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Booze and anxiety

Booze and anxiety

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Booze and anxiety

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  1. Booze and anxiety

  2. The alcohol mystery

  3. Known mechanisms

  4. Known mechanisms • Suppression of excitation through ionotropic glutamate receptors • NMDA/AMPA Ethanol

  5. Known mechanisms • Enhancing GABAergic transmission

  6. Known mechanisms • Enhancing GABAergic transmission GABA allopregnanolone Cl- Protein kinase C

  7. Subjective effects • What’s responsible?

  8. Subjective effects • What’s responsible? • Energized • Talkative • “Up” • Excited • Excited • Stimulated depressant • Drowsy • “Burned out” • Tired • Sluggish • Sedated stimulant

  9. Etiology • Positive reinforcement • Negative reinforcement • Shifting contingencies + reinforcement - reinforcement • Social/enhancement motives • Enhancement expectancies

  10. Corticotropin-releasing hormone (CRH) • Synthesized in the paraventricular nucleus (PVN) of the hypothalamus in response to stress • Travels to the pituitary via the hypophyseal portal • Pituitary increases levels of ACTH received by adrenal cortex, which in turn, produces glucocorticoids, which inhibit ACH in the brain

  11. Corticotropin-releasing hormone (CRH) • CRH has anxiogenic effects (?!) • But, stimulates β-endorphin release in the pituitary (+ ACTH) and HYP • Repeated cycles of alcohol exposure and withdrawal are associated with increased anxiety and sensitivity to stress • May be a result of adaptations in the CRH system (i.e., increased CRH release and CRH receptors) • “Up regulation” of CRH system under ethanol exposure

  12. Endogenous opioid system • Three classes of endogenous peptides • Dynorphins • Enkephalins • Endorphins • Β-endorphins

  13. Endogenous opioid system • Ethanol  β-endorphin release from pituitary and HYP • An inverse U-shaped, dose-response curve • Larger β-endorphin release for alcohol-preferring rats? • Ethanol may also ↑ directly in NAc, VTA, and CeA Β-endorphin ethanol

  14. Endogenous opioid system • Naloxazine ↓ ethanol-induced DA release in NAc • Naloxone and naltrexone = reduced consumption and longer time to relapse (but small overall effect!)

  15. Endogenous opioid system

  16. introduction • Both CRH and β-endorphin ↑ in CeA in response to alcohol • Goals: • Alcohol  ↑ CRH release in CeA, and that this  behavior • Microinjection of CRH in CeA would ↑ extracellular concentrations of β-endorphin • Microinjection of CRH agonists would ↓ alcohol-induced β-endorphin release in CeA

  17. experiment 1 • Method • Canulas placed in CeA, given either saline or 2, 2.4, 2.8 g ethanol/kg body weight • Recorded quadrant crossing, grooming activity

  18. experiment 1 • Results • Significant main effect of dose on extracellular CRH concentration • At dose levels 2.4 and 2.8g/kg • At time points 120, 150, 180 after dose

  19. experiment 1 • Results • Locomotor activity • Main effect of time • No effect of dose • Grooming • No main effect of dose • Main effect of time • Time x dose interaction

  20. experiment 2 • Method • Canulae placed in CeA, given 0.5 ml of either 0.25 mg CRH, 0.25 mg antalarmin hydrochloride (CRH1 antagonist), or 0.25 mg anti-sauvagine-30 (CRH2 antagonist) • Concentrations of CRH and β-endorphin using antibodies

  21. experiment 2 • Results • 0.25 CRH • Dose x time interaction • 2.8 g/kg ethanol • Dose x time interaction

  22. experiment 2 • Results • Inj of CHRR1 antagonist + ethanol • Significant interaction between drug/vehicle and ethanol/saline • CHRR1 antagonist buffered against ethanol-related β-endorphin release over time

  23. experiment 2 • Results • Inj of CHRR2 antagonist + ethanol • Significant three-way interaction between drug/vehicle, ethanol/saline, time • CHRR2 antagonist attenuated β-endorphin release after ethanol injection between 60 and 180 min after dose