title: Differential modulation of respiratory neuronal discharge patterns by GABA(A) receptor and apamin-sensitive K(+) channel antagonism.
abstract: The discharge patterns of respiratory neurons of the caudal ventral respiratory group (cVRG) appear to be subject to potent GABAergic gain modulation. Local application of the GABA(A) receptor antagonist bicuculline methochloride amplifies the underlying discharge frequency (F(n)) patterns mediated by endogenous excitatory and inhibitory synaptic inputs. Gain modulation can also be produced by alterations in the amplitude of spike afterhyperpolarizations (AHPs) mediated by apamin-sensitive small-conductance Ca(2+)-activated K(+) (SK) channels. Since methyl derivatives of bicuculline (BICm) also have been shown to reduce the amplitude of AHPs, in vitro, it is possible that the BICm-induced gain modulation is due to a block of SK channels. The purpose of these studies was to determine the mechanisms by which BICm produces gain modulation and to characterize the influence of SK channels in the control of respiratory neuron discharge. Six protocols were used in this in vivo study of cVRG inspiratory (I) and expiratory (E) neurons in decerebrate, paralyzed, ventilated dogs. The protocols included characterizations of the neuronal responses to 1) BICm and apamin on the same neuron, 2) BICm during maximum apamin-induced block of AHPs, 3) apamin during maximum BICm-induced gain modulatory responses, 4) the specific GABA(A) receptor antagonist, (+)beta-hydrastine, 5) the specific GABA(A) receptor agonist, muscimol, and 6) the GABA uptake inhibitor, nipecotic acid. For protocols 3, 5, and 6, only E neurons were studied. Four-barrel micropipettes were used for extracellular single neuron recording and pressure ejection of drugs. Cycle-triggered histograms were used to quantify the F(n) patterns and to determine the drug-induced changes in the gain (slope) and offset of the F(n) patterns. Compared to apamin at maximum effective dose rates, BICm produced a 2.1-fold greater increase in peak F(n) and a 3.1-fold greater increase in average F(n). BICm and apamin produced similar increases in gain, but the offsets due to apamin were more negative. The responses to hydrastine were similar to BICm. During maximum apamin block, BICm produced an additional 112 +/- 22% increase in peak F(n). Conversely, apamin produced an additional 176 +/- 74% increase in peak F(n) during the maximum BICm-induced response. Muscimol and nipecotic acid both decreased the gain and offset of the discharge patterns. Taken together, these results suggest that the gain modulatory effect of BICm is due to a reduction of GABA(A)-ergic shunting inhibition rather than a reduction in AHPs by block of SK channels in canine cVRG neurons.
authors.affiliation: Zablocki Veterans Affairs Medical Center, Research Service, Wisconsin, Milwaukee 53295, USA.
authors.forename: V
authors.initials: V
authors.lastname: Tonkovic-Capin
authors.forename: A G
authors.initials: AG
authors.lastname: Stucke
authors.forename: E A
authors.initials: EA
authors.lastname: Stuth
authors.forename: M
authors.initials: M
authors.lastname: Tonkovic-Capin
authors.forename: M
authors.initials: M
authors.lastname: Krolo
authors.forename: F A
authors.initials: FA
authors.lastname: Hopp
authors.forename: D R
authors.initials: DR
authors.lastname: McCrimmon
authors.forename: E J
authors.initials: EJ
authors.lastname: Zuperku
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology*; D044182:Benzylisoquinolines; D001640:Bicuculline / Q000031:analogs & derivatives; D004285:Dogs; D004594:Electrophysiology; D018755:GABA Agonists / Q000494:pharmacology; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009557:Nipecotic Acids / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000502:physiology*; D012143:Respiratory Physiological Phenomena
chemical_list: D000470:Alkaloids; D044182:Benzylisoquinolines; D018755:GABA Agonists; D009557:Nipecotic Acids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011963:Receptors, GABA-A; C030278:nipecotic acid; D001030:Apamin; D009118:Muscimol; C013024:hydrastine; D001640:Bicuculline