Transcript Tyler Wray - USD Biology

Booze and anxiety
The alcohol mystery
Known mechanisms
Known mechanisms
• Suppression of excitation through ionotropic
glutamate receptors
– NMDA/AMPA
Ethanol
Known mechanisms
• Enhancing GABAergic transmission
Known mechanisms
• Enhancing GABAergic transmission
allopregnanolone
GABA
Cl-
Protein kinase C
Subjective effects
• What’s responsible?
Subjective effects
• What’s responsible?
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Energized
Talkative
“Up”
Excited
Excited
Stimulated
stimulant
depressant
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Drowsy
“Burned out”
Tired
Sluggish
Sedated
Etiology
• Positive reinforcement
• Negative reinforcement
• Shifting contingencies
+ reinforcement
•
•
Social/enhancement
motives
Enhancement
expectancies
- reinforcement
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
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
Endogenous opioid system
• Three classes of endogenous peptides
– Dynorphins
– Enkephalins
– Endorphins
• Β-endorphins
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?
Β-endorphin
• Ethanol may also ↑ directly in NAc, VTA, and CeA
ethanol
Endogenous opioid system
• Naloxazine ↓ ethanol-induced DA release in NAc
• Naloxone and naltrexone = reduced consumption and longer
time to relapse (but small overall effect!)
Endogenous opioid system
introduction
• Both CRH and β-endorphin ↑ in CeA in response to
alcohol
• Goals:
1) Alcohol  ↑ CRH release in CeA, and that this 
behavior
2) Microinjection of CRH in CeA would ↑ extracellular
concentrations of β-endorphin
3) Microinjection of CRH agonists would ↓ alcohol-induced
β-endorphin release in CeA
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
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
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
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 antisauvagine-30 (CRH2 antagonist)
– Concentrations of CRH and β-endorphin using antibodies
experiment 2
• Results
– 0.25 CRH
• Dose x time interaction
– 2.8 g/kg ethanol
• Dose x time interaction
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
experiment 2
• Results
– Inj of CHRR2 antagonist +
ethanol
• Significant three-way interaction
between drug/vehicle,
ethanol/saline, time
• CHRR2 antagonist attenuated βendorphin release after ethanol
injection between 60 and 180 min
after dose