Increased Number and Activity of a Lateral Subpopulation of Hypothalamic Orexin/Hypocretin Neurons Underlies the Expression of an Addicted State in Rats

Biol Psychiatry. 2019 Jun 1;85(11):925-935. doi: 10.1016/j.biopsych.2018.07.022. Epub 2018 Aug 7.


Background: The orexin (hypocretin) system is important for reward-driven motivation but has not been implicated in the expression of a multiphenotype addicted state.

Methods: Rats were assessed for economic demand for cocaine before and after 14 days of short access, long access, or intermittent access (IntA) to cocaine. Rats were also assessed for a number of other DSM-5-relevant addiction criteria following differential access conditions. Orexin system function was assessed by quantification of numbers and activity of orexin cells, pharmacological blockade of the orexin-1 receptor, and subregion-specific knockdown of orexin cell populations.

Results: IntA produced a cluster of addiction-like behaviors that closely recapitulate key diagnostic criteria for addiction to a greater extent than long access or short access. IntA was accompanied by an increase in number and activity of orexin-expressing neurons within the lateral hypothalamic subregion. This increase in orexin cell number and activity persisted during protracted withdrawal from cocaine for at least 150 days and was accompanied by enhanced incubation of craving in the same rats. Selective knockdown of lateral hypothalamic orexin neurons reduced motivation for cocaine, and orexin-1 receptor signaling played a larger role in drug seeking after IntA.

Conclusions: We provide the first evidence that lateral hypothalamic orexin system function extends beyond general reward seeking to play a critical role in expression of a multiphenotype addiction-like state. Thus, the orexin system is a potential novel target for pharmacotherapies designed to treat cocaine addiction. In addition, these data point to the IntA model as a preferred approach to modeling addiction-like behavior in rats.

Keywords: Behavioral economics; Cocaine; Hypothalamus; Intermittent access; Long access; Plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoxazoles / pharmacology
  • Cell Count / statistics & numerical data
  • Cocaine / pharmacology*
  • Drug-Seeking Behavior / physiology*
  • Extinction, Psychological
  • Gene Knockdown Techniques
  • Hypothalamic Area, Lateral / physiology*
  • Hypothalamic Hormones / metabolism
  • Male
  • Melanins / metabolism
  • Microinjections
  • Morpholinos / administration & dosage
  • Morpholinos / pharmacology
  • Motivation
  • Naphthyridines / pharmacology
  • Neurons / physiology*
  • Orexins / antagonists & inhibitors
  • Orexins / genetics
  • Orexins / physiology*
  • Pituitary Hormones / metabolism
  • Rats
  • Self Administration
  • Urea / analogs & derivatives
  • Urea / pharmacology


  • 1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
  • Benzoxazoles
  • Hypothalamic Hormones
  • Melanins
  • Morpholinos
  • Naphthyridines
  • Orexins
  • Pituitary Hormones
  • melanin-concentrating hormone
  • Urea
  • Cocaine