title: Microinfusion of a corticotrophin-releasing hormone receptor 1 antisense oligodeoxynucleotide into the dorsal hippocampus attenuates stress responses at specific times after stress exposure.
abstract: Corticotrophin-releasing hormone (CRH) plays a key role in the adjustment of neuroendocrine and behavioural adaptations to stress. Dysregulation in CRH systems has been implicated in a variety of stress-related psychiatric disorders such as post-traumatic stress disorder (PTSD). The present study examined the relationship between stress-induced PTSD-like behavioural response patterns and levels of CRH, CRH receptor (CHR-R)1 and phosphorylated extracellular signal-regulated kinase (pERK1/2) in the rat hippocampus subregions. The effects of pharmacological manipulations on behavioural, physiological and response patterns of brain-derived neurotrophic factor (BDNF) and pERK1/2 expression using a CRH receptor (CRH-R)1-antisense oligodeoxynucleotide (CRH-R1-ASODN) were evaluated. CRH and CRH-R1 mRNA and pERK1/2 protein levels were assessed in the hippocampus subregions 7 days after exposure to predator scent stress (PSS). The effects of CRH-ASODN versus CRH-Scrambled-ODN microinfusion to the dorsal hippocampus either 1 h or 48 h post-exposure on behavioural tests (elevated plus maze and acoustic startle response) were evaluated 7 days later, 14 days after PSS exposure. Localised brain expression of BDNF and ERK1/2 was subsequently assessed. All data were analysed in relation to individual behaviour patterns. A distinct pattern associated with extreme behavioural response (EBR) was revealed in the bioassay of behavioural study subjects, classified according to their individual patterns of behavioural response at 7 days. These EBR individuals displayed significantly higher CRH and CRH-R1 mRNA levels in the CA1 and CA3 areas, mediating down-regulation of pERK1/2 protein levels. Microinfusion of a CRH-R1-ASODN into the dorsal hippocampus 48 h after stress exposure, although not immediately after exposure (1 h), significantly reduced behavioural disruption and was associated with concomitant up-regulation of BDNF and pERK1/2 protein levels compared to CRH-R1-Scrambled -ODN controls. CRH/CRH-R1 is actively involved in the neurobiological response to predator scent stress processes and thus warrants further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.
authors.affiliation: Ministry of Health Mental Health Center, Anxiety, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Kozlovsky
authors.forename: J
authors.initials: J
authors.lastname: Zohar
authors.forename: Z
authors.initials: Z
authors.lastname: Kaplan
authors.forename: H
authors.initials: H
authors.lastname: Cohen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D013216:Reflex, Startle; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D048049:Extracellular Signal-Regulated MAP Kinases