NMDA receptor
What it is
Glutamate-gated ion channel; primary excitatory neurotransmitter receptor in CNS. Ethanol antagonises NMDA at concentrations corresponding to social drinking.
Ethanol’s action
- Non-competitive antagonist at NMDA receptors
- Blocks glutamate-mediated excitatory neurotransmission
- Contributes to ethanol’s anticonvulsant, anxiolytic, and amnesic effects
The glutamate rebound problem
- With chronic ethanol → NMDA receptors upregulate (compensatory)
- When ethanol clears → unopposed glutamate activity → hyperexcitability
- This drives: anxiety, tremor, seizures, insomnia, and rebound sympathetic activation during hangover
The hangover connection
NMDA rebound = autonomic hyperexcitability overnight and next morning:
- Elevated RHR (↑10–25 bpm)
- Suppressed HRV (RMSSD ↓ 30–50%)
- This is not dehydration — it’s neurotransmitter rebound
Relationship with GABA-A
GABA-A (inhibitory) and NMDA (excitatory) are reciprocally regulated by ethanol:
- Acute ethanol: GABA-A ↑ + NMDA ↓ → net inhibition
- Withdrawal: GABA-A ↓↓ + NMDA ↑↑ → hyperexcitability