Activation of orexin/hypocretin projections to basal forebrain and paraventricular thalamus by acute nicotine

Brain Res Bull. 2008 Dec 16;77(6):367-73. doi: 10.1016/j.brainresbull.2008.09.014. Epub 2008 Oct 23.


Orexin/hypocretin neurons of the lateral hypothalamus/perifornical area project to a diverse array of brain regions and are responsive to a variety of psychostimulant drugs. It has been shown that orexin neurons are activated by systemic nicotine administration suggesting a possible orexinergic contribution to the effects of this drug on arousal and cognitive function. The basal forebrain and paraventricular nucleus of the dorsal thalamus (PVT) both receive orexin inputs and have been implicated in arousal, attention and psychostimulant drug responses. However, it is unknown whether orexin inputs to these areas are activated by psychostimulant drugs such as nicotine. Here, we infused the retrograde tract tracer cholera toxin B subunit (CTb) into either the basal forebrain or PVT of adult male rats. Seven to 10 days later, animals received an acute systemic administration of (-) nicotine hydrogen tartrate or vehicle and were euthanized 2h later. Triple-label immunohistochemistry/immunofluorescence was used to detect Fos expression in retrogradely-labeled orexin neurons. Nicotine increased Fos expression in orexin neurons projecting to both basal forebrain and PVT. The relative activation in lateral and medial banks of retrogradely-labeled orexin neurons was similar following basal forebrain CTb deposits, but was more pronounced in the medial bank following PVT deposits of CTb. Our findings suggest that orexin inputs to the basal forebrain and PVT may contribute to nicotine effects on arousal and cognition and provide further support for the existence of functional heterogeneity across the medial-lateral distribution of orexin neurons.

Publication types

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

MeSH terms

  • Animals
  • Cholera Toxin / administration & dosage
  • Cholera Toxin / metabolism
  • Efferent Pathways / cytology
  • Efferent Pathways / drug effects
  • Efferent Pathways / metabolism*
  • Fluorescent Antibody Technique / methods
  • Globus Pallidus / cytology
  • Globus Pallidus / drug effects
  • Globus Pallidus / metabolism
  • Immunohistochemistry / methods
  • Injections, Intraperitoneal
  • Intracellular Signaling Peptides and Proteins / administration & dosage
  • Intracellular Signaling Peptides and Proteins / drug effects
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Midline Thalamic Nuclei / cytology
  • Midline Thalamic Nuclei / drug effects
  • Midline Thalamic Nuclei / metabolism*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuropeptides / administration & dosage
  • Neuropeptides / metabolism
  • Neurotransmitter Agents / administration & dosage
  • Neurotransmitter Agents / metabolism
  • Neurotransmitter Agents / pharmacology
  • Nicotine / administration & dosage
  • Nicotine / pharmacology*
  • Orexins
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Substantia Innominata / cytology
  • Substantia Innominata / drug effects
  • Substantia Innominata / metabolism
  • Thalamus / cytology
  • Thalamus / drug effects
  • Thalamus / metabolism


  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Neurotransmitter Agents
  • Orexins
  • Proto-Oncogene Proteins c-fos
  • Nicotine
  • Cholera Toxin