Prefrontal cortical norepinephrine release is critical for morphine-induced reward, reinstatement and dopamine release in the nucleus accumbens.

Increasing evidence suggests that in addition to the mesoaccumbens dopamine (DA) system other neurotransmitter and brain systems are also involved in opiate addiction. Recent evidence points to a major involvement of brain norepinephrine (NE) in the behavioral and central effects of opiates and, more specifically, indicates that NE in the prefrontal cortex may have a critical role in rewarding effects of opiates. Moreover, a body of data points to regions within the medial prefrontal cortex (mpFC) acting as final common pathway of drug relapse behavior. The present experiments were aimed at investigating the possibility of a selective involvement of the prefrontal cortical NE in the rewarding and reinstating effects of morphine. In a first set of experiments, we found that morphine enhances NE and DA release in the mpFC and DA release in the nucleus accumbens, as measured by intra-cerebral microdialysis. Selective depletion of medial prefrontal cortical noradrenergic afferents abolished the morphine-induced increase in DA release in the nucleus accumbens. In a second series of experiments, we demonstrated that the same lesion impaired both conditioned place preference (CPP) induced by morphine and reinstatement of an extinguished CPP. The present results indicate that an intact prefrontal cortical NE transmission is necessary for morphine-induced rewarding effects, reinstatement, and mesoaccumbens dopamine release.