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Repeated Cocaine Treatment Enhances HIV-1 Tat-induced Cortical Excitability via Over-activation of L-type Calcium Channels

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Abstract

The prefrontal cortex (PFC) is dysregulated in neuroAIDS and during cocaine abuse. Repeated cocaine treatment upregulates voltage gated L-type Ca2+ channels in pyramidal neurons within the rat medial PFC (mPFC). L-type Ca2+ 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 Ca2+ 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. Ca2+ influx was increased (indicated by prolonged Ca2+ 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 Ca2+ 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.

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Acknowledgements

Drs. Napier and Chen made equal contributions to this project. This study was supported by the National Institute on Drug Abuse (DA026746, DA033882), the Peter F. McManus Charitable Trust, the Daniel and Ada Rice Foundation, the Chicago Developmental Center for AIDS Research (P30AI082151) and the Center for Compulsive Behavior and Addiction at Rush University Medical Center. We thank Dr. Jingli Zhang for his technical contribution, and Drs. Lena Al-Harthi and Steven Graves for their helpful discussions.

Conflict of Interest

There is no conflict of interest for any of the authors in this study.

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Authors and Affiliations

  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

    T. Celeste Napier

  2. Department of Pharmacology, Center for Compulsive Behavior and Addiction, Rush University Medical Center, 1735 W. Harrison Street, Cohn Research Building, Rm. 414, Chicago, IL, 60612, USA

    Lihua Chen & Xiu-Ti Hu

  3. National Center for Biodefense and Infectious Diseases, George Mason University, Discovery Hall, Room 306, 10900 University Blvd. MS 1H8, Manassas, VA, 20110, USA

    Fatah Kashanchi

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  1. T. Celeste Napier
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Correspondence to Xiu-Ti Hu.

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Napier, T.C., Chen, L., Kashanchi, F. et al. Repeated Cocaine Treatment Enhances HIV-1 Tat-induced Cortical Excitability via Over-activation of L-type Calcium Channels. J Neuroimmune Pharmacol 9, 354–368 (2014). https://doi.org/10.1007/s11481-014-9524-6

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