Pharmacology of the β-Carboline FG-7142, a Partial Inverse Agonist at the Benzodiazepine Allosteric Site of the GABAA Receptor: Neurochemical, Neurophysiological, and Behavioral Effects

Abstract

Given the well-established role of benzodiazepines in treating anxiety disorders, β-carbolines, spanning a spectrum from full agonists to full inverse agonists at the benzodiazepine allosteric site for the GABA_A receptor, can provide valuable insight into the neural mechanisms underlying anxiety-related physiology and behavior. FG-7142 is a partial inverse agonist at the benzodiazepine allosteric site with its highest affinity for the α1 subunit-containing GABA_A receptor, although it is not selective. FG-7142 also has its highest efficacy for modulation of GABA-induced chloride flux mediated at the α1 subunit-containing GABA_A receptor. FG-7142 activates a recognized anxiety-related neural network and interacts with serotonergic, dopaminergic, cholinergic, and noradrenergic modulatory systems within that network. FG-7142 has been shown to induce anxiety-related behavioral and physiological responses in a variety of experimental paradigms across numerous mammalian and non-mammalian species, including humans. FG-7142 has proconflict actions across anxiety-related behavioral paradigms, modulates attentional processes, and increases cardioacceleratory sympathetic reactivity and neuroendocrine reactivity. Both acute and chronic FG-7142 treatment are proconvulsive, upregulate cortical adrenoreceptors, decrease subsequent actions of GABA and β-carboline agonists, and increase the effectiveness of subsequent GABA_A receptor antagonists and β-carboline inverse agonists. FG-7142, as a partial inverse agonist, can help to elucidate individual components of full agonism of benzodiazepine binding sites and may serve to identify the specific GABA_A receptor subtypes involved in specific behavioral and physiological responses.