Noradrenergic modulation of cortical acetylcholine release is both direct and gamma-aminobutyric acid-mediated.
The effect of norepinephrine (NE) on the outflow of gamma-aminobutyric acid (GABA) as well as the influence of endogenous GABA on NE-induced inhibition of acetylcholine (ACh) release have been investigated in guinea-pig cortical slices, in order to clarify the role of this amino acid in the noradrenergic control of the cholinergic signal. NE in the range of 9 to 30 microM increased GABA outflow from unstimulated slices, doubling it at 30 microM. This effect was antagonized by prazosin (0.1 microM) and by tetrodotoxin (0.5 microM), suggesting an involvement of alpha-1 receptors and of sodium-dependent mechanisms. 2,4-diaminobutyric acid (DABA), an inhibitor of neuronal GABA uptake, at 60 microM steadily doubled the amino acid outflow without affecting ACh release However, DABA increased the GABA-induced inhibition of electrically evoked ACh release by a factor of about 10 and the NE-induced inhibition by a factor of 2.8. Prazosin (1 microM) reduced the effects of NE (60 microM) on the spontaneous and evoked ACh release in normal slices and the effects of NE (30 microM) in DABA-treated slices. Thus, an alpha-1 GABA-mediated component of NE influence on ACh can be demonstrated even in vitro (beside the well-known alpha-2 direct inhibition), provided high NE concentrations are used or the GABA availability is enhanced. On the other hand, bicuculline and picrotoxin antagonized not only GABA but also NE, whereas yohimbine counteracted not only NE but also GABA inhibition of ACh release, suggesting a close assembly of alpha-2 and GABAA receptors on the cholinergic axons.(ABSTRACT TRUNCATED AT 250 WORDS)
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D011942:Receptors, Adrenergic, alpha; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D000109:Acetylcholine; D009638:Norepinephrine; D011224:Prazosin