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
GABA
Cl-
Protein kinase C

7. Subjective effects
What’s responsible?

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

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 Grooming Main effect of time
No effect of dose
Grooming
No main effect of dose
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

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