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Younglim Lee, Stephanie Fitz, Phillip L Johnson and Anantha Shekhar

Repeated Stimulation of CRF Receptors in the BNST of Rats Selectively Induces Social but not Panic-Like Anxiety. Younglim Lee, Stephanie Fitz, Phillip L Johnson and Anantha Shekhar. Background.

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Younglim Lee, Stephanie Fitz, Phillip L Johnson and Anantha Shekhar

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  1. Repeated Stimulation of CRF Receptors in the BNST of Rats Selectively Induces Social but not Panic-Like Anxiety Younglim Lee, Stephanie Fitz, Phillip L Johnson and Anantha Shekhar

  2. Background • 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: • EPM • Social Interaction (SI) • Open Field • Conflict Test • Acoustic Startle • Conditioned Fear Response • Both CRF1 & CRF2 receptors found in the BNST

  3. Don't Do Drugs • 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

  4. Previous Studies Found • 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

  5. Sodium lactate given IV induces panic (Johnson et al. 2007)

  6. Sodium lactate given IV induces panic (Johnson et al. 2007)

  7. Hypothesis & Investigation • That acute stimulation of CRF receptors in BNST will anxiety & repeated stimulation will elicit persistent anxiety-like behaviors • Investigated • 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

  8. Animals • Male Wistar Rats (275-300g) • Individually housed at 22C, food/water ad libitum • 12h light/dark, lights on at 0700h

  9. Surgical Procedures • Implantation of telemetry probes • Measuring • Arterial pressure • Heart rate • Femoral arterial line connected to telemetric probe • BNST cannulation • Only unilaterally

  10. Behavior Tests • Social Interaction (SI) • Anxiety test • Wooden box, place exp rat in with novel rat and video tape behavior • Grooming, sniffing, playful behavior • EPM

  11. Exp. 1 -Injecting UCn1 in BNST (not adjacent area) will induce anxiety in rats measured in SI Results Fig a. suggest dose dependent reduction of SI following CRF receptor activation

  12. Experiment 2 • Repeated injections of UCn1 into BNST will lead to long-lasting anxiety

  13. Exp. 2 Results • UCn1 of 6-fmol dose (subthreshold)

  14. Exp. 2 Results cont. • No difference in EPM!

  15. Experiment 3 • 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!!!

  16. Exp. 3 results • Astressin completely blocked UCn1 priming in the BNST

  17. Experiment 4 • UCn1 priming of BNST will not increase sensitivity to a subsequent challenge w/ sodium lactate

  18. Exp. 4 Timeline

  19. Exp. 4 Results

  20. Exp. 4 Results cont. • No change in SI or physiological responses w/ lactate infusion

  21. Discussion • 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)

  22. Discussion cont. • 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

  23. Discussion cont. • 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

  24. Discussion cont. • If social anxiety develops from CRF modulation in BNST • & If CRF stimulation w/in BNST modulates drug-seeking behavior • Then use UCn1 priming in BNST to search for vulnerability w/ substance abuse & psychiatric disorders

  25. CRF1 & CRF2 Receptors • 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

  26. Take Home • 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!!!

  27. The End

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