Coordinated Recruitment of Cortical-Subcortical Circuits and Ascending Dopamine and Serotonin Neurons During Inhibitory Control of Cocaine Seeking in Rats

Cereb Cortex. 2015 Sep;25(9):3167-81. doi: 10.1093/cercor/bhu112. Epub 2014 May 28.


People with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical-striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking.

Keywords: Fos activation; cortical-subcortical circuits; dopamine; inhibition of cocaine seeking; serotonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Afferent Pathways / cytology*
  • Afferent Pathways / drug effects
  • Animals
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cocaine / administration & dosage*
  • Conditioning, Operant / drug effects
  • Corpus Striatum / metabolism
  • Discrimination, Psychological / drug effects
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Dopaminergic Neurons / physiology*
  • Drug-Seeking Behavior / drug effects*
  • Inhibition, Psychological
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Wistar
  • Serotonergic Neurons / physiology*
  • Tryptophan Hydroxylase / metabolism
  • Tyrosine 3-Monooxygenase / metabolism


  • Dopamine Uptake Inhibitors
  • Proto-Oncogene Proteins c-fos
  • Tyrosine 3-Monooxygenase
  • Tryptophan Hydroxylase
  • Cocaine