Cocaine increases quantal norepinephrine secretion through net-dependent PKC activation in locus coeruleus neurons.

Abstract

The norepinephrine neurons in locus coeruleus (LC-NE neurons) are essential for sleep arousal, pain sensation, and cocaine addiction. According to previous studies, cocaine increases NE overflow by blocking the NE reuptake. NE overflow is determined by NE release via exocytosis and reuptake through NE transporter (NET). However, whether cocaine directly affects vesicular NE release has not been directly tested. By recording quantal NE release from LC-NE neurons, we report that cocaine directly increases the frequency of quantal NE release through regulation of NET and downstream protein kinase C (PKC) signaling, and this facilitation of NE release modulates the activity of LC-NE neurons and cocaine-induced stimulant behavior. Thus, these findings demonstrate NET as a release enhancer in LC-NE neurons, and provide potential sites for treatment of cocaine addiction.