Are "GABAergic" Agents Really So Selective for GABA? Implications for Single- versus Multi-Site Hypotheses From Promiscuous Behavior of Anesthetics and Their Molecular Targets In Vitro.

In the literature, anesthetic agents are commonly described as if their hypnotic action is mediated by a predominant molecular target, using terminology such as "GABAergic" or "NMDAergic." The justification for this is unclear. The authors might thereby imply a single target hypothesis (ie, the named target is the sole or predominant molecular mechanism for that agent); or that in an in vitro dose-response plot, the potency or efficacy of this agent is distinctly (ie, several orders of magnitude) highest for interaction with the named target as compared with others. We explored if this last was the case, through review of data reported across 310 in vitro studies. We found that all but a few agents were highly "promiscuous," influencing several different molecular targets with similar potency, making it difficult to justify that any one was predominant. Notably, propofol, often cited as a "typical GABAergic agent" in fact shows higher potency at nicotinic receptors and HCN ion channels than for GABA A receptors (GABA A Rs). Exceptions to promiscuity were, to an extent, etomidate and dexmedetomidine, which were relatively "monogomous" for GABA A R and α2-adrenoreceptors, respectively, and ketamine for NMDA receptors. Moreover, molecular targets were also promiscuous for which agents they were influenced by. This was in a manner that did not always correspond to the "preference" of an agent for a receptor. We discuss how this mutual promiscuity is consistent with a multi-site mechanism of anesthetic action.