Finally it has been emphasized that the PAG receives CRF

Finally, it has been emphasized that the PAG receives CRF-containing neuron projections from other anxiety-related Pam3CSK4 Biotin synthesis 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). More recently, evidence suggests that dysregulation of CRF signaling may also be implicated in panic disorder. For instance, polymorphisms in the CRF1, but not CRF2, gene have been associated with susceptibility to panic disorder in German and Japanese population samples (Ishitobi et al., 2012, Keck et al., 2008). There is also an association of polymorphisms in the CRF gene with inhibited temperament in children at risk for panic disorder (Smoller et al., 2005). Only few animal studies have so far addressed where in the brain changes in CRF-mediated neurotransmission/modulation may influence panic-associated behavioral and autonomic responses. Sajdyk et al. (1999) reported that repeated intra-basolateral amygdala (BLA) injections of sub-anxiogenic doses of urocortin 1, a peptide that binds to both CRF1 and CRF2 receptors (Vaughan et al., 1995), induce synaptic/biochemical changes that render animals sensitive to sodium lactate. More specifically, in animals treated with this peptide, but not in sham-treated subjects, intravenous injection of lactate causes anxiogenic-like behavioral and cardiovascular responses. The importance of this finding to panic is that in panic disorder patients, but not in healthy volunteers, lactate evokes fear and autonomic responses similar as those experienced in a panic attack (Griez and Schruers, 1998). Therefore, it seems likely that a persistent subthreshold stimulation of CRF receptors in the BLA may predispose individuals to panic-evoking stimuli.