Repeated cocaine treatment enhances HIV-1 Tat-induced cortical excitability via over-activation of L-type calcium channels

J Neuroimmune Pharmacol. 2014 Jun;9(3):354-68. doi: 10.1007/s11481-014-9524-6. Epub 2014 Feb 25.


The prefrontal cortex (PFC) is dysregulated in neuroAIDS and during cocaine abuse. Repeated cocaine treatment upregulates voltage gated L-type Ca(2+) channels in pyramidal neurons within the rat medial PFC (mPFC). L-type Ca(2+) channels are also upregulated by the HIV-1 neurotoxic protein, Tat, but the role of Tat in pyramidal cell function is unknown. This represents a major knowledge gap as PFC pyramidal neurons are important mediators of behaviors that are disrupted in neuroAIDS and by chronic cocaine exposure. To determine if L-channel-mediated Ca(2+) dysregulation in mPFC pyramidal neurons are a common neuropathogenic site for Tat and chronic cocaine, we evaluated the electrophysiological effects of recombinant Tat on these neurons in forebrain slices taken from rats 1-3 days after five, once-daily treatments of cocaine (15 mg/kg, ip) or saline. In saline-treated rats, bath-applied Tat facilitated membrane depolarization and firing. Ca(2+) influx was increased (indicated by prolonged Ca(2+) spikes) with low concentrations of Tat (10-40nM), but reduced by higher concentrations (80-160nM), the latter likely reflecting dysfunction associated with excessive excitation. Tat-mediated effects were detected during NMDA/AMPA receptor blockade, and abolished by blocking activated L-channels with diltiazem. In neurons from cocaine-treated rats, the Tat-induced effects on evoked firing and Ca(2+) spikes were significantly enhanced above that obtained with Tat in slices from saline-treated rats. Thus, glutamatergic receptor-independent over-activation of L-channels contributed to the Tat-induced hyper-reactivity of mPFC pyramidal neurons to excitatory stimuli, which was exacerbated in rats repeatedly exposed to cocaine. Such effects may contribute to the exaggerated neuropathology reported for HIV(+) cocaine-abusing individuals.

Publication types

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

MeSH terms

  • Action Potentials / drug effects*
  • Action Potentials / physiology
  • Animals
  • Calcium Channels, L-Type / metabolism*
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / physiology
  • Cocaine / administration & dosage*
  • Male
  • Neurons / drug effects
  • Neurons / physiology
  • Organ Culture Techniques
  • Rats
  • Rats, Sprague-Dawley
  • tat Gene Products, Human Immunodeficiency Virus / toxicity*


  • Calcium Channels, L-Type
  • tat Gene Products, Human Immunodeficiency Virus
  • Cocaine