Figure 9.

Diagram of the hypothetical “within-system” and “between-system” changes that lead to the “darkness within.” (Top) Circuitry for drug reward with major contributions from mesolimbic dopamine and opioid peptides that converge on the nucleus accumbens. During the binge/intoxication stage of the addiction cycle, the reward circuitry is excessively engaged, Middle. Such excessive activation of the reward system triggers “within-system” neurobiological adaptations during the withdrawal/negative affect stage, including activation of cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB), downregulation of dopamine D₂ receptors, and decreased firing of ventral tegmental area (VTA) dopaminergic neurons, Bottom. As dependence progresses and the withdrawal/negative affect stage is repeated, two major “between-system” neuroadaptations occur. One is activation of dynorphin feedback that further decreases dopaminergic activity. The other is recruitment of extrahypothalamic norepinephrine (NE)-corticotropin-releasing factor (CRF) systems in the extended amygdala. Facilitation of the brain stress system in the prefrontal cortex is hypothesized to exacerbate the between-system neuroadaptations while contributing to the persistence of the dark side into the preoccupation/anticipation stage of the addiction cycle [taken with permission from Ref. (191)].