Lack of presynaptic interaction between glucocorticoid and CB1 cannabinoid receptors in GABA- and glutamatergic terminals in the frontal cortex of laboratory rodents.

Rafael M. Bitencourt, Alán Alpár, Valentina Cinquina, Samira G. Ferreira, Bárbara S. Pinheiro, Cristina Lemos, Catherine Ledent, Reinaldo N. Takahashi, Fernando J. Sialana, Gert Lubec, Rodrigo A. Cunha, Tibor Harkany, Attila Köfalvi
Neurochemistry International. 2015-11-01; 90: 72-84
DOI: 10.1016/j.neuint.2015.07.014

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Bitencourt RM(1), Alpár A(2), Cinquina V(3), Ferreira SG(4), Pinheiro BS(5), Lemos C(5), Ledent C(6), Takahashi RN(7), Sialana FJ(8), Lubec G(9), Cunha RA(4), Harkany T(10), Köfalvi A(11).

Author information:
(1)CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal; Laboratory of Psychopharmacology, Dept. Pharmacology, Universidade Federal de Santa Catarina, Florianopolis 88049-900,
Brazil.
(2)Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
(3)Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria; University of Insubria, Via Ravasi, 2, 21100 Varese, Italy.
(4)CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal; FMUC, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
(5)CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal.
(6)IRIBHM, Université Libre de Bruxelles, Brussels B-1070, Belgium.
(7)Laboratory of Psychopharmacology, Dept. Pharmacology, Universidade Federal de Santa Catarina, Florianopolis 88049-900, Brazil.
(8)Department of Pediatrics, Medical University of Vienna, Währinger Gürtel 18, A-1090 Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Lazarettgasse 14, AKH BT 25.3, A-1090 Vienna, Austria.
(9)Department of Pediatrics, Medical University of Vienna, Währinger Gürtel 18, A-1090 Vienna, Austria.
(10)Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden; Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.
(11)CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal. Electronic address: .

Corticosteroid and endocannabinoid actions converge on prefrontocortical circuits
associated with neuropsychiatric illnesses. Corticosteroids can also modulate
forebrain synapses by using endocannabinoid effector systems. Here, we determined
whether corticosteroids can modulate transmitter release directly in the frontal
cortex and, in doing so, whether they affect presynaptic CB1 cannabinoid
receptor- (CB1R) mediated neuromodulation. By Western blotting of purified
subcellular fractions of the rat frontal cortex, we found glucocorticoid
receptors (GcRs) and CB1Rs enriched in isolated frontocortical nerve terminals
(synaptosomes). CB1Rs were predominantly presynaptically located while GcRs
showed preference for the post-synaptic fraction. Additional confocal microscopy
analysis of cortical and hippocampal regions revealed vesicular GABA
transporter-positive and vesicular glutamate transporter 1-positive nerve
terminals endowed with CB1R immunoreactivity, apposing GcR-positive post-synaptic
compartments. In functional transmitter release assay, corticosteroids,
corticosterone (0.1-10 microM) and dexamethasone (0.1-10 microM) did not
significantly affect the evoked release of [(3)H]GABA and [(14)C]glutamate in
superfused synaptosomes, isolated from both rats and mice. In contrast, the
synthetic cannabinoid, WIN55212-2 (1 microM) diminished the release of both
[(3)H]GABA and [(14)C]glutamate, evoked with various depolarization paradigms.
This effect of WIN55212-2 was abolished by the CB1R neutral antagonist, O-2050 (1
microM), and was absent in the CB1R KO mice. CB2R-selective agonists did not
affect the release of either neurotransmitter. The lack of robust presynaptic
neuromodulation by corticosteroids was unchanged upon either CB1R activation or
genetic inactivation. Altogether, corticosteroids are unlikely to exert direct
non-genomic presynaptic neuromodulation in the frontal cortex, but they may do so
indirectly, via the stimulation of trans-synaptic endocannabinoid signaling.

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