• Brief Communication
• Open Access

• Received: 2 August 2001
• Published: 17 August 2001

In vivo local application of the selective GABA_A receptor antagonist bicuculline methochloride (BIC) to respiratory neurons in the caudal VRG of dogs produces a profound increase in their discharge frequency (F_n) pattern. The resulting F_n pattern is an amplified replica on the underlying control F_n pattern even when the pattern is reflexly altered, for example by lung inflation, or enhanced by changes in chemodrive [1]. These results suggested the presence of a tonic GABAergic gain modulation (GM) that normally attenuates the pattern to typically less than 50% of the F_n unblocked pattern. This multiplicative process can be modeled as: F_out = (1-α)^*F_in, where F_out and F_in are the instantaneous F_ns in the presence and absence of GABAergic inhibition, respectively, and α is the relative magnitude of tonic inhibition. The pharmacology of this mechanism is unusual in that picrotoxin, a noncompetitive GABA_A receptor antagonist, does not produce GM, but is able to block the silent phase inhibition [2]. Also, recent in vitro studies have shown that the methyl derivatives of bicuculline block spike afterhyperpolarizations (AHPs) mediated by small conductance Ca²⁺ activated K⁺ channels (SK) [3]. The main objective of this study was to compare the in vivo effects of BIC with those of the SK channel blocker apamin on endogenously- (spontaneous) and exogenously-induced neuronal activities to discern the mechanism for BIC effects.

Multibarrel micropipettes were used to record single unit activity from cVRG neurons in decerebrate dogs before and during picoejection of agonists and antagonists. Cycle-triggered histograms were used to quantify the F_n patterns and to determine the drug-induced changes in the gain and offset of the spontaneous F_n patterns. For the exogenous aspect of the study, the net increase in F_n due to repeated short duration picoejections of the glutamate receptor agonist, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), was quantified before and during locally induced antagonism of 1) GABA_A receptors by BIC or 2) SK channels by apamin.

BICm and apamin produced similar marked increases in gain, but different offsets. During maximum SK channel block with apamin, 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. The net AMPA-induced increases in F_n were not significantly altered by BIC, but were amplified in accordance with the gain increase produced by apamin block of AHPs.

These results suggest that the BIC-sensitive GM of canine cVRG neurons is not due to a nonspecific block of AHPs, but is due to a GABAergic mechanism that modulates endogenously-, but not exogenously-induced activity. GABAergic GM, acting possibly via a shunting inhibition, may be functionally isolated from the soma/spike initiation zone to allow multiple nonrespiratory behaviors to be expressed by the same neurons, while providing adaptive respiratory gain control.