## Neurobiology of Alcohol Withdrawal ### GABAergic and Glutamatergic Imbalance **Key Point:** Alcohol is a CNS depressant that enhances GABAergic (inhibitory) neurotransmission and suppresses glutamatergic (excitatory) neurotransmission. With chronic use, the brain adapts by downregulating GABA~A~ receptors and upregulating NMDA glutamate receptors to maintain homeostasis. ### Mechanism of Withdrawal When alcohol is suddenly withdrawn: 1. GABAergic inhibition is reduced (fewer functional GABA receptors) 2. Glutamatergic excitation becomes unopposed (upregulated NMDA receptors remain active) 3. This creates a state of **CNS hyperexcitability** **High-Yield:** This GABAergic hypofunction + glutamatergic hyperactivity explains all withdrawal manifestations: - Tremor, autonomic hyperactivity (tachycardia, hypertension, diaphoresis) - Anxiety, agitation - Seizures (in severe cases) - Delirium tremens (hallucinations, disorientation) ### Clinical Correlation **Clinical Pearl:** Benzodiazepines (which enhance GABAergic transmission) and baclofen (GABA~B~ agonist) are the mainstay of withdrawal management because they restore the inhibitory tone lost during alcohol cessation. [cite:Harrison 21e Ch 474]
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