Serotonin and norepinephrine transporters (SERT/NET)

Class

serotonin-norepinephrine reuptake inhibitor (SNRI)

Pathway

inhibits reuptake of serotonin and norepinephrine at presynaptic transporters, increasing synaptic availability of both neurotransmitters in the CNS

The serotonin transporter (SERT) and norepinephrine transporter (NET) are presynaptic membrane proteins that normally clear the neurotransmitters serotonin and norepinephrine from the synaptic cleft after they have been released, ending their signaling and allowing them to be recycled. Serotonin-norepinephrine reuptake inhibitors (SNRIs) block both transporters, so more of each neurotransmitter remains available to act on postsynaptic receptors, prolonging and amplifying signaling in relevant neural circuits. The rationale for inhibiting both transporters rather than just one is that serotonin and norepinephrine circuits contribute differently to mood regulation and to descending pain-modulating pathways in the spinal cord and brainstem; combined enhancement is thought to produce broader effects on mood and on pain perception than modulating either system alone. This dual mechanism is broadly relevant to major depressive disorder and generalized anxiety, where monoamine signaling is implicated in symptom regulation, and to chronic pain conditions such as diabetic peripheral neuropathy and fibromyalgia, where norepinephrine's role in descending inhibitory pain pathways is thought to be particularly important. Because norepinephrine also acts outside the central nervous system, this class of agents can influence physiological processes such as blood pressure and heart rate.