- Brief Communication
- Open Access
Physiological and pharmacological properties of GABA-ergic gain modulation of canine ventral respiratory group (VRG) neurons
Respiratory Researchvolume 2, Article number: 4.3 (2001)
In vivo local application of the selective GABAA receptor antagonist bicuculline methochloride (BIC) to respiratory neurons in the caudal VRG of dogs produces a profound increase in their discharge frequency (Fn) pattern. The resulting Fn pattern is an amplified replica on the underlying control Fn pattern even when the pattern is reflexly altered, for example by lung inflation, or enhanced by changes in chemodrive . These results suggested the presence of a tonic GABAergic gain modulation (GM) that normally attenuates the pattern to typically less than 50% of the Fn unblocked pattern. This multiplicative process can be modeled as: Fout = (1-α)*Fin, where Fout and Fin are the instantaneous Fns 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 GABAA receptor antagonist, does not produce GM, but is able to block the silent phase inhibition . 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) . 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 Fn patterns and to determine the drug-induced changes in the gain and offset of the spontaneous Fn patterns. For the exogenous aspect of the study, the net increase in Fn 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) GABAA 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 Fn. Conversely, apamin produced an additional 176 ± 74% increase in peak Fn during the maximum BICm-induced response. The net AMPA-induced increases in Fn 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.
McCrimmon DR, Zuperku EJ, Hayashi F, Dogas Z, Hinrichsen CFL, Stuth EA, Tonkovic-Capin M, Krolo M, Hopp FA: Modulation of the synaptic drive to respiratory premotor and motor neurons. Resp Physiol. 1997, 110: 161-176. 10.1016/S0034-5687(97)00081-9.
Dogas Z, Krolo M, Stuth EA, Tonkovic-Capin M, Hopp FA, McCrimmon DR, Zuperku EJ: Differential effects of GABAA receptor antagonists in the control of respiratory neuronal discharge patterns. J Neurophysiol. 1998, 80: 2368-2377.
Seutin V, Johnson SW: Recent advances in the pharmacology of quaternary salts of bicuculline. Trends Pharmacol Sci. 1999, 20: 268-270. 10.1016/S0165-6147(99)01334-6.
Approved by the Subcommittee on Animal Studies, Zablocki VA Medical Center. Supported by VA Medical Research Funds & NIH GM 59234-01.