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

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

Author information

1
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.

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.

PMID:
24567038
PMCID:
PMC4019717
DOI:
10.1007/s11481-014-9524-6
[Indexed for MEDLINE]
Free PMC Article

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