A receptor-based model for dopamine-induced fMRI signal

Highlights

• We modeled fMRI signal in basal ganglia induced by dopaminergic drugs.

• The model includes D1 and D2 receptor arms, weighted by densities and occupancies.

• Different affinities of dopamine for D1 and D2 receptors drive the kinetics.

• We acquired simultaneous PET/fMRI data at two doses of amphetamine.

• The model provides a good description of literature data and our new fMRI data.

Abstract

This report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine's effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET ¹¹C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations.

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).