Dorsal Hippocampus Drives Context-Induced Cocaine Seeking via Inputs to Lateral Septum

Neuropsychopharmacology. 2018 Apr;43(5):987-1000. doi: 10.1038/npp.2017.144. Epub 2017 Jul 11.


Lateral septum (LS) has re-emerged as an important structure in reward and addiction; however, LS afferents that drive addiction behaviors are unknown. Here, we used a modified self-administration/reinstatement procedure combined with anatomical, pharmacological, and chemogenetic techniques to characterize LS, and hippocampal inputs to LS, in two established triggers of drug relapse-context- and cue-induced reinstatement of cocaine seeking. We found that inactivation of LS neurons attenuated both context- and cue-induced reinstatement of cocaine seeking. However, dorsal hippocampus inputs to LS showed enhanced neuronal activation (as measured by Fos expression) during context-induced, but not cue-induced reinstatement. Additionally, chemogenetic inhibition of dorsal, but not ventral, hippocampal inputs to LS specifically attenuated context-induced reinstatement. Together these findings elucidate the importance of LS in reinstatement of cocaine seeking, and indicate that dorsal hippocampal inputs to LS mediate context-, but not cue-induced, reinstatement of cocaine seeking.

MeSH terms

  • Animals
  • Baclofen / pharmacology
  • Behavior, Addictive
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Cocaine / pharmacology*
  • Cues
  • Drug-Seeking Behavior / drug effects
  • Drug-Seeking Behavior / physiology*
  • Extinction, Psychological / drug effects
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Locomotion / drug effects
  • Male
  • Microinjections
  • Muscimol / pharmacology
  • Neuroanatomical Tract-Tracing Techniques
  • Oncogene Proteins v-fos / metabolism
  • Rats
  • Self Administration
  • Septal Nuclei / drug effects
  • Septal Nuclei / physiology*


  • Oncogene Proteins v-fos
  • Muscimol
  • Baclofen
  • Cocaine
  • Clozapine
  • clozapine N-oxide