‘Opioid addiction vs. ‘sugar addiction’: Mesocorticolimbic stimulation controls motivation for remifentanil or alternative reward
Year: 2026
Type: preprint
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. Significance Statement Optogenetic central amygdala (CeA) circuitry in rats can selectively recruit mesolimbic circuitry to arbitrarily direct, amplify, and narrow incentive motivation onto either cocaine or sucrose. However, opioid drugs have additional effects that differ from psychostimulants and may resist such CeA control. We allowed CeA ChR2 rats to rats to freely choose to earn either intravenous remifentanil or sucrose pellet rewards. One group of CeA ChR2 rats had laser paired with sucrose but not remifentanil, whereas another group had laser paired with remifentanil but not sucrose. CeA ChR2 rats that had laser paired with sucrose, exclusively chose sucrose and ignored the opportunity for intravenous remifentanil. By contrast CeA ChR2 rats that had laser paired with remifentanil chose remifentanil and ignored sucrose.
Authors: Ileana Morales, David Nguyen, Kent C. Berridge
Institution: University of Michigan
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223377348