Time-varying SUVr reflects the dynamics of dopamine increases during methylphenidate challenges in humans

Abstract

Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate’s brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [11C]raclopride’s binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [11C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of “high”. We show for the first time that the “high” is associated with the fast dopamine increases induced by methylphenidate.

Brain connectivity changes to fast versus slow dopamine increases

“…Fourth, oral and IV drug administrations may vary on other unmeasured factors aside from the speed of dopamine increases, such as differences in MP metabolism when administered orally versus IV. However, in a prior analysis of this dataset [ 6 ] we confirmed that the oral and IV MP doses elicited similar overall striatal dopamine increases supporting the interpretation that the differences we observed are driven by the rate of dopamine change. Still, IV MP likely elicits a greater peak dopamine increase than oral MP, which we hypothesize could also contribute to greater D1R stimulation and unique connectivity patterns.…”

“…Here, we replicated some of these results and found that connectivity patterns are crucially related to the dynamics of dopamine increases. The oral and IV doses in this study (60 mg and 0.25 mg/kg, respectively) occupy roughly equivalent quantities of striatal dopamine transporters (~70%) in humans [ 52 , 53 ], and produce roughly the same overall magnitude of dopamine increases [ 6 ]. Yet the connectivity patterns to slow and fast dopamine increases were opposing in most networks, and no regions showed significant overlap in connectivity patterns.…”

“…Some of the PET data and the behavioral data (‘high’ ratings) were previously reported in a recent publication [ 6 ]. Here, we investigated the relationship between dynamic dopamine changes and brain functional connectivity assessed with fMRI.…”

“…Recently, we developed a new approach to measure the temporal dynamics of dopamine changes optimally suited for the current experimental design [ 6 ], which because of the PET/MR setup, did not allow us to perform a continuous [11 C]raclopride infusion as required by LSSRM (for a demonstration of the similarities between this method and prior methods, and for advantages of the current method for this particular study design, see the Supplement , including Supplementary Fig. S1 ).…”

“…In rats, speedier delivery of cocaine produces a faster rise in dopamine and, accordingly, greater cocaine self-administration [ 3 – 5 ]. Likewise, in humans, intravenous compared to oral drug administration produces faster increases in striatal dopamine [ 6 ], and chronic drug misuse via faster routes of administration are associated with faster transition to substance use disorder (SUD) and more severe symptomatology [ 7 , 8 ]. These studies support the theory that fast dopamine increases elicit neuroplastic changes in large-scale brain circuits underlying reward, promoting further drug-seeking behavior [ 1 ].…”