Marc Laruelle

Imaging Synaptic Neurotransmission with in Vivo Binding Competition Techniques: A Critical Review:

Several groups have provided evidence that positron emission tomography (PET) and single-photon emission computed tomography (SPECT) neuroreceptor imaging techniques might be applied to measure acute fluctuations in dopamine (DA) synaptic concentration in the living human brain. Competition between DA and radioligands for binding to D2 receptor is the principle underlying this approach. This new application of neuroreceptor imaging provides a dynamic measurement of neurotransmission that is likely to be informative to our understanding of neuropsychiatric conditions. This article reviews and discusses the body of data supporting the feasibility and potential of this imaging paradigm. Endogenous competition studies performed in rodents, nonhuman primates, and humans are first summarized. After this overview, the validity of the model underlying the interpretation of these imaging data is critically assessed. The current reference model is defined as the occupancy model, since changes in radiotracer binding potential (BP) are assumed to be directly caused by changes in occupancy of D2 receptors by DA. Experimental data supporting this model are presented. The evidence that manipulation of DA synaptic levels induces change in the BP of several D2 radiotracers (catecholamines and benzamides) is unequivocal. The fact that these changes in BP are mediated by changes in DA synaptic concentration is well documented. The relationship between the magnitude of BP changes measured with PET or SPECT and the magnitude of changes in DA concentration measured by microdialysis supports the use of these noninvasive techniques to measure changes in neurotransmission. On the other hand, several observations remain unexplained. First, the amphetamine-induced changes in the BP of D2 receptor antagonists [123I]IBZM and [11C]raclopride last longer than amphetamine-induced changes in DA extracellular concentration. Second, nonbenzamide D2 receptor antagonists, such as spiperone and pimozide, are not affected by changes in DA release, or are affected in a direction opposite to that predicted by the occupancy model. Similar observations are reported with D1 radiotracers. These results suggest that the changes in BP following changes in DA concentration might not be fully accounted by a simple occupancy model. Specifically, the data are reviewed supporting that agonist-mediated receptor internalization might play an important role in characterizing receptor-ligand interactions. Finally, it is proposed that a better understanding of the mechanism underlying the effects observed with benzamides is essential to develop this imaging technique to other receptor systems.

Prefrontal Dopamine D1 Receptors and Working Memory in Schizophrenia

Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D1 receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for working memory processing. The defective ability of patients with schizophrenia at working memory tasks is a core feature of this illness. It has been postulated that this impairment relates to a deficiency in mesocortical DA function. In this study, D1 receptor availability was measured with positron emission tomography and the selective D1 receptor antagonist [11C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [11C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of patients with schizophrenia (1.63 ± 0.39 ml/gm) compared with control subjects (1.27 ± 0.44 ml/gm; p = 0.02). In patients with schizophrenia, increased DLPFC [11C]NNC 112 BP was a strong predictor of poor performance at the n-back task, a test of working memory. These findings confirm that alteration of DLPFC D1 receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D1 receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.

Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D2 receptor parameter measurements in ventral striatum

Dopamine transmission in the ventral striatum (VST), a structure which includes the nucleus accumbens, ventral caudate, and ventral putamen, plays a critical role in the pathophysiology of psychotic states and in the reinforcing effects of virtually all drugs of abuse. The aim of this study was to assess the accuracy and precision of measurements of D2 receptor availability in the VST obtained with positron emission tomography on the high-resolution ECAT EXACT HR+ scanner (Siemens Medical Systems, Knoxville, TN, U.S.A.). A method was developed for identification of the boundaries of the VST on coregistered high-resolution magnetic resonance imaging scans. Specific-to-nonspecific partition coefficient (V3″) and binding potential (BP) of [11C]raclopride were measured twice in 10 subjects, using the bolus plus constant infusion method. [11C]Raclopride V3″ in the VST (1.86 ± 0.29) was significantly lower than in the dorsal caudate (DCA, 2.33 ± 0.28) and dorsal putamen (DPU, 2.99 ± 0.26), an observation consistent with postmortem studies. The reproducibility of V3″ and BP were appropriate and similar in VST (V3″ test–retest variability of 8.2% ± 6.2%, intraclass correlation coefficient = 0.83), DCA (7.7% ± 5.1%, 0.77), DPU (6.0% ± 4.1%, 0.71), and striatum as a whole (6.3% ± 4.1%, 0.78). Partial volume effects analysis revealed that activities in the VST were significantly contaminated by counts spilling over from the adjacent DCA and DPU: 70% ± 5% of the specific binding measured in the VST originated from D2 receptors located in the VST, whereas 12% ± 3% and 18% ± 3% were contributed by D2 receptors in the DCA and DPU, respectively. Thus, accuracy of D2 receptor measurement is improved by correction for partial voluming effects. The demonstration of an appropriate accuracy and precision of D2 receptor measurement with [11C]raclopride in the VST is the first critical step toward the use of this ligand in the study of synaptic dopamine transmission at D2 receptors in the VST using endogenous competition techniques.

