Stimulant-dependent DA increases in the striatum are associated with the feeling of “high.” A: Distribution volume (DV) images of [¹¹C]raclopride for one of the subjects at baseline and after administration of 0.025 and 0.1 mg/kg i.v. of MPH. MPH-reduced binding of [¹¹C]raclopride dose-dependently in the striatum, where it competes with DA for binding to DA D2 receptors (D2R). B: MPH significantly increased ratings of high. Regression lines for the correlation between MPH-induced changes in D2R availability in striatum and MPH-induced changes in self-reports of high (r 0.78, df₂₂, p < 0.0001). PET studies are carried out with a radiolabeled compound such as [¹¹C]raclopride that binds to dopamine receptors (D2R) whenever they are not occupied by DA. Measurements are done first after injection of a placebo and then, after drug administration, such that the difference in [¹¹C]raclopride (positron) signal between the two conditions can be used to estimate the amount of receptor occupancy and, thus, the magnitude of any drug-induced DA increase. MPH was administered IV at the following doses (in mg/kg): 0.5 (circles), 0.25 (squares), 0.1 (diamonds), and 0.025 (triangles). Modified with permission from Volkow et al. [14].

A: Axial brain images of the distribution of [¹¹C]methamphetamine at different times (minutes) after its administration. B: Time activity curve for the concentration of [¹¹C]methamphetamine in striatum alongside the temporal course for the “high” experienced after intravenous administration of pharmacological doses of methamphetamine. Modified with permission from Fowler et al. [55].

Brain images of DA D2 receptors (D2R) at the level of the striatum in control subjects and substance drug abusers. Images were obtained with [¹¹C]raclopride. Modified with permission from Volkow et al. [30].

A: Images obtained with fluorodeoxyglucose (FDG) to measure brain metabolism in a control and in a cocaine abuser. Note the reduced metabolism in the orbitofrontal cortex (OFC) in the cocaine abuser when compared with the control. B: Correlations between DA D2 Receptors (D2R) in striatum and glucose metabolism in orbito-frontal cortex (OFC) in cocaine abusers. Modified with permission from Volkow et al. [29].

MPH induced increases (assessed by its inhibition of raclopride's specific binding or Bmax/Kd) in controls and in detoxified alcoholics. Alcoholics show decreased DA release. Modified with permission from Volkow et al. [34].

Areas of the brain where DA D2 receptors (D2R) were significantly correlated with brain metabolism in subjects with family history of alcoholism. Modified with permission from Volkow et al. [40].

A: Average DV images of [¹¹C]raclopride in a group of active cocaine abusers (n = 17) tested while viewing a (B) neutral video (nature scenes), and while viewing a (C) video with cocaine cues (subjects procuring and administering cocaine). Modified with permission from Volkow et al. [44].

Model proposing a network of four circuits underlying addiction: reward (red: located in the nucleus accumbens of the ventral astriatum and VP); motivation (green: located in OFC, subcallosal cortex, dorsal striatum, and motor cortex); memory (gold: located in the amygdala and hippocampus); and executive control (blue: located in dorsolateral prefrontal, anterior CG, and inferior frontal cortex). These circuits work together and change with experience. Each is linked to an important concept: saliency (reward), internal state (motivation/drive), learned associations (memory), and conflict resolution (control). A: When these circuits operate in an integrated and balanced fashion the result is manifested as the execution of appropriate behaviors (proper inhibitory control and decision making) in a broad range of circumstances. B: During addiction, the enhanced value of the drug in the reward, motivation, and memory circuits overcomes the inhibitory control exerted by the PFC, thereby favoring a positive-feedback loop initiated by the consumption of the drug and perpetuated by the enhanced activation of the motivation/drive and memory circuits [47]. In addition, these circuits also interact with circuits involved in the regulation of mood (pink: including stress reactivity) and interoception (yellow: that contributes to the awareness of drug craving and mood), which also become recalibrated during the process of addiction (represented by a darker shade of gray in the ascending arrows) further tilting the balance away from inhibitory control towards craving. Modified with permission from Volkow et al. [47].