Converging evidence suggests that reduced
Converging evidence suggests that reduced glutamate transmission in the LS is linked to increased anxiety-like behaviors (Radulovic et al., 1999, Henry et al., 2006, Bakshi et al., 2002, Liu et al., 2004). Therefore, attenuated CRF1 receptor-mediated excitatory transmission in the LS following ASV-treatment of saline rats may disrupt the overall balance of activity in anxiety-regulating circuits to have an anxiogenic effect. Future work should directly test this and other possibilities. For example, it is also possible that other mechanisms related to changes in CRF receptors underlie the anxiolytic effects of ASV in saline pre-treated rats which were not detected by the current study. This could be due to the limitations of not being able to distinguish surface from cytosolic receptor expression, not differentiating CRF receptor SID 26681509 in the subregions of each region studied, or simply that effects occurred in regions that were not studied here.
In conclusion, the current study demonstrates that central antagonism of CRF2 receptors attenuates anxiety-like behaviors of rats during amphetamine withdrawal. Opposing effects of CRF2 receptor antagonism on anxiety-like behavior of amphetamine and saline pre-treated rats appear to be due to a combination of blocking elevated levels of CRF2 receptors in the dRN of amphetamine pre-treated rats (Pringle et al., 2008, Vuong et al., 2010) and CRF2 receptor antagonism in the LS unmasking the effects of decreased CRF1 receptors in saline pre-treated rats. Overall, the findings highlight the effectiveness of central CRF2 antagonism as a possible pharmacological strategy to treat anxiety during abstinence in psychostimulant-dependent individuals, to reduce the risk of relapse.
Acknowledgements We would like to thank Dr. Jeffrey Barr for his assistance with these experiments. This work was funded by grants NIHR01 DA019921 (GF). ER was supported by a University of South Dakota Undergraduate Research Award, a University of South Dakota INBRE Summer Fellowship (NIH P20 RR016479) and a Medical Student Summer Fellowship from the Sanford School of Medicine.
Introduction Exposure to excessive or uncontrollable stress is a major factor associated with a variety of illnesses including psychopathology. Psychosocial stressors may trigger mood disorders or exacerbate the symptoms of schizophrenia as well as contributing to its relapse , , . In early life, exposure to stress may increase the risk of developing behavioral problems and may sensitize the young to stressors elevating the risk for stress-induced psychopathology , . As a result, there is an intense effort to identify and unravel the key systems responsible for mediating the body\'s response to stress . One system that has attracted considerable attention in the last two decades involves corticotropin-releasing factor (CRF). This 41-amino acid peptide is hypothesized to play an essential role in coordinating endocrine, autonomic, immune, and behavioral responses to stress , , , , . CRF and urocortin, a CRF-like peptide, are widely distributed throughout the mammalian brain , , , , . These peptides exert their biological actions via two major G protein-coupled seven-transmembrane domain receptor subtypes known as CRF1, ,  and CRF2, . The CRF2 receptor has α- and β-splice variants. In addition, a CRF2γ receptor is found in human brain . Studies demonstrate that CRF1 and CRF2 receptors have distinct pharmacological profiles and unique distribution patterns in brain and peripheral tissues , . For example, in the rat, high densities of CRF1 receptors are found in the pituitary, brain stem, cerebellum, amygdala, and cortex whereas CRF2α receptors are found predominantly in the lateral septum, ventromedial hypothalamus, and olfactory bulb , . A somewhat similar receptor distribution pattern is found in the rhesus monkey brain with the exception of increased densities of CRF2 receptors in the brain regions including the neocortex, amygdala, and hippocampal formation . CRF2β receptors occur in nonneuronal cells of the brain such as the choroid plexis and in peripheral tissue including the heart, lung, and skeletal muscle , , . In addition to CRF1 and CRF2 receptors, CRF and urocortin also bind to a CRF-binding protein .