title: Cannabinoids Occlude the HIV-1 Tat-Induced Decrease in GABAergic Neurotransmission in Prefrontal Cortex Slices.
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.
authors.affiliation: Department of Psychology & Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Changqing
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Psychology & Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hermes
authors.affiliation: Department of Psychological & Brain Sciences, Indiana University, Bloomington, IN, 47405, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Edmond and Lily Safra Center for Brain Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Bogna M
authors.initials: BM
authors.lastname: Ignatowska-Jankowska
authors.affiliation: Department of Psychology & Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, 27599, USA. sfitting@email.unc.edu.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Fitting
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism; D015497:HIV-1; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009924:Organ Culture Techniques; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D054322:tat Gene Products, Human Immunodeficiency Virus; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
keywords: Calcium; Cannabinoid; Cannabinoid 1 receptor; GABA neurotransmission; HIV-1 Tat; Prefrontal cortex