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Paper   IPM / Cognitive Sciences / 15007
School of Cognitive Sciences
  Title:   The role of medial hypothalamus orexin circuits in prescription opioid abuse
1.  J. Fragale
2.  K. Porter-Stransky
3.  A. Mohammadkhani
4.  C. Pantazis
5.  M. James
6.  G. Aston-Jones
  Status:   In Proceedings
  Proceeding: SFN 2017
  Year:  2018
  Supported by:  IPM
Prescription opioid abuse is a chronic and relapsing disorder that is marked by an excessive motivation for the abused drug. Although rates of prescription opioid abuse are high, not all individuals prescribed an opioid become addicted. Motivated drug taking can be assessed using a behavioral economics (BE) task that our lab has used to measure the rate of consumption as the effort to maintain the desired drug concentration increases (Bentzley et al., 2013; 2014). The BE measure Qo describes the theoretical consumption of a drug when no effort is required and is a measure of hedonic set point. The BE parameter α is a measure of demand elasticity (price sensitivity; inverse of motivation) and is a quantitative measure of motivation. The orexin/hypocretin system is implicated in motivated drug taking and we showed that the orexin-1 receptor (Ox1R) antagonist SB-334867 (SB) decreases hedonic set point and increases demand elasticity for the prescription opioid remifentanil on our BE task (Porter-Stransky et al., 2015). In this study, we investigated the relationship between individual differences in remifentanil demand and orexin neuron activity. Rats were trained to self-administer remifentanil, tested on BE, and sacrificed 90 min after the point of maximum responding (Pmax). Double-labeled immunohistochemistry for Fos and orexin somata in hypothalamus was performed. We found that the percentage of Fos-expressing orexin neurons in dorsal medial hypothalamus (DMH), but not in perifornical (PeF) or lateral hypothalamus (LH), correlated with Qo. Specifically, subjects with a greater percentage of Fos-expressing orexin neurons had a greater Qo (higer hedonic setpoint). Correlations were not observed between the percentage of Fos-expressing orexin neurons and demand elasticity (α). Additionally, relationships were not observed between total number of orexin neurons in DMH, PeF, or LH, and Qo or α. These results indicate that DMH orexin neurons may contribute to prescription opioid abuse by regulating an individual’s hedonic set point for the drug. We are currently assessing Fos activation in regions densely innervated by DMH orexin neurons to identify downstream targets of orexin neurons that might contribute to these results.

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