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