Autoreceptor · Grey Matter

An autoreceptor is a receptor on a neuron that responds to the neuron's own transmitter, usually on its terminals, and it works as a thermostat: when release runs high, the transmitter in the cleft turns release down.

Autoreceptor. An autoreceptor is a receptor on a neuron that responds to the neuron's own transmitter, usually on its terminals, and it works as a thermostat: when release runs high, the transmitter in the cleft turns release down.

Most autoreceptors are metabotropic. When they bind transmitter they activate G proteins that inhibit the terminal's calcium channels and open potassium channels, so the next spike lets in less calcium and releases less. Classic examples are the D2 receptors on dopamine terminals, the alpha-2 adrenergic receptors on noradrenaline terminals, the 5-HT1A receptors on the cell bodies of serotonin neurons (which slow their firing), and GABA-B receptors on GABA terminals. A receptor on a terminal that responds to a different cell's transmitter does the same job from outside and is called a heteroreceptor.

They set a ceiling on release. Blocking them lets the terminal release more per spike, which is part of how some drugs raise transmitter levels.

They explain delays in drug action. One explanation for why antidepressants that raise serotonin take weeks to work is that the 5-HT1A autoreceptors first hold serotonin neurons back, and their gradual desensitisation lets the effect through.

Clonidine acts as an agonist at alpha-2 receptors and reduces noradrenaline release, which lowers blood pressure and calms withdrawal symptoms.

An autoreceptor lets a synapse measure its own output.

That negative feedback keeps release in range, and drugs that tilt it change how much transmitter a neuron delivers per spike.

Questions: How does a dopamine neuron limit its own release? Dopamine terminals and cell bodies carry D2 receptors that respond to the dopamine they have just released. Through inhibitory G proteins these autoreceptors reduce calcium entry and release at the terminal, slow the cell's firing at the soma, and turn down the synthesis of new dopamine. The loop keeps release in range: blocking D2 autoreceptors, as some antipsychotics do in part, transiently increases dopamine release and synthesis. Together with reuptake by the dopamine transporter, this feedback shapes how long a burst of dopamine lasts. If SSRIs raise serotonin within hours, why do they take weeks to work? Blocking the serotonin transporter raises serotonin around the raphe neurons first, where it acts on their 5-HT1A autoreceptors and slows their firing, so serotonin in the forebrain rises less than expected at the start. Over two to several weeks those autoreceptors desensitise and the neurons fire normally again with the transporter still blocked, which is one classic explanation for the delay. Other proposed explanations involve slow changes downstream (plasticity, new gene expression, changes in how emotional information is processed), and the delay is probably the sum of several of them. The question matters because it shows that a drug's immediate chemical effect and its clinical effect can be separated by weeks of adaptation.