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bioRxiv · 10.64898/2026.10.12.758585

Opioid addiction vs. sugar addiction: Mesocorticolimbic stimulation controls motivation for remifentanil or alternative reward

Morales, I.·Berridge, K. C.·Nguyen, D.
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Abstract

Addiction is characterized by intense incentive motivation that becomes narrowly focused on particular targets. Laboratory studies have modeled intensification, directional targeting, and narrowing of the focus of incentive motivation using paired optogenetic stimulation of central amygdala CeA circuitry, which can create addictive-like motivation focused on either cocaine or on sucrose, as directed by experimenters. However, opioid drugs have been suggested to be different from cocaine in both reward and addictive effects, to be less dependent on mesolimbic incentive salience circuitry, and so may be potentially exempt from such control. To test if opoioid motivation is subject to similar control, CeA ChR2 rats were allowed to freely choose between intravenous remifentanil (2 ug/kg) or sucrose. One group had CeA stimulation selectively paired with earning sucrose, while the other group had stimulation paired with remifentanil. The sucrose-paired CeA ChR2 rats came to nearly exclusively pursue sucrose, ignoring remifentanil. By contrast, remifentanil-paired CeA ChR2 rats specifically pursued remifentanil, ignoring sucrose (control eYFP rats had no overall preference). To confirm whether CeA ChR2 pairing also intensified incentive motivation for remifentanil, as well as controlling its target, a separate CeA ChR2 group chose between two remifentanil options: one paired with CeA Stimulation, and the other unpaired. CeA ChR2 stimulation both focused pursuit specifically on laser-paired remifentanil, and escalated breakpoint for laser-paired remifentanil in a progressive ratio test of motivation intensity. Despite this ability to control motivation for opioid or sucrose, CeA ChR2 laser on its own had only low to moderate incentive value. For example, some CeA ChR2 rats above completely failed to self-stimulate CeA laser by itself. It appears that amygdala-related recruitment of mesocorticolimbic circuitry can transform the incentive salience of opioid drugs, similar to that for cocaine or sucrose, and gate the induction of intense but narrowly focused wanting in an addictive-like fashion.

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Morales, I., Berridge, K. C., Nguyen, D.. 2026-10-19. Opioid addiction vs. sugar addiction: Mesocorticolimbic stimulation controls motivation for remifentanil or alternative reward. https://doi.org/10.64898/2026.10.12.758585

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