporter knockout mice, important molecules in the opioid and dopamine systems.


Mice were implanted with electrodes into the right lateral hypothalamus (l hour). Mice were then trained to put their muzzle into the hole in the head-dipping chamber for intracranial electrical stimulation, and the influences of gene knockout were assessed.


Significant differences are observed between opioid and dopamine systems in reward function. µ-Opioid receptor knockout mice exhibited enhanced intracranial electrical stimulation, which induced dopamine release. They also exhibited greater motility under conditions of "despair" in both the tail suspension test and water wheel test. In contrast, dopamine transporter knockout mice maintained intracranial electrical stimulation responding even when more active efforts were required to obtain the reward.


The absence of µ-opioid receptor or dopamine transporter did not lead to the absence of intracranial electrical stimulation responsiveness but rather differentially altered it. The present results in µ-opioid receptor knockout mice are consistent with the suppressive involvement of µ-opioid receptors in both positive incentive motivation associated with intracranial electrical stimulation and negative incentive motivation associated with depressive states. In contrast, the results in dopamine transporter knockout mice are consistent with the involvement of dopamine transporters in positive incentive motivation, especially its persistence. Differences in intracranial electrical stimulation in µ-opioid receptor and dopamine transporter knockout mice underscore the multidimensional nature of reward.


ICSS; dopamine transporter; knockout mouse; reward function; µ-opioid receptor

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