While GSK561679 was not superior to placebo overall, it was associated with a significantly stronger symptom reduction in a subset of patients with probable CRF system hyperactivity, i.e., patients with child abuse and CRHR1 SNP rs110402 GG carriers.
Further, we review the known sex differences and estradiol modulation of these neuron populations and CRF signaling at their synapses to address the question of whether females are more susceptible to the development of comorbid addiction and stress-related neuropsychiatric diseases because of hyperactive extrahypothalamic CRF circuits compared to males.
These results together demonstrate that AEO exerts anxiolytic and antidepressant effects which are related to the inhibition of CRF and hyperactivity of the HPA axis.
Over-activation of corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) plays a key role in the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and is a prominent feature in depression.
Hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA) and impairment of the central corticotropin-releasing factor (CRF) system are factors in the pathogenesis of depression.
This study tested whether the hyper-responsiveness was due to a lowered threshold of response to corticotropin releasing factor (CRF) or an exaggerated response to a standard dose of CRF.
These changes, including increased availability of corticotropin-releasing factor and cortisol, are also associated with hyperactivity of the amygdala, hypoactivity of the hippocampus, and decreased serotonergic neurotransmission, which together result in increased vulnerability to stress.
To test the hypothesis that elevated CRF output from the amygdala would reproduce HPA axis hyperactivity and behavioral symptoms of chronic stress, we developed a lentiviral vector in which 3.0kb of the CRF promoter drives overexpression of CRF (LVCRFp3.0CRF).
Hyperactivity of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus is a prominent feature in depression and may be important in the etiology of this disease.
Accumulating evidence suggests that the neuroendocrine and behavioural symptoms observed in patients suffering from major depression are at least in part linked to a hyperactivity of the CRH system.
The evidence that the HPA axis is hyperactive in MDD, probably as a result of a primary hyperdrive of CRH, comes from multiple sources: biochemical studies, functional HPA axis tests, neuroimaging and postmortem studies, and clinical trials with HPA axis-related compounds.
Preclinical data based on animal models including selectively bred rat lines and mouse mutants support the notion that CRH neurons are hyperactive also in neuroanatomical regions that are involved in behavioral regulation but are located outside the neuroendocrine system.