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 allopregnanolone GABA Cl- Protein kinase C

Subjective effects What’s responsible?

Subjective effects What’s responsible? Energized Talkative “Up” Excited Stimulated stimulant depressant 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 CeA Β-endorphin 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: 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

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

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