DAT blockade

What it is

Cocaine’s primary psychopharmacological mechanism. It’s a competitive, use-dependent triple monoamine reuptake inhibitor — highest affinity for DAT (dopamine transporter), then NET (norepinephrine transporter), then SERT (serotonin transporter).

Why it matters

• DAT blockade → cytosolic DA accumulates → cannot be cleared → overflows into synaptic cleft → nucleus accumbens DA surge → euphoria
• NET blockade → synaptic NE accumulation → sympathetic overdrive → tachycardia, hypertension, hyperthermia
• SERT blockade → 5-HT accumulation → modulatory effect on mood, impulse control

The relative DAT:NET:SERT affinity explains cocaine’s profile: strong reward (DAT) + strong autonomic activation (NET) + modest serotonergic modulation (SERT).

Secondary mechanism: Na⁺ channel blockade

Cocaine also blocks voltage-gated sodium channels (local anaesthetic effect). This is mechanistically distinct from the DAT/NET/SERT effects and is the primary driver of cardiac arrhythmia risk.

Use-dependent kinetics: higher HR (from catecholamine surge) worsens Na⁺ blockade → pro-arrhythmic positive feedback loop.

Crash not driven by DAT per se

DAT itself doesn’t change acutely. The crash is driven by:

• D2 autoreceptor-mediated vesicular redistribution → functional presynaptic deficit
• PKC-mediated DAT dysregulation (cocaine blocks PKC phosphorylation of DAT → keeps DAT levels high → pulls DA out of synapse faster during recovery)
• See Cocaine crash

Related

Cocaine, Cocaine crash, Cardiovascular signatures, Cocaethylene