Corticotropin-Releasing Factor in Brain: A Role in Activation, Arousal, and Affect Regulation

Abstract

Organisms exposed to challenging stimuli that alter the status quo inside or outside of the body are required for survival purposes to generate appropriate coping responses that counteract departures from homeostasis. Identification of an executive control mechanism within the brain capable of coordinating the multitude of endocrine, physiological, and functional coping responses has high utility for understanding the response of the organism to stressor exposure under normal or pathological conditions. The corticotropin-releasing factor (CRF)/urocortin family of neuropeptides and receptors constitutes an affective regulatory system due to the integral role it plays in controlling neural substrates of arousal, emotionality, and aversive processes. In particular, available evidence from pharmacological intervention in multiple species and phenotyping of mutant mice shows that CRF/urocortin systems mediate motor and psychic activation, stimulus avoidance, and threat recognition responses to aversive stimulus exposure. It is suggested that affective regulation is exerted by CRF/urocortin systems within the brain based upon the sensitivity of local brain sites to CRF/urocortin ligand administration and the appearance of hypothalamo-pituitary-adrenocortical activation following stressor exposure. Moreover, these same stress neuropeptides may constitute a mechanism for learning to avoid noxious stimuli by facilitating the formation of so-called emotional memories. A conceptual framework is provided for extrapolation of animal model findings to humans and for viewing CRF/urocortin activation as a continuum measure linking normal and pathological states.Many experimental studies performed in animals support the role of corticotropin-releasing factor (CRF) peptides and receptors as mediators of interoceptive coping reactions to environmental or physiological challenges; however, the advent of small molecule ligands for CRF receptors suitable for administration in human beings raises the question of what insights, if any, anti-stress pharmacology exerted via CRF manipulations in animals provides for human biology and psychopathology. The present review addresses how the evidence for the adaptive utility of CRF systems provides a basis for predicting the consequences of brain CRF system activation or deactivation in man. The thesis most strongly supported by the available experimental evidence is that: 1) activating, 2) avoidant, and 3) learning/memory functions of CRF systems have evolved to serve affective regulatory needs in man and animals. The term affective can be defined as "relating to, arising from, or influencing feelings or emotions" (Webster's Ninth Collegiate Dictionary) whereas the related phrase affective disorder describes a disturbance of mood where mood is defined as a prolonged emotion that colors the whole psychic life (American Psychiatric Association, 1994). The reader familiar with the term homeostasis may be interested in one testable postulate that a certain environmental stimulus intensity...

Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits

“…[1][2][3][4] CRF, Ucns and their receptors are implicated in the control of arousal, anxiety, cognitive functions and appetite. Chronic hyperactivation of the CRF system has been linked to stress-related emotional disorders such as anxiety, anorexia nervosa and depression.…”

Resilience and mental health

“…These behavioural mechanisms may, at least in part, be mediated through neurobiological factors of potential interest in relation to resilience in contexts of specific internal and external environments: oxytocin, prolactin, dehydroepiandrosterone (DHEA), corticotropin-releasing hormone (CRH) effects on CRH-2 receptors, neuropeptide Y, galanin, brain-derived neurotrophic factor (BDNF), GABA-benzodiazepine receptors, serotonin effects on the 5-HT1A receptors, and testosterone (Charney, 2004;Feder et al, 2009;Heinrichs & Koob, 2004;Slattery & Neumann, 2008, Southwick et al, 2005. Underlying neurobiological processes can also be described neuroanatomically with particular regions of interest including the medial prefrontal cortex, anterior cingulate, nucleus accumbens, amygdala, hippocampus, ventral tegmental area, and hypothalamus (Feder et al, 2009).…”

Effects of Low- and High-Nicotine Cigarette Smoking on Mood States and the HPA Axis in Men

“…cocaine administration under similar experimental conditions . HPA axis activation is also a response to 'stress' variously defined, and there has been considerable interest in the relationship between 'stress' and vulnerability to drug addiction (Koob and Le Moal, 2001;Sinha, 2001;Grammatopoulos and Chrousos, 2002;Marinelli and Piazza, 2002;Heinrichs and Koob, 2004), as well as other psychiatric disorders (see for review Chrousos, 1994, 2002). HPA axis hormones, as well as gonadal steroid hormones, appear to influence some behavioral responses to cocaine (Goeders, 1997(Goeders, , 2002aMello and Mendelson, 2002).…”

“…Although the interactions between the hypothalamicpituitary-adrenal (HPA) axis and the abuse-related effects of drugs are poorly understood, HPA axis activation is thought to contribute to drug abuse at several phases of the addictive process (Koob and Le Moal, 2001;Sinha, 2001;Marinelli and Piazza, 2002;Contoreggi et al, 2003;Heinrichs and Koob, 2004). For example, it has been suggested that high CRH levels may contribute to the anxiety and irritability often associated with nicotine withdrawal (Watkins et al, 2000).…”