The dopaminergic mechanisms that control reward-motivated behavior are the subject of intense study, but it is yet unclear how, in humans, neural activity in mesolimbic reward-circuitry and its functional neuroimaging correlates are related to dopamine release. To address this question, we obtained functional magnetic resonance imaging (fMRI) measures of reward-related neural activity and [¹¹C]raclopride positron emission tomography measures of dopamine release in the same human participants, while they performed a delayed monetary incentive task. Across the cohort, a positive correlation emerged between neural activity of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic neurotransmission, during reward anticipation and reward-related [¹¹C]raclopride displacement as an index of dopamine release in the ventral striatum, major target of SN/VTA dopamine neurons. Neural activity in the ventral striatum/nucleus accumbens itself also correlated with ventral striatal dopamine release. Additionally, high-reward-related dopamine release was associated with increased activation of limbic structures, such as the amygdala and the hippocampus. The observed correlations of reward-related mesolimbic fMRI activation and dopamine release provide evidence that dopaminergic neurotransmission plays a quantitative role in human mesolimbic reward processing. Moreover, the combined neurochemical and hemodynamic imaging approach used here opens up new perspectives for the investigation of molecular mechanisms underlying human cognition.

It is currently hypothesized that adenosine is involved in the induction of sleep after prolonged wakefulness. This effect is partially reversed by the application of caffeine, which is a nonselective blocker of adenosine receptors. Here, we report that the most abundant and highly concentrated A₁subtype of cerebral adenosine receptors is upregulated after 24 h of sleep deprivation. We used the highly selective A₁adenosine receptor (A₁AR) radioligand [¹⁸F]CPFPX ([¹⁸F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine) and quantitative positron emission tomography to assess cerebral A₁ARs before and after sleep deprivation in 12 healthy volunteers and a control group (n= 10) with regular sleep. In sleep deprived subjects, we found an increase of the apparent equilibrium total distribution volume in a region-specific pattern in all examined brain regions with a maximum increase in the orbitofrontal cortex (15.3%;p= 0.014). There were no changes in the control group with regular sleep. This is the first molecular imaging study that providesin vivoevidence for an A₁AR upregulation in cortical and subcortical brain regions after prolonged wakefulness, indicating that A₁AR expression is contributing to the homeostatic sleep regulation.

Significance: Our study reveals that prolonged sleep deprivation is accompanied by an A ₁ adenosine receptor (A ₁ AR) upregulation in the human brain. Recovery sleep quickly restores A ₁ AR availability to control levels. High individual A ₁ AR availability is related to a low sleep pressure and good cognitive performance. Sleep deprivation is an efficient but short-lasting therapeutic strategy in depression. A causal sleep–wake dysregulation has been proposed, possibly mediated by cerebral adenosine and its A ₁ AR. The restoration of the A ₁ AR availability after recovery from sleep deprivation mimics the rapid relapse following the end of therapeutic sleep deprivation. Understanding the adenosine regulation under sleep restriction, especially regarding individual characteristics, might improve the rationale for the individual indication and design of therapeutic sleep modulation in depression.

Caffeine is the neuroactive agent in coffee and tea and is a broadly consumed stimulant. It is a nonselective antagonist of the neuromodulator adenosine and, if applied in commonly consumed doses, evokes its stimulating effects through the blockade of adenosine receptors. ¹⁸F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (¹⁸F-CPFPX) has been established as a highly selective and affine PET ligand for the A₁ adenosine receptor (A₁AR). The objective of the present study was to visualize and quantify the in vivo occupancy of the human cerebral A₁AR by caffeine using ¹⁸F-CPFPX and PET. Methods: Fifteen subjects (age range, 24–68 y) underwent a 140-min bolus–plus–constant-infusion PET experiment after at least 36 h of caffeine abstinence. Metabolite-corrected blood data were used to calculate steady-state distribution volumes (V_T) during the baseline condition of the scan between 70 and 90 min. Subsequently, subjects received a 10-min infusion of varying concentrations (0.5–4.3 mg/kg of body weight) of caffeine at 90 min. Occupancy V_T of the A₁AR was thereafter estimated using data acquired between 120 and 140 min. Occupancy levels were calculated using the Lassen plot, from which the inhibitory concentrations of 50% were derived. Plasma levels of caffeine were determined at regular intervals. One subject received an intravenous vehicle as a placebo. Results: Caffeine displaced 5%–44% of ¹⁸F-CPFPX binding in a concentration-dependent manner. There was no change of radioligand binding after the administration of placebo. Half-maximal displacement was achieved at a plasma caffeine concentration of 67 μM, which corresponds to 450 mg in a 70-kg subject or approximately 4.5 cups of coffee. Conclusion: Given a biologic half-life of about 5 h, caffeine might therefore occupy up to 50% of the cerebral A₁AR when caffeinated beverages are repeatedly consumed during a day. Furthermore, the present study provides evidence that ¹⁸F-CPFPX PET is suitable for studying the cerebral actions of caffeine, the most popular neurostimulant worldwide.

Sleep deprivation increases the levels of extracellular adenosine and A1 receptor (A1R)mRNA in the cholinergic zone of the basal forebrain, a region involved in sleep homeostasis. To evaluate homeostatic control mechanisms, we examined the sleep deprivation-induced changes in the A1R density in rodent brain using [3H]CPFPX receptor autoradiography. We also examined the role of nuclear factor-κB (NF-κB) in transcriptional upregulation of A1R mRNA by use of the inhibitor peptide SN50 to inhibit nuclear translocation of NF-κB. We found a significant increase in cholinergic basal forebrain A1R density following 24 h of sleep deprivation and evidence that the upregulation of A1R is mediated by NF-κB. The A1R increase may be important in sleep homeostasis, since the increase in A1R density would increase the inhibitory effect of given level of adenosine, thus increasing the gain of the homeostat.