Noradrenergic modulation of gamma-aminobutyric acid outflow from the human cerebral cortex.
The noradrenergic modulation of endogenous gamma-aminobutyric acid (GABA) outflow from slices and synaptosomes prepared from human cerebral cortex biopsies has been studied. GABA outflow was responsive to depolarizing stimuli such as ouabain and high potassium. Basal GABA outflow in slices, but not in synaptosomes, appeared to be largely dependent upon neuronal activity, being prevented by tetrodotoxin (TTX). 10 mM K(+)-evoked outflow in synaptosomes also proved to be TTX sensitive. Norepinephrine (NE) concentration dependently increased basal GABA outflow both in slices and synaptosomes. This effect was alpha 1-adrenoreceptor-mediated because it was prevented by a selective antagonist of the alpha 1-adrenoreceptor class (prazosin) but not by the alpha 2 antagonist idazoxan. However, an alpha 2-mediated inhibitory modulation was also present in the preparations used, since (1) in slices, NE significantly inhibited GABA outflow in the presence of prazosin; (2) in synaptosomes, NE significantly inhibited 10 mM K(+)-evoked outflow in the presence of prazosin. Both of these effects were prevented by idazoxan. No beta-adrenoreceptor modulation could be demonstrated. A comparison between species was also conducted. The response to ouabain and to TTX proved similar in human, rat and guinea-pig cerebral cortex. In the most simple tissue preparation used (synaptosomes), a close similarity between the three species could be observed. In all species, NE stimulated basal GABA outflow, an effect prevented by prazosin. This suggests a predominant alpha 1-adrenoreceptor-mediated stimulatory effect. In a more complex preparation (slices), differences between species could be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
Ferraro
L
L
Institute of Pharmacology, University of Ferrara, Italy.
Tanganelli
S
S
Caló
G
G
Antonelli
T
T
Fabrizi
A
A
Acciarri
N
N
Bianchi
C
C
Beani
L
L
Simonato
M
M
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D019329:Idazoxan; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D009638:Norepinephrine / Q000494:pharmacology*; D010042:Ouabain / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D004146:Dioxanes; D010656:Phenylephrine; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D010042:Ouabain; D007545:Isoproterenol; D011188:Potassium; D009638:Norepinephrine; D011224:Prazosin; D019329:Idazoxan