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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 allopregnanolone GABA Cl- Protein kinase C Subjective effects • What’s responsible? Subjective effects • What’s responsible? • • • • • • Energized Talkative “Up” Excited Excited Stimulated stimulant depressant • • • • • 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