Indirect agonists: reuptake inhibitors, enzyme inhibitors and releasers
Explains drugs that never touch the receptor but still boost signaling by raising the neurotransmitter in the cleft: blocking reuptake, blocking breakdown, or forcing release.
Where this fitsConnects to 3 · Unlocks 2
- Connects to
- The synapse: release, binding and termination — Each mechanism changes one step of the synapse you already know.
- Norepinephrine and serotonin — and serotonin syndrome — SSRIs, MAOIs and serotonin syndrome come back as mechanisms.
- Dopamine: receptor families, clearance and pathways — The dopamine synapse is the worked example: every step has a drug.
- Unlocks
- Safety: therapeutic index, dosing across species, allergy and polypharmacy — Stacking these mechanisms (MAOI + MDMA) is the classic dangerous interaction.
- The reward circuit: reinforcement and dopamine — Cocaine and amphetamine raise dopamine in the reward circuit through these mechanisms.
Walk through
Reuptake inhibitor
The drug blocks the transporter that pulls neurotransmitter back into the terminal, so more stays in the cleft. SSRIs (Prozac) block the serotonin transporter; cocaine and methylphenidate (Ritalin) block the dopamine transporter.
Analogy and worked example
Analogy: Think of the synaptic cleft as a bathtub. Release is the tap, reuptake is the drain, the enzyme is a sponge soaking water up. A reuptake inhibitor plugs the drain. An enzyme inhibitor takes the sponge away. A releaser opens the tap by itself — even when no one turned it on — and can run the tank dry.
Cocaine and amphetamine both raise dopamine in the cleft. What's the mechanistic difference?
- Cocaine binds the dopamine transporter and blocks it: released dopamine stays in the cleft longer. It depends on the neuron firing.
Tip: the ← and → keys move through the lesson.
Full lesson: Monoamine transport