title: Repeated cocaine treatment enhances HIV-1 Tat-induced cortical excitability via over-activation of L-type calcium channels.
abstract: 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.
authors.affiliation: Departments of Pharmacology and Psychiatry, Center for Compulsive Behavior and Addiction, Rush University Medical Center, 1735 W. Harrison Street, Cohn Research Building, Rm. 424, Chicago, IL, 60612, USA.
authors.forename: T Celeste
authors.initials: TC
authors.lastname: Napier
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
authors.forename: Xiu-Ti
authors.initials: XT
authors.lastname: Hu
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000633:toxicity*
chemical_list: D020746:Calcium Channels, L-Type; D054322:tat Gene Products, Human Immunodeficiency Virus; D003042:Cocaine