Addiction: decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain's control circuit

Abstract

Based on brain imaging findings, we present a model according to which addiction emerges as an imbalance in the information processing and integration among various brain circuits and functions. The dysfunctions reflect (a) decreased sensitivity of reward circuits, (b) enhanced sensitivity of memory circuits to conditioned expectations to drugs and drug cues, stress reactivity, and (c) negative mood, and a weakened control circuit. Although initial experimentation with a drug of abuse is largely a voluntary behavior, continued drug use can eventually impair neuronal circuits in the brain that are involved in free will, turning drug use into an automatic compulsive behavior. The ability of addictive drugs to co-opt neurotransmitter signals between neurons (including dopamine, glutamate, and GABA) modifies the function of different neuronal circuits, which begin to falter at different stages of an addiction trajectory. Upon exposure to the drug, drug cues or stress this results in unrestrained hyperactivation of the motivation/drive circuit that results in the compulsive drug intake that characterizes addiction.

Figure 1

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].

Figure 2

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].

Figure 3

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].

Figure 4

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].

Figure 5

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].

Figure 6

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].

Figure 7

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].

Figure 8

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].