Recent data obtained with etifoxine

Recent data obtained with etifoxine suggest that facilitation of GABAergic inhibition may be also associated with an indirect mechanism implying activation of the peripheral benzodiazepine receptor with a subsequent increase in neurosteroid production (Schlichter et al., 2000, Verleye et al., 2005). These compounds, such as allopregnanolone (major metabolite of progesterone) are potent agonists of the GABAA receptor complex (Majewska et al., 1986) and it has been shown that the anxiolytic effects of allopregnanolone are mediated through interactions with hypothalamic CRF. For example, a study reported that allopregnanolone counteracted the anxiety state induced by exogenously administered CRF in rats (Patchev et al., 1994). Taken together, these observations support that potentiation of the activity of GABAergic inhibitory neurotransmission by etifoxine results in a decrease in CRF activity mediated by a direct effect on the chloride channel site coupled to the GABAA receptor and/or an indirect effect through neurosteroids. Investigations are currently planned to study the in vitro effects of etifoxine on CRF mRNA expression and on CRF biosynthesis. However, an other possible mechanism, unrelated to CRF system direct modulation, that could explain how etifoxine reduced the exogenous CRF-induced anxiogenic-like effects, can be suggested. Indeed, it has been shown that CRF stimulates prostaglandin endoperoxide synthase serotonergic and noradrenergic systems (Kagamiishi et al., 2003, Murphy et al., 2003). Considering the numerous complex interactions between the different central specific neurotransmitters systems (see Millan, 2003), it can be proposed that etifoxine-enhanced inhibition of GABAergic pathways counteracts or exercises a braking effect on the CRF-induced hyperactivity of monoaminergic neurotransmission. In addition, the action of CRF in brain and in periphery can also be modulated by a binding protein (CRF-BP). CRF-BP, co-localized with CRF in the brain, is though to act as a negative regulator of the effects of CRF by modulating the availability of “free” CRF to interact with its receptors and may be involved in CRF-clearance or degradation (Behan et al., 1996, Van Den Eede et al., 2005). A potential interaction between etifoxine and CRF-BP in the way of an up-regulation of this protein is a possibility worthy of further investigation. In conclusion, the present study suggests that etifoxine administration-induced attenuation of the “anxiogenic” behavioral effects of CRF involves the GABAergic properties of this compound and does not support the hypothesis of a direct interaction between etifoxine and the CRF1 and CRF2 receptors.
Acknowledgements
Introduction Whereas the CRF1 receptors appear to contribute to stress-associated anxiety, the role of CRF2 receptors and their selective endogenous ligands urocortin-2 and -3 remains unclear and may depend on drug dose, brain location, or testing environment. CRF2 receptors are expressed at different densities throughout the central nervous system and in peripheral tissues. Intense expression of CRF2 receptor mRNA is observed in structures of the olfactory system, corticomedial parts of the amygdala, fields CA1–CA4 of the hippocampus, the ventromedial hypothalamus, the lateral septal nucleus, the choroid plexus and several brain stem nuclei [1], [2]. Some data indicate a role for urocortins and CRF2 receptors in mediation of anxiety and panic responses within the basolateral amygdala and lateral septum of rat brain [3], [4]. However, urocortin-2 and -3 were also found to decrease anxiety in some preclinical models [5], [6], [7], [8]. In our previous study, intracerebroventricular-administered urocortin-2 enhanced a conditioned freezing fear response and significantly decreased rat exploratory activity in the open field test [9]. Exogenous urocortin-2 enhanced the conditioned fear-induced expression of c-Fos in the central amygdala (CeA) and parvocellular neurons of the paraventricular hypothalamic nucleus (pPVN), revealed the effect of conditioned fear in the medial amygdala (MeA) and increased the density of CRF-related immunoreactive complexes in the lateral septum (LS). These data suggest a role for urocortin-2 in the behavioral and immunocytochemical responses to stress, in which it was shown to strengthen the behavioral and biochemical measures of anxiety-like responses. These results correspond with many of the previously published reports indicating that the CRF system promotes anxiety after stimulation of CRF2 receptors within the brain [10], [11], [12], [13], [14], [15], [16], [17]. For example, septal administration of the selective CRF2 antagonist astressin-2B, but not the CRF1-selective antagonist antalarmin, blocked the anxiogenic effects of urocortin-2 [16]. Antisauvagine-30, a potent CRF2 receptor antagonist, produced a significant dose-dependent reduction in conditioned freezing and facilitated exploratory activity in an open field, but had no significant effects on locomotor activity [10]. On the other hand, mice deficient for CRF2 receptors were hypersensitive to stress and displayed increased anxiety-like behavior [6], [8]. Using another strain of CRF1 and CRF2 receptor knock-out mice, it was found that footshock-induced increases in startle reflex were completely absent in CRF1 receptor knock-out mice and significantly attenuated in CRF2 receptor knock-out mice; the selective CRF2 receptor agonist urocortin-2 increased acoustic startle reflex, albeit with less efficacy than the non-selective CRF receptor agonist h/r-CRF [13], [15]. These results support an additive model of CRF1 and CRF2 receptor activation on the fear-potentiated behavioral response.