Presynaptic α₂-adrenoceptors control the inhibitory action of presynaptic CB₁ cannabinoid receptors on prefrontocortical norepinephrine release in the rat.
Endocannabinoids play a crucial neuromodulator role in both physiological and pathological states in various brain regions including the prefrontal cortex (PFC). We examined, whether presynaptic cannabinoid receptors are involved in the modulation of basal and electrical field stimulation-evoked [³H]norepinephrine ([³H]NE) release from rat PFC slices. WIN55,212-2, a nonselective CB₁ receptor (CB₁R) agonist, inhibited the electrical stimulation-evoked efflux of [³H]NE in a concentration-dependent fashion, which was antagonized by the CB₁R antagonist/inverse agonist, AM251 (1 μM). Idazoxan, a selective α₂-adrenoceptor antagonist, augmented the evoked [³H]NE release. In the presence of idazoxan, the effect of WIN55,212-2 was exacerbated or attenuated, depending on the applied concentration and stimulation frequency. Moreover their combined, but not individual application elicited a depressive-like phenomenon in the forced-swim test. These data were bolstered with fluorescent and confocal microscopy analysis, which revealed that CB₁R immunoreactivity co-localized with dopamine-β-hydroxylase positive (i.e. noradrenergic) fibers and the inhibitory α(2A) adrenergic autoreceptors (α(2A)R) in the PFC. Furthermore, idazoxan triggered a decrease in CB₁R density in the PFC, suggesting that high extracellular level of norepinephrine downregulates CB₁Rs.
Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences-IEM-HAS, H-1083 Budapest, Szigony U. 43, Hungary.
Hardy
H
Richter
Filipe M
FM
Teixeira
Samira G
SG
Ferreira
Ágnes
Á
Kittel
Attila
A
Köfalvi
Beáta
B
Sperlágh
D000320:Adrenergic Fibers / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000009:adverse effects / Q000494:pharmacology; D054022:Cerebrum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003863:Depression / Q000139:chemically induced; D015536:Down-Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009928:Organ Specificity; D009994:Osmolar Concentration; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*
D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; D009419:Nerve Tissue Proteins; D043884:Receptor, Cannabinoid, CB1; D018341:Receptors, Adrenergic, alpha-2; D009638:Norepinephrine