Short-term Effects of Alcohol - Pathophysiology

Pathophysiology

At low or moderate doses, alcohol acts primarily as a positive allosteric modulator of GABA_A. Alcohol binds to several different subtypes of GABA_A, but not to others. The main subtypes responsible for the subjective effects of alcohol are the α₁β₃γ₂, α₅β₃γ₂, α₄β₃δ and α₆β₃δ subtypes, although other subtypes such as α₂β₃γ₂ and α₃β₃γ₂ are also affected. Activation of these receptors causes most of the effects of alcohol such as relaxation and relief from anxiety, sedation, ataxia and increase in appetite and lowering of inhibitions that can cause a tendency toward violence in some people.

Alcohol has a powerful effect on glutamate as well. Alcohol decreases glutamate's ability to bind with NMDA and acts as an antagonist of the NMDA receptor, which plays a critical role in LTP by allowing Ca2+ to enter the cell. These inhibitory effects are thought to be responsible for the "memory blanks" that can occur at levels as low as 0.03% blood level. In addition, reduced glutamate release in the dorsal hippocampus has been linked to spatial memory loss. Chronic alcohol users experience an upregulation of NMDA receptors because the brain is attempting to reestablish homeostasis. When a chronic alcohol user stops drinking for more than 10 hours, apoptosis can occur due to excitotoxicity. The seizures experienced during alcohol abstinence are thought to be a result of this NMDA upregulation. Alteration of NMDA receptor numbers in chronic alcoholics is likely to be responsible for some of the symptoms seen in delirium tremens during severe alcohol withdrawal, such as delirium and hallucinations. Other targets such as sodium channels can also be affected by high doses of alcohol, and alteration in the numbers of these channels in chronic alcoholics is likely to be responsible for as well as other effects such as cardiac arrhythmia. Other targets that are affected by alcohol include cannabinoid, opioid and dopamine receptors, although it is unclear whether alcohol affects these directly or if they are affected by downstream consequences of the GABA/NMDA effects. People with a family history of alcoholism may exhibit genetic differences in the response of their NMDA glutamate receptors as well as the ratios of GABA_A subtypes in their brain.

Contrary to popular belief, research suggests that acute exposure to alcohol is not neurotoxic in adults and actually prevents NMDA antagonist-induced neurotoxicity.