ANXIOGENIC AND AVERSIVE EFFECTS OF CRF IN THE BNST

IN THE RAT: ROLE OF CRF RECEPTOR SUBTYPES

M.F. Olive et al

BNST

Mediates behavioral and autonomic responses to stressors

Stimulation > behavioral/endocrine changes similar to those brought on by stress

Inhibition > decreased response to conditioned and/or unconditioned stimulus Also see increase in learned despair with lesions

and uncontrollable stress Coping mechanism?

Hypothalamus - PVN

Pituitary

Adrenal

Systemic Circulation

amygdala

BNST

CRFCRF

CRF

ACTH

Glucocorticoids

CRF = neurotransmitterCRF1 = receptorCRF2 = receptor

May (and often do) have different functions

AIMS

IntraBNST administration of CRF > stress response

There are CRF1 and CRF2 receptors in the BNST What is the roll of each of these receptors? Let’s see what happens when we shut one of

them down with an antagonist

SPECIFICS

Long-Evans (250-300g) handled

Stress study while they should be asleep!

BNST Cannulated Bilateral FITC labeled CRF to check placement 390 to 4700mw habituation

CRF1 antagonist CP154526

CRF2 antagonist Antisauvagine-30 (AS-30)

TIME LINE

Cannula

tio

nEPM

test

ing

5 days

≥ 1 week

CPP te

stin

g

ELEVATED PLUS MAZE (EPM)

Cannula

tio

nEPM

test

ing

5 days

1 hourhabituate

dinjection

Elevated

plus maze

5 min 10 min

EPM

CONDITIONED PLACE PREFERENCE (CPP)

CPP

EPM te

stin

g

≥ 1 week

Pairing of drug w/chamber days1-6

Testing Day 8

CPP testing

EPM

CP154,526 = CRF1 antagonist

AS30 = CRF2 antagonist

CRF with and without antagonist

EPM

CP154,526 = CRF1 antagonist

AS30 = CRF2 antagonist

Antagonist alone

CP154,526 = CRF1 antagonist

AS30 = CRF2 antagonist

CPP

DISCUSSION

Intra-BNST administration of CRF axiogenic effects

Under basal levels of CRF neither antagonist effects anxiety

No caged controls

Affects performance on EPM

Affects performanc

e in CPP

Affects Unconditione

d anxiety

Affects Conditioned Aversive Learning

ELEVATED PLUS MAZE VS. CONDITIONED PLACE PREFERENCE

CRF1 is responsible for the anxiogenic effects of CRF CRF has a higher affinity for CRF1

More CRF1 then CRF2 in BNST

Other studies show that CRF2 does mediate stress to a degree

These studies are nonspecific (icv, genetic knockout)

o Not remembering vs not acting on bad memories

o CRF 1 + 2 both increase hippocampal LTP

THAT MEDICAL STUFF

Chronic stress elevates CRF levels in the BNST Excititory inputs from:

Amygdala Ventral subiculum Limbic cortices

Was 1 nano mole a physiological dose simulating a stressor?

Hallmarks of PTSD Anxiety Avoidance of people, objects or places

associated