title: Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: evidence for mediation through the beta-adrenoceptor-coupled cyclic AMP system.
abstract: Previous in vivo studies from our laboratory have consistently shown that iontophoretically applied norepinephrine (NE) can potentiate gamma-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 beta-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-bromo-3',5'-cyclic AMP (BcAMP) or 3-isobutyl-1-methyl xanthine (IBMX) or bath application of forskolin (10-30 microM). In a second group of in vivo studies, extracellularly recorded responses of individual cerebellar Purkinje (P) cells to iontophoretic pulses of GABA or beta-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 preparations, 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 beta-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 beta-receptor activation, adenyl cyclase stimulation and increased intracellular production of cAMP.
authors: Department of Physiology and Biophysics, Hahnemann University, Philadelphia, PA 19102.
authors: F M
authors: FM
authors: Sessler
authors: R D
authors: RD
authors: Mouradian
authors: J T
authors: JT
authors: Cheng
authors: H H
authors: HH
authors: Yeh
authors: W M
authors: WM
authors: Liu
authors: B D
authors: BD
authors: Waterhouse
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D011943:Receptors, Adrenergic, beta; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine