A receptor-based model for dopamine-induced fMRI signal
Introduction
Many pharmacological and natural stimuli elevate synaptic levels of dopamine (DA) and elicit functional responses in flow and metabolism that are measurable using non-invasive neuroimaging methods within the DA-rich basal ganglia. However, basic mechanisms underlying DA-mediated function in health and disease are poorly understood at the level of systems biology despite an emerging picture of the relevant biomolecular pathways. Based upon decades of molecular studies, DA receptors can be grouped into D1-like and D2-like receptor families that produce opposing effects on the production of cyclic-AMP through activation or inhibition of adenylate cyclase (Neves et al., 2002, Stoof and Kebabian, 1981). The G-protein coupled D1 and D2 signaling pathways affect a host of functions, including regulation of metabolic enzymes, ion channels, and plasticity through gene transcription (Carlezon et al., 2005, Neves et al., 2002). Although the complexity of these cellular signaling pathways makes it difficult to define a precise mechanistic relationship between receptor binding and gross indices of tissue function, as measured by the group of techniques collectively called fMRI (BOLD signal, CBV, CBF, …), it is clear that D1 and D2 receptor families produce opposing effects at the top level of the G-protein coupled signaling cascade.
Use of selective dopaminergic agonists and antagonists can reveal the functional roles of D1 and D2 receptors in vivo using systemic administration and recording methods such as autoradiography to determine glucose utilization (e.g., Trugman and James, 1993) or IRON fMRI to measure CBV (Mandeville, 2012). In rats, D1 agonism increases CBV in basal ganglia (Choi et al., 2006), whereas antagonism decreases CBV (Marota et al., 2000). Conversely, D2 agonists and antagonists produce effects on CBV that are opposite in sign to those produced by the respective D1 agents (Chen et al., 2005, Choi et al., 2006). These results clearly demonstrate that any understanding of DA-mediated function must consider the relative balance of D1-mediated excitation versus D2-mediated inhibition.
Viewing DA-mediated function in terms of opposing D1 and D2 contributions helps explain some subtle features of data in domains of dose and time and reconciles some pronounced differences observed across species and versus drug dosages. Amphetamine stimulation in the rat produces pronounced increases in CBV except at very small doses, where responses become slightly negative, an effect that was attributed to the high affinity of DA for a subset of D2-like receptors (Ren et al., 2009). In the temporal domain, cocaine infusion produces a subtle decrease in CBV in rats prior to the dominant positive response (Chen et al., 2011, Marota et al., 2000, Schwarz et al., 2004), and segmentation of this temporal component produces a D2-like spatial map (Chen et al., 2011).
The most basic aspects of dopaminergic function appear to be similar across species except in the laboratory rat, one of the mainstays of scientific research. Glucose autoradiography reported cocaine-induced elevation of metabolism in rats (Porrino, 1993) but decreased metabolism in non-human primates (NHP) (Lyons et al., 1996) and mice (Zocchi et al., 2001). Similarly, IRON fMRI reported cocaine-induced elevation of CBV in rats (Chen et al., 2011, Marota et al., 2000, Schwarz et al., 2004) but decreased CBV in NHP (Mandeville et al., 2011) and wild-type mice (Perles-Barbacaru et al., 2011). Because the different fMRI responses in rats and NHP occur despite similar levels of evoked DA (Bradberry, 2000, Chen et al., 2010, Schwarz et al., 2004), we previously hypothesized that these different responses might be attributable to the ratio of D1 to D2 receptors (Mandeville et al., 2011), which is much higher in laboratory rats than in humans, NHP, or wild-type mice. Neuroadaptations in human cocaine-abusing populations, such as blunted dopamine release (Martinez et al., 2007) and down-regulated D2 receptor densities (Volkow et al., 1993), complicate a comparison with preclinical data, but the preponderance of evidence from a variety of neuroimaging techniques suggests that cocaine produces functional inhibition in human striatum in a manner similar to NHP results (Johnson et al., 1998, Kaufman et al., 1998, Kufahl et al., 2005, London et al., 1990, Wallace et al., 1996). However, the conundrum remains that cocaine infusion produces an opposite fMRI response in rats and NHP, but amphetamine stimulation increases CBV in both species at the doses that have been tested (Chen et al., 1999, Jenkins et al., 2004). This observation could be related to the different mechanisms of action between these drugs, or it might be that a single model can account for this difference based upon the different levels of DA induced by the two drugs.
This study describes a model of DA-induced function coupled to biochemistry through receptor occupancies using standard pharmacological principles. The goal was to develop an intuitive and extensible model that provides an integrative explanation of fMRI observations using dopaminergic drugs, while adhering to a mathematical approach that is testable using non-invasive neuroimaging. Predictions for fMRI signal are based upon a classical occupancy model driven by estimates in DA levels from the microdialysis literature. Because PET can detect changes in DA release through 11C-raclopride displacement, albeit through mechanisms that are not fully understood (Ginovart, 2005), we acquired fMRI and PET data simultaneously in several sessions to evaluate relationships between these signals and the common unmeasured temporal function – evoked DA – that drives responses for both modalities. Note that D1-targeted PET ligands show little sensitivity to changes in DA levels, for reasons that may be related to ligand characteristics (Laruelle, 2000), so no D1-targeted PET studies were performed.
Model results are compared to prior literature and also to simultaneous PET/fMRI experiments in NHP using smaller doses of amphetamine than have been employed previously by fMRI studies using NHP (Jenkins et al., 2004). Although literature comparisons focus on preclinical results using the commonly employed IRON fMRI technique, the expectation is that the model calculations also will be applicable to future human studies based upon robust techniques like BOLD signal at very high field strengths, or the IRON method in standard clinical MRI scanners (Qiu et al., 2012). This model approach has been presented previously in preliminary form (Mandeville et al., 2012, Normandin et al., 2012a).
Section snippets
An fMRI model coupled to receptor occupancy
Pharmacological effects in biological systems often have been interpreted within the context of the classical receptor occupancy model (Clark, 1937), in which a response is a function of the fraction of receptors that are occupied. Furthermore, a classical occupancy model, or a “pure competition” model within the context of raclopride displacement studies (Ginovart, 2005, Laruelle, 2000), views receptors as static targets that are not dynamically regulated by processes like internalization
Results
To investigate model accuracy relative to data published previously or acquired in this study, we first generate simulations employing the model defined by the parameters in Table 1 and by the DA efflux curves described in the Methods. Fig. 2, Fig. 3, Fig. 4 conform to this fixed model. We then evaluate the sensitivity of the model to changes in individual parameters across ranges defined by our estimates of literature variance (Fig. 5), and we also investigate covariance between parameters
Discussion
The goal of this report was to develop a simple and testable receptor-based model capable of producing a consistent description of the growing body of preclinical fMRI data using drugs of abuse and selective agonists and antagonists. The model produces compelling descriptions of literature data and also predicts a new observation—the functional response of NHP basal ganglia to amphetamine is inhibition at moderate doses and a biphasic response at higher doses. We discuss assumptions,
Conclusions
This study developed a first-order multi-receptor model of DA-induced fMRI signal and showed that this model is capable of consistently describing a wide range of literature results. Within the model, fMRI signal arises from competing excitatory and inhibitory influences of D1 and D2 receptor stimulation, respectively, so that the net functional output depends upon relative receptor densities, affinities, and the level of evoked DA. In specific regimes, the model supports empirical observations
Acknowledgments
We thank Helen Deng, Steve Carlin, Chris Moseley, Grae Arabasz and Shirley Hsu for their help with animal handling, radioligand synthesis, and MR-PET imaging. This research was supported by NIH grants R21NS072148, P41RR14075, P30DA28800, S10RR026666, S10RR017208, S10RR022976, and S10RR019933.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
References (84)
- et al.
A novel method for noninvasive detection of neuromodulatory changes in specific neurotransmitter systems
NeuroImage
(2003) - et al.
The many faces of CREB
Trends Neurosci.
(2005) - et al.
Brain hemodynamic changes mediated by dopamine receptors: role of the cerebral microvasculature in dopamine-mediated neurovascular coupling
NeuroImage
(2006) - et al.
A multimodality investigation of cerebral hemodynamics and autoregulation in pharmacological MRI
Magn. Reson. Imaging
(2007) - et al.
Neural responses to acute cocaine administration in the human brain detected by fMRI
NeuroImage
(2005) - et al.
Simplified reference tissue model for PET receptor studies
NeuroImage
(1996) - et al.
Remifentanil administration reveals biphasic phMRI temporal responses in rat consistent with dynamic receptor regulation
NeuroImage
(2007) IRON fMRI measurements of CBV and implications for BOLD signal
NeuroImage
(2012)- et al.
Cocaine activation discriminates dopaminergic projections by temporal response: an fMRI study in rat
NeuroImage
(2000) - et al.
A population-average MRI-based atlas collection of the rhesus macaque
NeuroImage
(2009)
Neural correlates of the formation and retention of cocaine-induced stimulus–reward associations
Biol. Psychiatry
Estimating neurotransmitter kinetics with ntPET: a simulation study of temporal precision and effects of biased data
NeuroImage
A linear model for estimation of neurotransmitter response profiles from dynamic PET data
NeuroImage
In vivo detection of striatal dopamine release during reward: a PET study with [(11)C]raclopride and a single dynamic scan approach
NeuroImage
Quantitative pharmacologic MRI: mapping the cerebral blood volume response to cocaine in dopamine transporter knockout mice
NeuroImage
Dopaminergic activities in the human striatum: rostrocaudal gradients of uptake sites and of D1 and D2 but not of D3 receptor binding or dopamine
Neuroscience
Contrast-enhanced functional blood volume imaging (CE-fBVI): enhanced sensitivity for brain activation in humans using the ultrasmall superparamagnetic iron oxide agent ferumoxytol
NeuroImage
Neural correlates of high and craving during cocaine self-administration using BOLD fMRI
NeuroImage
Concurrent pharmacological MRI and in situ microdialysis of cocaine reveal a complex relationship between the central hemodynamic response and local dopamine concentration
NeuroImage
The absolute density of neurotransmitter receptors in the brain. Example for dopamine receptors
J. Pharmacol. Methods
D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: a PET study in a receptor internalization-deficient mouse model
NeuroImage
Imaging the high-affinity state of the dopamine D2 receptor in vivo: fact or fiction?
Biochem. Pharmacol.
The third dopamine receptor (D3) as a novel target for antipsychotics
Biochem. Pharmacol.
D1 dopamine agonist and antagonist effects on regional cerebral glucose utilization in rats with intact dopaminergic innervation
Brain Res.
A simple method to measure baseline occupancy of neostriatal dopamine D2 receptors by dopamine in vivo in healthy subjects
Neuropsychopharmacology
Dopamine D1 and D2 receptor selectivities of phenyl-benzazepines in rhesus monkey striata
Eur. J. Pharmacol.
Differential effects of cocaine on local cerebral glucose utilization in the mouse and in the rat
Neurosci. Lett.
Increased baseline occupancy of D2 receptors by dopamine in schizophrenia
Proc. Natl. Acad. Sci. U. S. A.
An energy budget for signaling in the grey matter of the brain
J. Cereb. Blood Flow Metab.
Acute and chronic dopamine dynamics in a nonhuman primate model of recreational cocaine use
J. Neurosci.
Comparison of bolus and infusion methods for receptor quantitation: application to [18F]cyclofoxy and positron emission tomography
J. Cereb. Blood Flow Metab.
Detection of dopaminergic cell loss and neural transplantation using pharmacological MRI, PET and behavioral assessment
Neuroreport
Mapping dopamine D2/D3 receptor function using pharmacological magnetic resonance imaging
Psychopharmacology (Berl)
Pharmacologic neuroimaging of the ontogeny of dopamine receptor function
Dev. Neurosci.
Cocaine self-administration leads to alterations in temporal responses to cocaine challenge in limbic and motor circuitry
Eur. J. Neurosci.
A PET study of D(1)-like dopamine receptor ligand binding during altered endogenous dopamine levels in the primate brain
Psychopharmacology (Berl)
General Pharmacology
Differences in aggressive behavior and in the mesocorticolimbic DA system between A/J and BALB/cJ mice
Synapse
Absolute abundances and affinity states of dopamine receptors in mammalian brain: a review
Synapse
Absolute quantification by positron emission tomography of the endogenous ligand
J. Cereb. Blood Flow Metab.
Kinetic modeling of [11C]raclopride: combined PET–microdialysis studies
J. Cereb. Blood Flow Metab.
Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography
Proc. Natl. Acad. Sci. U. S. A.
Cited by (51)
Striatal dopamine supports reward expectation and learning: A simultaneous PET/fMRI study
2023, NeuroImageCitation Excerpt :Recent advances have allowed the simultaneous acquisition of both PET and fMRI data, suggesting the possibility of characterizing neural activity with both the spatial and temporal precision of fMRI with the molecular specificity provided by PET, though few studies to date have used this approach to study dopaminergic contributions to reward processing. Comparison of fMRI-based activation with [11C]Raclopride PET imaging has supported the formulation of refined models of DA-evoked neuronal activation (Mandeville et al., 2013), and mechanisms underlying functional connectivity (Kullmann et al., 2021). A recent report using such an approach to characterize reward processing in depression has demonstrated differences in D2/D3 receptor density that are not reflected in fMRI-based reward activation responses (Phillips et al., 2022).
Simultaneous fMRI and fast-scan cyclic voltammetry bridges evoked oxygen and neurotransmitter dynamics across spatiotemporal scales
2021, NeuroImageCitation Excerpt :Our method utilizing ground truth data to guide models is more effective than relying on assumptions that the evoked response would scale with the given stimulus inputs and can account for inter-subject response variability. Further, mathematical models that predict dopamine-influenced hemodynamic changes heavily favor post-synaptic effects as the assumed driver of the fMRI response (Mandeville et al., 2013), and though these models have close agreement with actual data, they are subject to potentially flawed parameter values (e.g., receptor dissociation constants (Marcellino et al., 2012)). Bruinsma et al. summarize how both pre- and post-synaptic effects must be explored to tease apart dopaminergic contributions to BOLD fMRI responses, and how this can be accomplished using FSCV, fMRI, optogenetics, and pharmacology (Bruinsma et al., 2018).
Modeling the acute pharmacological response to selective serotonin reuptake inhibitors in human brain using simultaneous PET/MR imaging
2019, European Neuropsychopharmacology