Synaptic physiology of central CRH system

Abstract

Corticotropin Releasing Hormone (CRH) or Corticotropin Releasing Factor (CRF) and its family of 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 2005). However, to maintain uniformity 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 (Hauger R.L. et al. 2003) to denote the type and subtype of receptors activated or antagonized by CRH ligands. CRH, as a hormone, has long been identified as the regulator of 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 identified . It is especially noteworthy that since the synapse has become a prime focus for a variety of mental diseases, e.g. schizophrenia (Fischbach 2007), and neurological disorders, e.g., Alzheimer's disease (Bell and Cuello 2006), we suggest that "THE STRESSED SYNAPSE" has been overlooked (c.f., Kim and Diamond 2002; Radley and Morrison 2005) 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 prefrontal 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 significant etiological factors that need to be considered in the pharmacotherapy of mental diseases associated with CNS synaptic transmission.

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…In turn, ACTH and glucocorticoids exert a negative feed-back to the activity of CRH [260]. More recently, ACTH, CRH and their receptors identified in different limbic brain regions were found to be involved in affective responses [261][262][263]. Data are available on the changes of CRH levels during development and in epilepsy models [264].…”

Differential behavioral profile induced by the injection of dipotassium chlorazepate within brain areas that project to the nucleus accumbens septi

“…Furthermore, an increased activity of both AMY and Hip has been reported in situations of encoding and consolidation of highly emotive, dangerous or stressor situations, suggesting the relevance of these memory related structures in these kinds of events [63]. In the same way, stress mediators, like corticotrophin releasing hormone (CRH), that have a significant anxiogenic effect when were injected to rats [22], exert their anxiogenic action within AMY [20]. Anxiety could disrupt attention and perception, mainly registering potential indicators of risk or danger, leading to misunderstandings in the interpretation of expressions, suggesting its influence in cognitive processes [9].…”

“…The effect of PFC inhibition induced here by benzodiazepine injection could explain the anxiogenic-like effect observed, with a decrease in time per entry. Furthermore, short circuitries could be involved within the studied structures, like those described within AMY for CRH pathways [20].…”

Synaptic Effects Induced by Alcohol

“…In contrast to classical neurotransmitters, neuropeptides are released in a frequencydependent fashion and often have a longer half-life of activity after release. These factors, among others, enable neuropeptides to produce long-lasting effects on cellular functions such as excitatory and inhibitory synaptic transmission, neuronal excitability, and gene transcription (Gallagher et al 2008). Thus, a long-lasting dysregulation of neuropeptides could have significant effects on the activity of neurons and consequently, behavior.…”