Learning Objective

By the end of this section, you should be able to explain how presynaptic α₂-autoreceptors regulate norepinephrine release and describe how amphetamines increase synaptic norepinephrine, including the roles of NET and VMAT.

Autonomic Drugs: Presynaptic Regulation of Norepinephrine

The release of norepinephrine (NE) from sympathetic nerve endings is tightly regulated by negative feedback:

• NE binds to presynaptic α₂-autoreceptors, which inhibit further NE release.

Amphetamines exploit this system to increase NE levels in the synaptic cleft:

1. Amphetamines enter the presynaptic neuron via the norepinephrine transporter (NET).
2. Inside the neuron, they are transported into neurosecretory vesicles by the vesicular monoamine transporter (VMAT).
3. Amphetamines displace NE from vesicles into the cytoplasm.
4. Once cytoplasmic NE reaches a threshold, the NET transporter reverses, expelling NE into the synaptic cleft.

This non-vesicular release of NE contributes to the sympathomimetic effects of amphetamines, including increased heart rate, blood pressure, and alertness.

Activity