The downward spiral from self-medication into addiction. The spiral depicts individuals who start using drugs primarily due to negative reinforcement mechanisms, such as seeking relief from chronic negative feelings, stress-related psychopathologies or victimization (indicated by the blue/grey shading). The drug-induced (large orange arrow) euphoria is likely attenuated in these individuals and the following post-intoxication “crash,” may temporarily exacerbate their initial dysphoria that continues unabated during drug-free periods (large grey arrows). As drug use becomes less regulated, the intervals between intoxicating events become shorter (as depicted by the narrowing of the spirals), intake increases, the positive effects become further attenuated and the dysphoria/negative affective state becomes more protracted/exacerbated. These features of addiction are the result of several interacting neurochemical changes in reward-related brain regions, including a hypodopaminergic state, characterized by reduced basal and stimulated DA concentrations (green arrows), and augmented NE (yellow arrow), CRF (pink arrow) and DYN (dark purple/blue arrow) signaling. The inhibition of other opioid systems (e.g., ENK/END/EM) (blue arrow) that contribute to positive affective state may also contribute to the dysphoria experienced by those with stress-related psychopathologies and during the development of dependence. Since many of these adaptations are already present in individuals coping with chronic stress and its associated psychopathologies even before drug use, the downward spiral may be accelerated. Women are more likely to develop stress-related psychopathologies, suggesting that a greater proportion of women may initiate drug use for self-medication, whereas a larger proportion of men may initiate drug use for their positive effects (Figure 1). Sex differences in individuals with comorbid psychopathology may also lead to different trajectories toward dependence in men and women, and in sex-specific neurochemical changes. (The magnitude of neurochemical responses is indicated by the relative sizes of the arrows, refer to text for details on sex differences).