Intravenous prenatal nicotine exposure increases orexin expression in the lateral hypothalamus and orexin innervation of the ventral tegmental area in adult male rats

Drug Alcohol Depend. 2013 Oct 1;132(3):562-70. doi: 10.1016/j.drugalcdep.2013.04.003. Epub 2013 May 7.


Background: Approximately 18% of pregnant women continue to smoke tobacco cigarettes throughout pregnancy. Offspring exposed to tobacco smoke in utero exhibit a higher incidence of drug use in later stages of development relative to non-exposed children. Animal models indicate that prenatal nicotine (PN) exposure alone alters the development of the mesocorticolimbic dopamine (DA) system, which, in part, organizes motivated behavior and reward. The orexin/hypocretin neuropeptide system, which originates in the lateral hypothalamus (LH), projects to key areas of the mesocorticolimbic DA pathway. Previous research suggests that orexin exerts a major influence on motivation and reward.

Methods: The present experiments determined if intravenous (IV) PN exposure alters (1) the expression of orexin neurons and melanin-concentrating hormone (MCH; positive control) in the LH; and (2) orexin projections from the LH onto DA neurons in the ventral tegmental area (VTA). Dams were injected with IV nicotine (0.05 mg/kg/injection) or saline 3×/day during gestational days 8-21. Tissues from adult male offspring (∼130 days) were examined using immunohistochemistry.

Results: Relative to controls, offspring of IV PN exposure showed (1) increased numbers of orexin neurons in the LH, and no changes in the expression of MCH; and (2) increased orexin appositions on DA cells in the VTA.

Conclusion: The findings indicate that the influence of PN exposure is enduring, and suggests that the PN-induced modification of orexin expression on mesolimbic circuitry may contribute to the reported changes in motivated behaviors related to food and drug reward observed in offspring prenatally exposed to nicotine.

Keywords: Immunohistochemistry; Intravenous; Lateral hypothalamus; Orexin; Prenatal nicotine; Ventral tegmental area.

Publication types

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

MeSH terms

  • Age Factors
  • Animals
  • Female
  • Gene Expression Regulation / drug effects
  • Hypothalamic Area, Lateral / drug effects
  • Hypothalamic Area, Lateral / metabolism*
  • Injections, Intravenous
  • Intracellular Signaling Peptides and Proteins / biosynthesis*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Neuropeptides / biosynthesis*
  • Neuropeptides / genetics
  • Nicotine / administration & dosage*
  • Orexins
  • Pregnancy
  • Prenatal Exposure Delayed Effects / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Sex Factors
  • Up-Regulation / drug effects
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism*


  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexins
  • Nicotine