Corticotropin-Releasing Hormone (CRH) or Corticotropin-Releasing
Factor (CRF) and its
family o
f related naturally occurring endogenous peptides and receptors are becoming recognized
for their actions within central (CNS) and peripheral (PNS) nervous systems. It should be recognized that the term ‘CRH’ has been displaced by ‘CRF’ [Guillemin, R., 2005. Hypothalamic hormones a.k.a. hypothalamic releasing
factors. J. Endocrinol. 184, 11–28]. However, to maintain uni
formity among contributions to this special issue we have used the original term, CRH. The term ‘CRF’ has been associated recently with CRH receptors and designated with subscripts by the IUPHAR nomenclature committee
f=""http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-4RR8YW9-1&_user=10&_coverDate=04 % 2F07 % 2F2008&_rdoc=6&_fmt=full&_orig=browse&_srch=doc-info( % 23toc % 234892 % 232008 % 23994169997 % 23683392 % 23FLA % 23display % 23Volume)&_cdi=4892&_sort=d&_docanchor=&_ct=20&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a1e4a8a60b21a80b523615148a678fd8#bib32"">[Hauger, R.L., Grigoriadis, D.E., Dallman, M.F., Plotsky, P.M., Vale, W.W., Dautzenberg, F.M., 2003. International Union of Pharmacology. XXXVI. Corticotrophin-releasing factor and their ligands. Pharmacol. Rev. 55, 21–26] to denote the type and subtype o
f receptors activated or antagonized by CRH ligands. CRH, as a hormone, has long been identi
fied as the regulator o
f basal and stress-induced ACTH release within the hypothalamo-pituitary-adrenal axis (HPA axis). But the concept, that CRH and its related endogenous peptides and receptor ligands have non-HPA axis actions to regulate CNS synaptic transmission outside the HPA axis, is just beginning to be recognized and identi
fied [
Orozco-
Cabal, L., Pollandt, S., Liu, J., Shinnick-Gallagher, P., Gallagher, J.P., 2006a. Regulation o
f Synaptic Transmission by CRF Receptors. Rev. Neurosci. 17, 279–307; Orozco-Cabal, L., Pollandt, S., Liu, J., Vergara, L., Shinnick-Gallagher, P., Gallagher, J.P., 2006b. A novel rat medial pre
frontal cortical slice preparation to investigate synaptic transmission
from amygdala to layer V prelimbic pyramidal neurons. J. Neurosci. Methods 151, 148–158] is especially noteworthy since this synapse has become a prime
focus
for a variety o
f mental diseases, e.g. schizophrenia [
f=""http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-4RR8YW9-1&_user=10&_coverDate=04 % 2F07 % 2F2008&_rdoc=6&_fmt=full&_orig=browse&_srch=doc-info( % 23toc % 234892 % 232008 % 23994169997 % 23683392 % 23FLA % 23display % 23Volume)&_cdi=4892&_sort=d&_docanchor=&_ct=20&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a1e4a8a60b21a80b523615148a678fd8#bib103"">Fischbach, G.D., 2007. NRG1 and synaptic function in the CNS. Neuron 54, 497–497], and neurological disorders, e.g., Alzheimer's disease [
f=""http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-4RR8YW9-1&_user=10&_coverDate=04 % 2F07 % 2F2008&_rdoc=6&_fmt=full&_orig=browse&_srch=doc-info( % 23toc % 234892 % 232008 % 23994169997 % 23683392 % 23FLA % 23display % 23Volume)&_cdi=4892&_sort=d&_docanchor=&_ct=20&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a1e4a8a60b21a80b523615148a678fd8#bib105"">Bell, K.F., Cuello, C.A., 2006. Altered synaptic function in Alzheimer's disease. Eur. J. Pharmacol. 545, 11–21]. We suggest that “The Stressed Synapse” has been overlooked [c.
f.,
f=""http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-4RR8YW9-1&_user=10&_coverDate=04 % 2F07 % 2F2008&_rdoc=6&_fmt=full&_orig=browse&_srch=doc-info( % 23toc % 234892 % 232008 % 23994169997 % 23683392 % 23FLA % 23display % 23Volume)&_cdi=4892&_sort=d&_docanchor=&_ct=20&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a1e4a8a60b21a80b523615148a678fd8#bib39"">Kim, J.J., Diamond, D.M. 2002. The stressed hippocampus, synaptic plasticity and lost memories. Nat. Rev., Neurosci. 3, 453–462;
f=""http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-4RR8YW9-1&_user=10&_coverDate=04 % 2F07 % 2F2008&_rdoc=6&_fmt=full&_orig=browse&_srch=doc-info( % 23toc % 234892 % 232008 % 23994169997 % 23683392 % 23FLA % 23display % 23Volume)&_cdi=4892&_sort=d&_docanchor=&_ct=20&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a1e4a8a60b21a80b523615148a678fd8#bib110"">Radley, J.J., Morrison, J.H., 2005. Repeated stress and structural plasticity in the brain. Ageing Res. Rev. 4, 271–287] as a major contributor to many CNS disorders. We present data demonstrating CRH neuroregulatory and neuromodulatory actions at three limbic synapses, the basolateral amygdala to central amygdala synapse; the basolateral amygdala to medial pre
frontal cortex synapse, and the lateral septum mediolateral nucleus synapse. A novel stress circuit is presented involving these three synapses. We suggest that CRH ligands and their receptors are signi
ficant etiological
factors that need to be considered in the pharmacotherapy o
f mental diseases associated with CNS synaptic transmission.