TY - JOUR
T1 - Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA
T2 - evidence for mediation through the β-adrenoceptor-coupled cyclic AMP system
AU - Sessler, Francis M.
AU - Mouradian, Robert D.
AU - Cheng, Jung Tung
AU - Yeh, Hermes H.
AU - Liu, Weimin
AU - Waterhouse, Barry D.
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 1989/10/9
Y1 - 1989/10/9
N2 - Previous in vivo studies from our laboratory have consistently shown that iontophoretically applied norepinephrine (NE) can potentiate γ-aminobutyric acid (GABA)-induced depressant responses of cerebrocortical, cerebellar and hypothalamic neurons. Additional experiments have further suggested that this noradrenergic facilitating action is specific for GABA and results from the activation of a β-type adrenoceptor. The goal of the present studies was to determine if the cAMP second messenger system might also be a component of the mechanism responsible for this NE modulatory action on GABA-mediated inhibition. In one set of in vitro experiments, we examined cerebellar neuronal responses to GABA before, during and after iontophoretic application of NE, 8-bromo3′,5′-cylic AMP (BcAMP) or 3-isobutyl-1-methyl xanthine (IBMX) or bath application of forskolin (10-30 μM). In a second group of in vivo studies, extracellularly recorded responses of individual cerebellar Purkinje (P) cells to iontophoretic pulses of GABA or β-alanine were examined before, during and after NE or BcAMP microiontophoresis. In 20 of 25 cerebellar cells recorded from tissue slices, iontophoretically applied NE markedly enhanced responses to GABA in a manner similar to that observed previously in vivo. In these in vitro preprarations, bath application of forskolin was also capable of potentiating GABA-induced inhibition in each of 4 cases tested whereas dideoxy-forskolin was not. Iontophoretic application of IBMX further enhanced the facilitating effects of NE on GABA-induced inhibition in 10 of 11 cases tested. Furthermore, under in vitro conditions, BcAMP augmented inhibitory responses to GABA in all cerebellar neurons tested. In the intact rat brain, iontophoretic administration of BcAMP caused a marked NE-like augmentation of P-cell responses to GABA in 73% of the cells tested. As with NE, BcAMP was ineffective in enhancing P-cell inhibitory responses to β-alanine, an agent which like GABA causes hyperpolarization, by increasing Cl- conductance. In summary, these results indicate that a membrane permeant analog of cAMP, a phosphodiesterase inhibitor and an agent which directly activates adenyl cyclase can mimic the previously observed GABA-potentiating actions of NE. Thus, these findings provide further support for the contention that noradrenergic enhancement of GABA inhibition results from a cascade of transmembrane events which includes β-receptor activation, adenyl cyclase stimulation and increased intracellular production of cAMP.
AB - Previous in vivo studies from our laboratory have consistently shown that iontophoretically applied norepinephrine (NE) can potentiate γ-aminobutyric acid (GABA)-induced depressant responses of cerebrocortical, cerebellar and hypothalamic neurons. Additional experiments have further suggested that this noradrenergic facilitating action is specific for GABA and results from the activation of a β-type adrenoceptor. The goal of the present studies was to determine if the cAMP second messenger system might also be a component of the mechanism responsible for this NE modulatory action on GABA-mediated inhibition. In one set of in vitro experiments, we examined cerebellar neuronal responses to GABA before, during and after iontophoretic application of NE, 8-bromo3′,5′-cylic AMP (BcAMP) or 3-isobutyl-1-methyl xanthine (IBMX) or bath application of forskolin (10-30 μM). In a second group of in vivo studies, extracellularly recorded responses of individual cerebellar Purkinje (P) cells to iontophoretic pulses of GABA or β-alanine were examined before, during and after NE or BcAMP microiontophoresis. In 20 of 25 cerebellar cells recorded from tissue slices, iontophoretically applied NE markedly enhanced responses to GABA in a manner similar to that observed previously in vivo. In these in vitro preprarations, bath application of forskolin was also capable of potentiating GABA-induced inhibition in each of 4 cases tested whereas dideoxy-forskolin was not. Iontophoretic application of IBMX further enhanced the facilitating effects of NE on GABA-induced inhibition in 10 of 11 cases tested. Furthermore, under in vitro conditions, BcAMP augmented inhibitory responses to GABA in all cerebellar neurons tested. In the intact rat brain, iontophoretic administration of BcAMP caused a marked NE-like augmentation of P-cell responses to GABA in 73% of the cells tested. As with NE, BcAMP was ineffective in enhancing P-cell inhibitory responses to β-alanine, an agent which like GABA causes hyperpolarization, by increasing Cl- conductance. In summary, these results indicate that a membrane permeant analog of cAMP, a phosphodiesterase inhibitor and an agent which directly activates adenyl cyclase can mimic the previously observed GABA-potentiating actions of NE. Thus, these findings provide further support for the contention that noradrenergic enhancement of GABA inhibition results from a cascade of transmembrane events which includes β-receptor activation, adenyl cyclase stimulation and increased intracellular production of cAMP.
KW - 3-Isobutyl-1-methylxanthine
KW - Adenosine 3′, 5′-monophosphate
KW - Forskolin
KW - In vitro cerebellum
KW - Noradrenaline
KW - γ-Aminobutyric acid
UR - http://www.scopus.com/inward/record.url?scp=0024460132&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0024460132&partnerID=8YFLogxK
U2 - 10.1016/0006-8993(89)91132-3
DO - 10.1016/0006-8993(89)91132-3
M3 - Article
C2 - 2478258
AN - SCOPUS:0024460132
SN - 0006-8993
VL - 499
SP - 27
EP - 38
JO - Brain Research
JF - Brain Research
IS - 1
ER -