Cannabinoids Occlude the HIV-1 Tat-Induced Decrease in GABAergic Neurotransmission in Prefrontal Cortex Slices

J Neuroimmune Pharmacol. 2016 Jun;11(2):316-31. doi: 10.1007/s11481-016-9664-y. Epub 2016 Mar 18.

Abstract

In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is now considered a chronic disease that specifically targets the brain and causes HIV-1-associated neurocognitive disorders (HAND). Endocannabinoids exhibit neuroprotective and anti-inflammatory properties in several central nervous system (CNS) disease models, but their effects in HAND are poorly understood. To address this issue, whole-cell recordings were performed on young (14-24 day old) C57BL/6J mice. We investigated the actions of the synthetic cannabinoid WIN55,212-2 (1 μM) and the endocannabinoid N-arachidonoyl ethanolamine (anandamide; AEA, 1 μM) in the presence of HIV-1 Tat on GABAergic neurotransmission in mouse prefrontal cortex (PFC) slices. We found a Tat concentration-dependent (5-50 nM) decrease in the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). The cannabinoid 1 receptor (CB1R) antagonist rimonabant (1 μM) and zero extracellular calcium prevented the significant Tat-induced decrease in mIPSCs. Further, bath-applied WIN55,212-2 or AEA by itself, significantly decreased the frequency, but not amplitude of mIPSCs and/or spontaneous IPSCs (sIPSCs), and occluded a further downregulation of IPSCs by Tat. Pretreatment with rimonabant but not the CB2R antagonist AM630 (1 μM) prevented the WIN55,212-2- and AEA-induced decrease in IPSCs frequency without any further Tat effect. Results indicated a Tat-induced decrease in GABAergic neurotransmission, which was occluded by cannabinoids via a CB1R-related mechanism. Understanding the relationship between Tat toxicity and endocannabinoid signaling has the potential to identify novel therapeutic interventions to benefit individuals suffering from HAND and other cognitive impairments.

Keywords: Calcium; Cannabinoid; Cannabinoid 1 receptor; GABA neurotransmission; HIV-1 Tat; Prefrontal cortex.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzoxazines / pharmacology
  • Cannabinoids / pharmacology*
  • Dose-Response Relationship, Drug
  • Female
  • GABAergic Neurons / drug effects*
  • GABAergic Neurons / metabolism
  • HIV-1*
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Organ Culture Techniques
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Rats
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / metabolism
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology
  • tat Gene Products, Human Immunodeficiency Virus / pharmacology*

Substances

  • Benzoxazines
  • Cannabinoids
  • Morpholines
  • Naphthalenes
  • Receptor, Cannabinoid, CB1
  • tat Gene Products, Human Immunodeficiency Virus
  • Win 55212-2