Autoreceptors

Autoreceptors are receptors located on the neuron that releases the neurotransmitter, serving as a negative feedback mechanism to regulate neurotransmitter synthesis and release. Most autoreceptors are G protein-coupled receptors that typically couple to Gi/o proteins, inhibiting adenylyl cyclase, reducing cAMP levels, decreasing calcium influx, and activating potassium channels to dampen neuronal activity.

Autoreceptors can be situated on somatodendritic regions, where they influence the firing rate of the neuron, or on axon terminals, where they modulate vesicular release of transmitter. They are found for multiple neurotransmitter systems, most notably dopamine (D2 autoreceptors), norepinephrine (alpha-2 autoreceptors), and serotonin (5-HT1A/1B autoreceptors). Some also regulate synthesis by inhibiting enzymes such as tyrosine hydroxylase in catecholamine systems.

Activation of autoreceptors generally decreases transmitter release and can reduce neuronal excitability. Conversely, blockade or desensitization of autoreceptors can lead to increased release. Pharmacological manipulation of autoreceptors underpins several clinical and research approaches; for example, alpha-2 agonists like clonidine activate autoreceptors to reduce sympathetic outflow, and presynaptic D2 autoreceptors influence dopaminergic signaling and can affect the action of antipsychotic drugs. Serotonin autoreceptors are implicated in mood regulation and the mechanism of antidepressants.

Chronic activity or drug exposure can induce adaptive changes in autoreceptors, including desensitization or alterations in receptor density, contributing to long-term modulation of neurotransmission. Autoreceptors thus play a key role in maintaining synaptic balance and shaping pharmacological responses across neurotransmitter systems.