Neural circuits respond to rapid dopamine surges

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In a recently published study, Dr Nature communicationResearchers performed simultaneous positron emission tomography (PET)-functional magnetic resonance imaging (fMRI) to assess dopamine signaling, brain connectivity/activity and the pharmacodynamics of self-reported ‘high’ following methylphenidate exposure.

Study: Neural circuits selective for fast but not slow dopamine enhance drug reward. Image credit: Pavlova Yuliia /

Dopamine and addiction

Increased dopamine in the cranial reward region leads to neuroplastic changes, addiction and drug use disorders. The rate and magnitude of dopamine increase determine a drug’s rewarding effects and potential for addiction.

More effective drug delivery routes, such as intravenous (IV) injection and smoking, result in more frequent and severe disorders, as well as higher rates of overdose. Rapid delivery routes also provide the most pleasurable self-reported effects of IV cocaine, thus emphasizing the importance of pharmacokinetic properties in the drug’s addictive potential and reward.

About the study

The present study was a randomized, counterbalanced, and double-blinded trial in which healthy participants were given methylphenidate orally and IV. The team hypothesized that slow increases in dopamine would activate inhibitory-type D2 receptors, while faster increases would stimulate low-binding affinity-type D1 receptors, leading to increases and decreases in activation in different brain regions.

The team studied the rate of increase in striatal dopamine in response to oral and IV methylphenidate and brain regions associated with slow and fast dopamine kinetics. Additionally, the researchers investigated whether brain circuits were temporally linked to individuals’ ‘high’ methylphenidate evaluations.

Each study participant was scanned three times 40 days apart under three pharmacological conditions. These included 60 mg oral methylphenidate and IV placebo, oral-placebo and 0.3 mg/kg IV methylphenidate and both oral and IV-placebo. Data was obtained between January 2018 and September 2021.

Participants had no history of nicotine or tobacco use and were broadly representative of the Washington, DC metropolitan area. Scientists have examined circuits that can manage dynamic functional connectivity and coordinate with dopamine fluctuations. Median delta SUVr

A functional connectivity analysis of insula seeds was performed. The researchers also investigated whether circuits identified in previous studies were related to individual differences in perceived drug reward.

Human Connectome Project (HCP) minimal pretreatment pipelines were used for image processing. Subjects with medical and neuropsychiatric disorders affecting brain function, history of substance use disorders, cardiac abnormalities, need for hypertension medications or arrhythmias, pregnancy, medications that may interact with methylphenidate, or ferromagnetic body implants contraindicated for MRI were excluded from the study.

Study results

The researchers investigated the activation of a corticostriatal circuit in response to rapid dopamine increases and high ratings. Drug status significantly affected systolic-type blood pressure, with no effect on heart rate.

A statistically significant interaction of medication condition and time was observed for both measures. Dopamine elevations started earlier after oral MP and were slower and moderate than the rapid and higher elevations after IV methylphenidate. Conventional static PET imaging analysis indicated a significant decrease in the standardized uptake value (SUVr), a marker of increased synaptic dopamine concentration, in the slow and fast methylphenidate administration routes.

For the 90-minute scan, IV and oral methylphenidate showed lower binding potential to the non-displaceable type (BPnd) than placebo. However, no significant difference was observed between oral and IV methylphenidate using the static technique.

For slower dopamine elevations, activity in the ventromedial region of the prefrontal cortex was reduced. For dopamine spikes, left-sided insula, as well as medial and dorsal anterior cingulate cortex (dACC) activity was increased.

Visual assessment of signals indicated a graduated decrease in activity starting with IV methylphenidate, followed by oral methylphenidate and placebo. However, the left insula and dACC demonstrated significantly increased activity in response to rapid dopamine increases.

Combined with rapid dopamine elevation, the left insula and dACC demonstrated significant functional connectivity with the contralateral dorsal caudate. A statistically significant temporal relationship was observed in the time-courses of functional connectivity between the anterior cingulate cortex and the dorsal side of the caudate and their ‘high’ rating time-courses.

No significant gender differences were observed in behavior, dopamine time-to-peak elevation estimated using PET data, baseline binding potential in the putamen, caudate and accumbens nucleus, or strength of association between dopamine elevation rate and functional MRI activation. Significant clusters.


Research findings demonstrate rapid dopamine elevation in humans associated with dACC and insula activation. The functions of salience networks in drug reward were also highlighted.

In cases where the route of drug administration resulted in rapid delivery to the brain and strong rewarding effects, salience networks involving the dACC were stimulated. The salience network has enhanced functional connectivity with the dorsal caudate, which receives significant dopamine input from the midbrain after IV methylphenidate administration. The ventromedial region of the prefrontal cortex monitors slow and fast dopamine pharmacokinetics without affecting the experience of drug reward.

Two different pathways to clinical remission of addiction were highlighted; However, further research is needed to elucidate the underlying biological pathways.

Journal Reference:

  • Manza, P., Tomasi, D., Shokri-Kozori, E., etc (2023). Neural circuits selective for fast but not slow dopamine enhance drug reward. Nature communication 14. doi:10.1038/s41467-023-41972-6

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