Transcript Repeated Stimulation of CRF Receptors in the BNST of Rats

Younglim Lee, Stephanie Fitz, Phillip L Johnson and Anantha Shekhar
 BNST identified as a key that relays and integrates limbic
and autonomic info related to stress responses
 CRF given centrally induces anxiogenic behaviors in
different models:
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EPM
Social Interaction (SI)
Open Field
Conflict Test
Acoustic Startle
Conditioned Fear Response
 Both CRF1 & CRF2 receptors found in the BNST
 UCn1 = urocortin 1 – CRF agonist
 CRF receptor 1 & 2 agonist (suggested CRF1 receptor)
 Astressin – CRF antagonist – not receptor specific
 mmol (mili mole) is 1 x 10-3 moles
µmol (micro mole) is 1 x 10-6 moles
nmol (nana mole) is 1 x 10-9 moles
pmol (pica mole) is 1 x 10-12 moles
fmol (fempta mole) is 1 x 10-15 moles
 Repeated priming injections into BLA w/ CRF receptor
agonist Ucn1 at subthreshold dose induces long lasting
behavioral change in SI & EPM
 Ucn1 priming in BLA produced anxiety behaviors and
physiological sensitivity to IV sodium lactate infusions as
seen in panic & PTSD disorders
Sodium lactate given IV induces panic (Johnson et al. 2007)
 That acute stimulation of CRF receptors in BNST will
anxiety & repeated stimulation will elicit persistent
anxiety-like behaviors
 Investigated
1.
2.
3.
Effects of different UCn1 doses in BNST to determine
subthreshold dose
Effects of repeated daily intra-BNST Ucn1 injections of found
subthreshold dose (UCn1 priming)
Changes in lactate sensitivity following UCn1 priming of BNST
 Male Wistar Rats (275-
300g)
 Individually housed at
22C, food/water ad
libitum
 12h light/dark, lights on
at 0700h
 Implantation of
telemetry probes
 Measuring
 Arterial pressure
 Heart rate
 Femoral arterial line
connected to telemetric
probe
 BNST cannulation
 Only unilaterally
 Social Interaction (SI)
 Anxiety test
 Wooden box, place exp
rat in with novel rat and
video tape behavior
 Grooming, sniffing,
playful behavior
 EPM
Results
Fig a. suggest dose dependent reduction of SI following CRF receptor
activation
 Repeated injections of
long-lasting anxiety
UCn1 into BNST will lead to
•UCn1 of 6-fmol dose (subthreshold)
•No difference in EPM!
 Pretreatment w/ CRF antagonist will block
development of Ucn1 priming in BNST
 Rats injected locally w/ Astressin- a nonselective CRF
antagonist prior to daily UCn1 dose (6-fmol)
 Astressin- intransitive verb- (a \ˈstres\ inn)
 Used colloquially in times of great stress
 Example: I’m astressin OUT!!!
 Astressin completely blocked UCn1 priming in the BNST
 UCn1 priming of BNST will not increase sensitivity to a
subsequent challenge w/ sodium lactate
•No change in SI or physiological
responses w/ lactate infusion
 UCn1 injected into BNST
anxiety behavior
 Suggests CRF system in BNST regulates certain anxiety behaviors
 Decreases SI but no effect on EPM (only uni not bicannulated!)
 BLA primed rats had anxiogenic effects in SI & EPM
 UCn1 primed rats did not have panic-like cardiovascular
responses to lactate infusion
 BNST critical in acquisition/expression social anxiety w/0
the physiological sensitivity to lactate (Clinical
Implications)
 Authors note difference in SI for different strains of
rats
 Wistar: 15-35s
 Sprague-Dawley: 40-70s
 Long-Evans: ???
 SI recorded in “light cycle” 9am-1pm
 Acknowledge behavior test in dark cycle may increase SI
 Drug seeking behavior modulated w/ CRF in BNST
circuitry
 Activation of CRF system for stress reinstatement of
drug-seeking behavior
 CRF receptor antagonism blocks this stress effect
 BNST key to mediation
 inject CRF drug-seeking
 Inject CRF antagonist block drug-seeking behavior
 Pathophysiology similar to many mental disorders
 If social anxiety develops from CRF modulation in
BNST
 & If CRF stimulation w/in BNST modulates drugseeking behavior
 Then use UCn1 priming in BNST to search for
vulnerability w/ substance abuse & psychiatric
disorders
 UCn1 & astressin high affinities for both CRF receptors
 UCn1 in SI mediated CRF1 not CRF2 (Maybe? Prelim results)
 Anxiogenic effects of CRF in BNST from CRF1 receptors
 Drug-seeking from both CRF1 & CRF2
 Repeated UCn1 priming into BNST = anxiety in SI but
not EPM
 Primed rats failed lactate challenge = no HR or
pressure increases!
 Priming may model social anxiety disorder!!!
 Repeated activation of BNST CRFR!!!