Motivational salience regulates the strength of goal seeking, the amount of risk taken, and the energy invested, from mild to extreme. Emotional experiences promote highly persistent memories. Although this phenomenon is adaptive in normal conditions, experiences with extremely high levels of motivational salience can promote the development of memories, resulting in maladaptive outcomes such as compulsive seeking or avoidance. We have offered evidence that prefrontal cortical norepinephrine transmission is a necessary condition for motivational salience attribution to highly salient stimuli through modulation of dopamine in the nucleus accumbens, a brain area involved in motivated behaviors. Moreover, the prefrontal-accumbal catecholamine system determines approach or avoidance responses to both reward- and aversion-related stimuli only when the salience of the unconditioned stimulus is high enough to induce sustained catecholamine activation, thus affirming that this system processes motivational salience attribution selectively to highly salient events. This system, when activated by highly salient stimuli, is likely to lead to motivational and neural processes that trigger mechanisms causing aberrant motivational salience attribution and to engage other frontal-subcortical systems, resulting in compulsion-driven behavioral disorders.