Adenoviral-mediated CRF hyper-expression: Implications for a novel preclinical model of depression.

FARROKHI; VIT; LACAYO; CASTRO; MANALO; LOWENSTEIN; PUNTEL; MUHAMMAD; REYES; PECHNICK

San Diego, California, US

Congreso; Society for Neuroscience; 2010

Corticotropin-releasing factor (CRF) has been examined extensively to elicudate its role in mediating neuroendocrine and behavioral responses to stress. Elevated CRF levels produce behavioral changes, decrease feeding, cause sleep disturbances, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in animals as well as in humans, and is a potential contributor to the symptoms of major depressive disorder. Until recently, preclinical models utilized intra-cerebral administration of CRF and synthetic agonist compounds to examine the behavioral effects of CRF. Whereas these models have been useful for examining CRF-induced stress responses, the kinetics of CRF and these compounds result in rapid onset and subsequent termination of the effects within hours of administration. This allows examination of acute responses but provides little information on the long-tern effects. Recent development of a recombinant adenoviral vector expressing CRF (CRF-AVV) has allowed us to examine chronic CRF up-regulation. The paraventicular nucleus of the hypothalamus (PVN) and the central amygdala (CeA) are regions containing CRF-expressing neurons and is densely populated with CRF receptors. They are primary centers involved in CRF-mediated HPA-axis regulation and behavioral responses. The purpose of this experiment was to assess the effects of CRF hyper-expression in these two regions. CRH-AVV was infused into the PVN or CeA of adult male rats. CRH-AVV produced CRF hyper-expression as demonstrated by increased CRF-positive staining that was detectable in both regions of the brain 7 and 30 days following administration. CRH-AVV infusion into either the CeA or PVN produced anhedonia-like behavior as measured by decreases in food intake and weight loss up to 30-days post vector treatment. Our findings also suggest that a dysregulation of the HPA-axis is present 33-days after infusion. Behavioral testing is continuing to examine further the effects of CRF hyper-expression and its potential for use as a preclinical model of depression.