The addictive potential of a drug is directly related to its speed of entry into the brain. However, the neural mechanisms responsible for this rate-dependent effect on reward remain unclear. Faster drug delivery, such as intravenous injection or smoking, leads to more intense rewarding effects and a higher risk of addiction compared to slower methods like oral administration, even when plasma levels are equivalent. Preclinical studies using stimulants like methylphenidate (MP) have shown a correlation between rapid dopamine increases, heightened activity in reward circuitry, and increased drug self-administration. In humans, while intravenous MP produces a similar overall dopamine increase as oral MP, only intravenous administration results in a reliable subjective 'high'. This suggests that the speed of dopamine increase, not just the magnitude, is crucial for the experience of reward. This study aimed to identify the specific brain circuits involved in processing the rate-dependent effects of MP on reward, focusing on potential candidates such as the nucleus accumbens, ventromedial prefrontal cortex (vmPFC), and the salience network (dACC and insula), given their known roles in drug reward and addiction.

Existing literature highlights the importance of dopamine in drug reward and addiction. Studies in rodents have demonstrated that faster delivery of cocaine results in faster striatal dopamine increases, greater metabolic activity in reward circuits, and increased self-administration. Faster routes of administration also correlate with stronger self-reported pleasurable effects in humans. Preclinical research using MP as a model drug further supports this relationship, but human data on the impact of pharmacokinetics on brain function remain limited. Early PET studies revealed that fast rises in striatal dopamine are associated with the 'high' feeling from stimulants. However, the conscious experience of drug reward involves larger-scale networks activated by dopamine signaling, making it necessary to investigate the contributions of other brain circuits beyond the striatum, such as the vmPFC and salience network, which is implicated in addiction based on lesion studies.

This double-blind, counterbalanced, randomized controlled trial used simultaneous PET-fMRI to examine brain activity in 20 healthy adults (9 female) who received oral (slow delivery) and intravenous (fast delivery) doses of MP, along with placebo. Cardiovascular responses (heart rate and blood pressure) were continuously monitored. PET imaging using [¹¹C]raclopride measured dopamine increases in the striatum. The rate of dopamine increase was estimated from the minute-by-minute changes in [¹¹C]raclopride binding. fMRI measured brain activity and functional connectivity. Participants rated their subjective 'high' on a 1-10 scale. Whole-brain voxelwise multiple regression analyses examined the association between fMRI activity and the rate of dopamine increases (separate analyses for slow and fast increases). Dynamic functional connectivity analysis, using significant activation clusters as seed regions, explored connectivity patterns associated with dopamine dynamics. Statistical analyses included repeated measures ANOVAs for cardiovascular and behavioral data, and SPM for fMRI data.

Cardiovascular responses showed a significant difference between IV and oral MP administration. While 'static' PET analysis showed no significant difference in overall dopamine increases between oral and IV MP (due to dose equivalence), a dynamic analysis using minute-by-minute changes in [¹¹C]raclopride binding revealed that IV MP caused faster and stronger dopamine increases. Whole-brain fMRI analysis revealed that a corticostriatal circuit, including the dACC and insula and their connections with the dorsal caudate, showed increased activity specifically during fast (IV) dopamine increases, but not slow (oral) dopamine increases. This activation paralleled subjective 'high' ratings. The vmPFC showed decreased activity in response to both oral and IV MP, but this was not significantly associated with subjective 'high' ratings. Dynamic functional connectivity analysis confirmed enhanced connectivity between the dACC and dorsal caudate during fast dopamine increases, further supporting the role of this corticostriatal circuit in the experience of drug reward. No significant sex differences were observed in behavioral measures, dopamine dynamics, or brain activation.

The findings strongly implicate the salience network (dACC and insula) in processing the rewarding effects of drugs delivered via fast routes of administration. The selective activation of this network by fast dopamine increases, coupled with its correlation to subjective 'high' ratings, underscores its critical role in the experience of intense drug reward and could provide new targets for addiction treatments. The contrasting response patterns observed in the salience network (increased activation) and vmPFC (decreased activation) are consistent with the hypothesis that fast dopamine increases preferentially stimulate excitatory D1 receptors (increasing activation in the salience network), whereas both fast and slow dopamine increases stimulate inhibitory D2 receptors (decreasing activation in the vmPFC). The lack of correlation between striatal BOLD responses and dopamine dynamics might be due to energetic effects being primarily observed in downstream projection regions rather than the cell bodies themselves.

This study identifies a specific corticostriatal circuit involving the dACC, insula, and dorsal caudate that is selectively responsive to fast dopamine increases and closely linked to the subjective experience of drug reward. These findings advance our understanding of the neurobiological basis of drug addiction and suggest that targeting the salience network, particularly the dACC, may be a promising strategy for addiction treatment. Future research should investigate the generalizability of these findings to other substance use disorders and explore the specific mechanisms underlying the differential sensitivity of the salience network and vmPFC to dopamine dynamics. Furthermore, investigations in diverse contexts and consideration of individual differences in response to drugs are also crucial for a more comprehensive understanding of addiction.

The study was conducted in healthy individuals naïve to stimulant drugs, limiting the generalizability to individuals with established substance use disorders. The laboratory setting has low ecological validity; real-world contexts influence drug use behavior. The use of 'high' ratings as a sole measure of reward might not fully encompass the complexities of reward processing, which includes factors such as genetic vulnerability, prior conditioning, and environmental context. The relatively small sample size may limit the power to detect smaller effects or interactions.