GSK1904529A Regarding the effects of CRF
Regarding the effects of CRF on anxiety, Sahuque et al. (2006) have demonstrated that this neuropeptide also enhances anxiety when injected into the bed nucleus of the stria terminalis (BNST), a GSK1904529A structure that has also been related to defensive behavior (Casada and Dafny, 1991, Chen et al., 2009, Walker et al., 2003). Those authors also demonstrated that intra-BNST injections of a CRF1 (but not CRF2) receptor antagonist prevented the anxiogenic effect produced by CRF. Importantly, Sahuque et al. (2006) demonstrated that intra-BNST ASV 30, at the same dose employed in the present study, was able to prevent place aversion induced by local CRF injection, but did not attenuate the anxiogenic effect produced by this neuropeptide in rats exposed to the EPM. In view of these findings, it seems that the emotional state elicited by EPM exposure does not recruit CRF2 receptors located within the BNST (Sahuque et al., 2006) and dPAG (present results) in rats and mice, respectively.
It has been demonstrated that CRF has a higher affinity for CRF1 receptors than for CRF2 receptors (Vaughan et al., 1995). This differential affinity might be the main reason for the presently observed lack of effect of ASV 30 on the anxiogenic and antinociceptive effects produced by CRF. However, it has been reported that the anxiogenic-like effects produced with i.c.v. injections of CRF (200pmol) in mice exposed to the startle paradigm were attenuated with i.c.v. injection of ASV 30 (Risbrough et al., 2003), at a similar dose to that used in the present study. Therefore, it is likely that the dose of 150pmol of CRF, which was directly injected into the dPAG, has been sufficiently high to activate CRF2 receptors in the present study. Moreover, while i.c.v. injection of a selective CRF1 receptor agonist, stressin-1A, produces anxiogenic-like effects in rats exposed to the shock probe test, no effects were observed with urocortine III, a selective CRF2 receptor agonist (Zhao et al., 2007). These inconsistent results indicate a need for further studies with different animal models of anxiety to better understand the role of CRF2 receptors in the neurobiology of emotional states. In this context, the present results indicate that the PAG CRF1 (but not CRF2) receptor is an important target on which CRF exerts its anxiogenic-like actions in mice exposed to the EPM.
Finally, it has been emphasized that the PAG receives CRF-containing neuron projections from other anxiety-related brain structures such as amygdala, hypothalamus and BNST (Gray and Magnuson, 1992). Furthermore, studies in vitro have shown an excitatory effect on PAG neurons following CRF administration (Bowers et al., 2003). Thus, the CRF anxiogenic and antinociceptive actions observed in the present study might be associated with a neuron-firing response as a consequence of membrane depolarization provoked by this neuropeptide within the PAG. Although both CRF1 and CRF2 receptors have been found in the PAG (Merchenthaler, 1984, Swanson et al., 1983), present results suggest that the anxiogenic and the antinociceptive effects of CRF introduced into the dPAG are related to CRF1 but not CRF2 receptor activation. However, given the contrasting effects observed with manipulation of CRF2 receptors in emotional tests (Bale et al., 2000, Kishimoto et al., 2000, Radulovic et al., 1999, Risbrough et al., 2003, Takahashi et al., 2001, Zhao et al., 2007), it is important to point out that further studies are needed to determine the role played by this CRF receptor subtype in the nociception response as well as in anxiety-related behavior.
Acknowledgments The authors thank Elisabete Lepera and Rosana Silva for technical support. The study was supported by FAPESP, CNPq and PADC/FCF-UNESP. T.T. Miguel was the recipient of a FAPESP (Proc. 05/05171-1) and R.L. Nunes-de-Souza of a CNPq (Proc. 303580/2009-7) fellowship.
Introduction Prior exposure to stressors has been consistently associated with the manifestation and/or exacerbation of psychiatric disorders, including anxiety disorders (Arborelius et al., 1999, Binder and Nemeroff, 2010). Corticotropin-releasing factor (CRF) is a hypothalamic neuropeptide that initiates and orchestrates stress hormonal, behavioral and autonomic responses (Reul and Holsboer, 2002, Vale et al., 1983). An increasing amount of evidence suggests that dysfunction in CRF-mediated neurotransmission/modulation may play an important role in some types of anxiety pathological conditions, particularly post-traumatic stress disorder (Binder and Nemeroff, 2010, Risbrough and Stein, 2006). CRF-modulating drugs, primarily those blocking CRF type 1 receptors (CRF1), have been considered as a putative therapeutic tool for these pathologies (Arborelius et al., 1999, Bailey et al., 2011, Valdez, 2006).