Anxiolytic Properties of the Selective, Non-peptidergic CRF1 Antagonists, CP154,526 and DMP695 A Comparison to Other Classes of Anxiolytic Agent

Abstract

The selective, non-peptidergic corticotropin-releasing factor (CRF) 1 receptor antagonists, CP154,526 and DMP695, dose-dependently increased punished responses of rats in a Vogel conflict test and enhanced social interaction (SI) of rats in an unfamiliarCorticotropin-releasing factor (CRF) plays a crucial role in modulation of the release of adrenocorticotrophic hormone from the anterior pituitary (De Souza 1995). In addition, CRF is broadly distributed throughout the mammalian central nervous system (CNS), being concentrated in corticolimbic regions such as amygdala, hippocampus, and periaqueductal gray (PAG) and frontal cortex (FCX), as well as the locus coeruleus (LC) and dorsal raphe nucleus (DRN), the origin of ascending adrenergic and serotonergic projections, respectively (Sawchenko et al. 1993;Van Bockstaele et al. 1996;Price et al. 1998;Steckler and Holsboer 1999). In line with this organization, independently of the hypothalamocorticotrophic axis, cerebral CRF-containing neurones fulfill an important role in the control of emotional behavior (Adamec and McKay 1993;De Souza 1995;Mitchell 1998;Steckler and Holsboer 1999;Smagin and Dunn 2000), actions expressed via two principal subtypes of CRF receptor, both of which positively couple to adenyl cyclase (Grigoriadis et al. 1996). CRF 1 receptors bind CRF and a related neuropeptide, urocortin, with high affinity whereas CRF 2 receptors display a NO . 4 distinct preference for the latter (Donaldson et al. 1996;Grigoriadis et al. 1996). Of several splice variants of the latter, the CRF 2 ␣ subtype is found predominantly in the rodent CNS, notably in several corticolimbic regions enriched in CRF itself, such as the hippocampus, medial amygdala, septum, olfactory bulb, and raphe nuclei, although species differences in this regard should be pointed out (Chalmers et al. 1995;Sánchez et al. 1999). Studies of mRNA encoding CRF 1 receptors and of the corresponding peptide have established a contrasting pattern of distribution in rats with a predominance of CRF 1 over CRF 2 ␣ sites in anterior pituitary, FCX and basolateral amygdala, as well as high levels in the hippocampus and PAG (Potter et al. 1994;Chalmers et al. 1995;Sánchez et al. 1999;Chen et al. 2000).These observations provide a neuroanatomical substrate for a potential role of CRF 1 and/or CRF 2 receptors in the control of mood (Coplan et al. 1996;Steckler and Holsboer 1999), and, in this regard, there is a diversity of evidence implicating CRF 1 sites in the modulation of anxious states. First, several studies have reported anxiogenic actions of CRF (and urocortin) upon i.c.v. administration (see Steckler and Holsboer, 1999) and similar effects have been seen upon direct introduction into the dorsal PAG (Martins et al. 1997), basolateral amygdala (Sajdyk et al. 1999), and hippocampus (Radulovic et al. 1999), structures possessing a high density of CRF 1 receptors. Second, direct evidence for participation of CRF 1 receptors in anxiogenic actions is derived from studies of antisense probes for their ...

A Centrally Acting, Anxiolytic Angiotensin II AT1 Receptor Antagonist Prevents the Isolation Stress-Induced Decrease in Cortical CRF1 Receptor and Benzodiazepine Binding

“…In the elevated plus-maze, a test of anxiety-related behavior (Lister, 1987), pretreatment with candesartan increased the number of entries into the open arm of the maze and the time spent in the open arm, indicating a clear anxiolytic effect, similar to that found after peripheral administration of other AT 1 receptor antagonists (Barnes et al, 1990;Kaiser et al, 1992) and to that of CRF 1 receptor antagonists (Korte and De Boer, 2003;Millan et al, 2001).…”

“…CRF 1 receptor activity is important for the induction of anxiety, and CRF 1 (corticotropin-releasing hormone) receptor antagonists decrease stress-induced anxiety (Menzaghi et al, 1994;Rodriguez de Fonseca et al, 1996;Millan et al, 2001;Smith et al, 1998).…”

Antidepressant-Like Effects of the Corticotropin-Releasing Factor 1 Receptor Antagonist, SSR125543, and the Vasopressin 1b Receptor Antagonist, SSR149415, in a DRL-72 s Schedule in the Rat

“…It has been demonstrated that the activity of classical antidepressants in DRL-72 s schedules relies on their ability to modulate 5-HT and NE neurotransmission (Britton and Koob, 1989;Richards and Seiden, 1991;Richards et al, 1993;Balcells-Olivero et al, 1998;Dekeyne et al, 2002). Experiments with the CRF1 receptor antagonist CP154,526 have shown that this compound did not alter basal levels of cortical 5-HT, NE, and dopamine, in freely moving rats (Millan et al, 2001). Similarly, SSR125543 (10 mg/kg, i.p.)…”

“…There has been increased interest in the antidepressant potential of drugs that block receptors for CRF, leading to the pharmaceutical development of several compounds that are antagonists at the CRF1 receptor (Griebel et al, 2002c;Keck and Holsboer, 2001;Okuyama et al, 1999;Schulz et al, 1996;Millan et al, 2001;Lelas et al, 2004;Seymour et al, 2003). The CRF1 receptor antagonist SSR122543 has been reported to induce anxiolytic-and antidepressant-like activities in several animal models of psychiatric diseases (Gully et al, 2002;Griebel et al, 2002b, c;Alonso et al, 2004).…”

Neurokinin1 Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization

“…As previously (Millan et al, 2001a), rats were initially placed in a chamber equipped with a grid floor and were exposed to six randomly distributed, electric shocks (800 mA, 8 s) over a 7 min period. After 24 h, they were placed in the chamber for 2 min and received a single shock.…”