Pharmacology of the beta-carboline FG-7,142, a partial inverse agonist at the benzodiazepine allosteric site of the GABA A receptor: neurochemical, neurophysiological, and behavioral effects

Abstract

Given the well-established role of benzodiazepines in treating anxiety disorders, beta-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-7,142 is a partial inverse agonist at the benzodiazepine allosteric site with its highest affinity for the alpha1 subunit-containing GABA(A) receptor, although it is not selective. FG-7,142 also has its highest efficacy for modulation of GABA-induced chloride flux mediated at the alpha1 subunit-containing GABA(A) receptor. FG-7,142 activates a recognized anxiety-related neural network and interacts with serotonergic, dopaminergic, cholinergic, and noradrenergic modulatory systems within that network. FG-7,142 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-7,142 has proconflict actions across anxiety-related behavioral paradigms, modulates attentional processes, and increases cardioacceleratory sympathetic reactivity and neuroendocrine reactivity. Both acute and chronic FG-7,142 treatment are proconvulsive, upregulate cortical adrenoreceptors, decrease subsequent actions of GABA and beta-carboline agonists, and increase the effectiveness of subsequent GABA(A) receptor antagonists and beta-carboline inverse agonists. FG-7,142, 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.

Figure 1

Structure of FG‐7142.

Figure 2

A diagram illustrates the forebrain and hindbrain sites of convergent action of FG‐7142 with three other anxiety‐related compounds: (1) caffeine, an adenosine receptor antagonist; (2) m‐chlorophenylpiperazine (mCPP), a nonselective 5‐HT_2C receptor agonist; and (3) yohimbine, an α₂‐adrenoceptor antagonist, as indicated by induction of c‐Fos protein expression following systemic drug injection (Singewald and Sharp 2000; Singewald et al. 2003). † indicates coexpression of c‐Fos and dopamine‐β‐hydroxylase immunostaining following systemic FG‐7142 (Salchner et al. 2006). ‡ indicates coexpression of c‐Fos and tryptophan hydroxylase immunoreactivity following systemic FG‐7142 (Abrams et al. 2005). Abbreviations: AH, anterior hypothalamus; AI, agranular insular cortex; BL, basolateral amygdaloid nucleus; BST, bed nucleus of the stria terminalis; CA1, CA1 region of the hippocampus; Ce, central amygdaloid nucleus; Cg1, cingulate cortex; DG, dentate gyrus; DM, hypothalamus, dorsomedial part; DRD, dorsal raphe nucleus, midrostrocaudal and caudal, dorsal part; IL, infralimbic cortex; PrL, prelimbic cortex; LC, locus coeruleus; LH, lateral hypothalamus; LSI, lateral septal nucleus, intermediate part; LSV, lateral septum, ventral part; M1, primary motor cortex; Me, medial amygdaloid nucleus; MnR, median raphe nucleus; NTS, nucleus of the solitary tract; Pa, hypothalamus, paraventricular nucleus; dlPAGr, dorsolateral periaqueductal gray, rostral part; vlPAGc, ventrolateral periaqueductal gray, mid‐rostrocaudal part; PB, parabrachial nucleus; RSD, retrosplenial dysgranular cortex; RSG, retrosplenial granular cortex; VLM, ventrolateral medulla.