Alcohol withdrawal pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[2] Aditya Govindavarjhulla, M.B.B.S. [3]

Under normal conditions in the brain, there is a balance between excitatory neurotransmitters such as glutamate and inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA). Chronic alcohol intake and acute discontinuation of alcohol intake affect the balance of the neurotransmitters and cause many of the symptoms observed in alcohol withdrawal.

Under normal conditions in the brain, there is a balance between excitatory neurotransmitters such as glutamate and inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA).^[1]

Chronic alcohol intake and acute discontinuation of alcohol intake affect the balance of the neurotransmitters and cause many of the symptoms observed in alcohol withdrawal.^{[2] [3][4][1]}

Acute Alcohol Consumption

• Increases the GABA neurotransmitter and sensitivity of GABA-A receptor subtypes, which in turn, increases inhibitory neurotransmission.
• Prevents the effects of glutamate (an excitatory neurotransmitter) on the N-methyl-d-aspartate (NMDA) receptors by inhibiting the binding of glycine to the NMDA receptors.^[5][6]

Chronic Alcohol Consumption

• Causes tolerance and compensation by downregulation GABA-A receptors and upregulating NMDA receptors, and requires higher blood levels of alcohol to cause the same effect.^[5][6]

Alcohol Withdrawal in Chronic Alcohol Consumption

• Exposes the downregulation of GABA-A receptors and the upregulation of NMDA receptors, resulting in hyperexcitability of the neurons that lower the threshold for seizures.^[2][7][8]
• Upregulation of noradrenergic and dopaminergic receptors cause the autonomic hyperactivity and hallucinations that are seen in patients with alcohol withdrawal.^[9]
• Kindling is increased excitability and sensitivity of the neurons after repeated events of alcohol withdrawal,^[10][11] and is suggested to be the reason for progressing from milder to more severe symptoms of alcohol withdrawal in some patients.^[2]