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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. GABA. - PowerPoint PPT Presentation
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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
GABAallopregnanolone
Protein kinase C
Cl-
Subjective effects• What’s responsible?
Subjective effects• What’s responsible?
stimulant depressant• Energized• Talkative• “Up”• Excited• Excited• Stimulated
• Drowsy• “Burned out”• Tired• Sluggish• Sedated
Etiology• Positive reinforcement• Negative reinforcement• Shifting contingencies
+ reinforcement - reinforcement
• Social/enhancement motives
• Enhancement expectancies
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?
• Ethanol may also ↑ directly in NAc, VTA, and CeAΒ-
endo
rphi
n
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
behavior2) Microinjection of CRH in CeA would ↑ extracellular
concentrations of β-endorphin3) 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 anti-sauvagine-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 β-endorphin release after ethanol injection between 60 and 180 min after dose