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Understanding the Link Between Alcohol and Anxiety: Mechanisms and Effects

This article explores the intricate relationship between alcohol consumption and anxiety, examining the known mechanisms behind these effects. It delves into how alcohol suppresses excitation through ionotropic glutamate receptors, enhances GABAergic transmission, and impacts the corticotropin-releasing hormone (CRH) and endogenous opioid systems. The article analyzes subjective effects such as energization and sedation, positive and negative reinforcement, and the biological underpinnings of anxiety during alcohol exposure and withdrawal.

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Understanding the Link Between Alcohol and Anxiety: Mechanisms and Effects

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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

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