In addition to resetting the brain’s reward system, repeated exposure to the dopamine-enhanc ing effects of most drugs leads to adaptations in the circuitry of the extended amygdala in the basal forebrain; these adaptations result in increases in a person’s reactivity to stress and lead to the emergence of negative emotions.32,33 This “antireward” system is fueled by the neurotransmitters involved in the stress response, such as corticotropin-releasing factor and dynorphin, which ordinarily help to maintain homeostasis. However, in the addicted brain, the antireward system becomes overactive, giving rise to the highly dysphoric phase of drug addiction that ensues when the direct effects of the drug wear off or the drug is withdrawn34 and to the decreased reactivity of dopamine cells in the brain’s reward circuitry.35 Thus, in addition to the direct and conditioned pull toward the “rewards” of drug use, there is a correspondingly intense motivational push to escape the discomfort associated with the aftereffects of use. As a result of these changes, the person with addiction transitions from taking drugs simply to feel pleasure, or to “get high,” to taking them to obtain transient relief from dysphoria (Fig. 1).
