Cocaine self-administration enhances excitatory responses of pyramidal neurons in the rat medial prefrontal cortex to human immunodeficiency virus-1 Tat

Eur J Neurosci. 2015 May;41(9):1195-206. doi: 10.1111/ejn.12853. Epub 2015 Feb 24.


The medial prefrontal cortex (mPFC) plays a critical role in reward-motivated behaviors. Repeated cocaine exposure dysregulates the dorsal mPFC, and this is thought to contribute to cocaine-seeking and relapse of abstinent abusers. Neuropathology of the mPFC also occurs in human immunodeficiency virus (HIV)-positive individuals, and this is exaggerated in those who also abuse cocaine. The impact of the comorbid condition on mPFC neuronal function is unknown. To fill this knowledge gap, we performed a behavioral and electrophysiological study utilising adult male rats that self-administered cocaine by pressing a lever for 14 once-daily operant sessions. Saline-yoked (SAL-yoked) rats served as controls. Cue reactivity (CR) was used to indicate drug-seeking, assessed by re-exposing the rats to cocaine-paired cues wherein non-reinforced lever pressing was quantified 1 day (CR1) and 18-21 days (CR2) after the 14th operant session. Only cocaine self-administration (COC-SA) rats showed CR. One day after CR2, brain slices were prepared for electrophysiological assessment. Whole-cell patch-clamp recordings of dorsal (prelimbic) mPFC pyramidal neurons from COC-SA rats showed a significant increase in firing evoked by depolarizing currents as compared with those from SAL-yoked control rats. Bath application of the toxic HIV-1 protein transactivator of transcription (Tat) also depolarized neuronal membranes and increased evoked firing. The Tat-induced excitation was greater in the neurons from withdrawn COC-SA rats than in controls. Tat also reduced spike amplitude, and this co-varied with cocaine-seeking during CR2. Taken together, these novel findings provide support at the neuronal level for the concept that the increased excitability of mPFC pyramidal neurons following cocaine self-administration drives drug-seeking and augments the neuropathophysiology caused by HIV-1 Tat.

Keywords: cue reactivity; excitability; over-excitation; patch-clamp recording.

Publication types

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

MeSH terms

  • Action Potentials*
  • Animals
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Cues
  • Drug-Seeking Behavior
  • Male
  • Membrane Potentials
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / physiology
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Self Administration
  • tat Gene Products, Human Immunodeficiency Virus / pharmacology*


  • tat Gene Products, Human Immunodeficiency Virus
  • Cocaine