Imaging Human Mesolimbic Dopamine Transmission with Positron Emission Tomography. Part II: Amphetamine-Induced Dopamine Release in the Functional Subdivisions of the Striatum

The human striatum is functionally organized into limbic, associative, and sensorimotor subdivisions, which process information related to emotional, cognitive, and motor function. Dopamine projections ascending from the midbrain provide important modulatory input to these striatal subregions. The aim of this study was to compare activation of dopamine D2 receptors after amphetamine administration in the functional subdivisions of the human striatum. D2 receptor availability (V3″) was measured with positron emission tomography and [11C]raclopride in 14 healthy volunteers under control conditions and after the intravenous administration of amphetamine (0.3 mg/kg). For each condition, [11C]raclopride was administered as a priming bolus followed by constant infusion, and measurements of D2 receptor availability were obtained under sustained binding equilibrium conditions. Amphetamine induced a significantly larger reduction in D2 receptor availability (ΔV3″) in limbic (ventral striatum, −15.3 ± 11.8%) and sensorimotor (postcommissural putamen, −16.1 ± 9.6%) regions compared with associative regions (caudate and precommissural putamen, −8.1 ± 7.2%). Results of this region-of-interest analysis were confirmed by a voxel-based analysis. Correction for the partial volume effect showed even greater differences in ΔV3″ between limbic (−17.8 ± 13.8%), sensorimotor (−16.6 ± 9.9%), and associative regions (−7.5 ± 7.5%). The increase in euphoria reported by subjects after amphetamine was associated with larger ΔV3″ in the limbic and sensorimotor regions, but not in the associative regions. These results show significant differences in the dopamine response to amphetamine between the functional subdivisions of the human striatum. The mechanisms potentially accounting for these regional differences in amphetamine-induced dopamine release within the striatum remain to be elucidated, but may be related to the asymmetrical feed-forward influences mediating the integration of limbic, cognitive, and sensorimotor striatal function via dopamine cell territories in the ventral midbrain.

Glutamate, Dopamine, and Schizophrenia

Abstract: The fundamental pathological process(es) associated with schizophrenia remain(s) uncertain, but multiple lines of evidence suggest that this condition is associated with (1) excessive stimulation of striatal dopamine (DA) D2 receptors, (2) deficient stimulation of prefrontal DA D1 receptors and, (3) alterations in prefrontal connectivity involving glutamate (GLU) transmission at N‐methyl‐d‐aspartate (NMDA) receptors. This chapter first briefly discusses the current knowledge status for these abnormalities, with emphasis on results derived from clinical molecular imaging studies. The evidence for hyperstimulation of striatal D2 receptors rests on strong pharmacological evidence and has recently received support from brain imaging studies. The hypothesis of deficient prefrontal cortex (PFC) D1 receptor stimulation is almost entirely derived from preclinical studies. Preliminary imaging data compatible with this hypothesis have recently emerged. The NMDA hypofunction hypothesis originates mainly from indirect pharmacological data. The interactions between DA and GLU systems relevant to schizophrenia are then reviewed. Animal and imaging data supporting the general model that the putative DA imbalance in schizophrenia (striatal excess and cortical deficiency) might be secondary to NMDA hypofunction in the PFC and its connections are presented. Equally important are the potential consequences of this DA imbalance for NMDA function in the striatum and the cortex, which are subsequently discussed. In conclusion, it is proposed that schizophrenia is associated with strongly interconnected abnormalities of GLU and DA transmission: NMDA hypofunction in the PFC and its connections might generate a pattern of dysregulation of DA systems that, in turn, further weakens NMDA‐mediated connectivity and plasticity.

Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies

Abnormalities of dopamine function in schizophrenia are suggested by the common antidopaminergic properties of antipsychotic medications. However, direct evidence of a hyperdopaminergic state in schizophrenia has been diffcult to demonstrate, given the diffculty of measuring dopamine transmission in the living human brain. This situation is rapidly changing. Recent developments in positron emission tomography and single-photon emission tomographic techniques enabled measurement of acute fluctuation of synaptic dopamine in the vicinity of D2 receptors. Using this technique, we, and others, measured the increase in dopamine transmission following aute amphetamine challenge in untreated patients with schizophrenia and matched healthy subjects. Following a brief overview of these new brain imaging techniques, the main results derived with this method in patients with schizophrenia are described: (1) amphetamine-induced dopamine release is elevated in patients with schizophrenia, supporting the idea that schizophrenia is associated with dysregulation of dopamine transmission; (2) following amphetamine, hyperactivity of dopamine transmission is associated with activation of psychotic symptomatology; (3) this dysregulation of dopamine release is not a long-term consequence of previous neuroleptic treatment, and is detected in never-medicated patients experiencing a first episode of the illness; and (4) in contrast, this exaggerated response of the dopamine system to amphetamine exposure is not detected in patients studied during a period of illness stabilization, suggesting that the hyperdopaminergic state associated with schizophrenia fluctuates over time. In conclusion, a hyperdopaminergic state might be present in schizophrenia during the initial episode and subsequent relapses, but not during periods of remission. This finding has important consequences for the development of new treatment strategies for the remission phase.

Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia

BACKGROUND Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the striatum. It has long been hypothesized that dysregulation of subcortical dopamine systems in schizophrenia might result from a failure of the prefrontal cortex (PFC) to adequately control subcortical dopaminergic function. The activity of midbrain dopaminergic neurons is regulated, in part, by glutamatergic projections from the PFC acting via glutamatergic N-methyl-D-aspartate (NMDA) receptors. The goal of this study was to test the hypothesis that a pharmacologically induced disruption of NMDA transmission leads to an increase in amphetamine-induced dopamine release in humans. METHODS In eight healthy volunteers, we compared striatal amphetamine-induced (0.25 mg/kg) dopamine release under control conditions and under sustained disruption of NMDA transmission induced by infusion of the noncompetitive NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine release was determined with single photon emission computed tomography, as the reduction in the binding potential (BP) of the radiolabeled D(2) receptor antagonist [(123)I]IBZM. RESULTS Ketamine significantly enhanced the amphetamine-induced decrease in [(123)I]IBZM BP, from -5.5% +/- 3.5% under control conditions to -12. 8% +/- 8.8% under ketamine pretreatment (repeated-measures analysis of variance, p =.023). CONCLUSIONS The increase in amphetamine-induced dopamine release induced by ketamine (greater than twofold) was comparable in magnitude to the exaggerated response seen in patients with schizophrenia. These data are consistent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutamatergic neuronal systems regulating dopaminergic cell activity.

The role of endogenous sensitization in the pathophysiology of schizophrenia: Implications from recent brain imaging studies

Long-term sensitization is a process whereby exposure to a given stimulus such as a drug or a stressor results in an enhanced response at subsequent exposures. Sensitization of mesolimbic dopamine systems has been postulated by several authors to underlie the development of dopaminergic abnormalities associated with schizophrenia. In this review, core features of stimulant-induced sensitization of dopamine systems in rodents are briefly reviewed, as well as the behavioral and clinical evidence suggesting the relevance of this process to drug-induced psychosis and schizophrenia. Results of recent brain imaging studies relevant to the question of sensitization in schizophrenia are then discussed. These studies indicate that schizophrenia is associated with increased amphetamine-induced dopamine release. This exaggerated response was detected in patients experiencing an episode of clinical deterioration but not in clinically stable patients. Since increased stimulant-induced dopamine release is a hallmark of sensitization, these results support the view that schizophrenia is associated with a process of endogenous sensitization. Based on the preclinical evidence that dopamine projection to the prefrontal cortex acts as a buffer that oppose the development of sensitization in subcortical dopamine projections, we propose that, in schizophrenia, neurodevelopmental abnormalities of prefrontal dopaminergic systems might result in a state of enhanced vulnerability to sensitization during late adolescence and early adulthood. It is also proposed that D(2) receptor blockade, if sustained, might allow for an extinction of this sensitization process, with possible re-emergence upon treatment discontinuation. A better understanding of the neurocircuitry associated with endogenous sensitization and its consequence in schizophrenia might be important for the development of better treatment and relapse prevention strategies.

Neurobiology of Dopamine in Schizophrenia

This chapter is an update on the dopamine (DA) imbalance in schizophrenia, including the evidence for subcortical hyperstimulation of D2 receptors underlying positive symptoms and cortical hypodopaminergia-mediating cognitive disturbances and negative symptoms. After a brief review of the anatomical neurocircuitry of this transmitter system as a background, we summarize the evidence for dopaminergic alterations deriving from pharmacological, postmortem, and imaging studies. This evidence supports a prominent role for D2 antagonism in the treatment of positive symptoms of schizophrenia and strongly suggests the need for alternative approaches to address the more challenging problem of negative symptoms and cognitive disturbances.

Validation and Reproducibility of Measurement of 5-HT1A Receptor Parameters with [carbonyl-11C]WAY-100635 in Humans: Comparison of Arterial and Reference Tissue Input Functions

Serotonin 5-HT1A receptors are implicated in the pathophysiology of neuropsychiatric conditions. The goal of this study was to evaluate methods to derive 5-HT1A receptor parameters in the human brain with positron emission tomography (PET) and [carbonyl-11C]WAY 100635. Five healthy volunteer subjects were studied twice. Three methods of analysis were used to derive the binding potential (BP), and the specific to nonspecific equilibrium partition coefficient (k3/k4). Two methods, kinetic analysis based on a three compartment model and graphical analysis, used the arterial plasma time-activity curves as the input function to derive BP and k3/k4. A third method, the simplified reference tissue model (SRTM), derived the input function from uptake data of a region of reference, the cerebellum, and provided only k3/k4. All methods provided estimates of regional 5-HT1A receptor parameters that were highly correlated. Results were consistent with the known distribution of 5-HT1A receptors in the human brain. Compared with kinetic BP, graphical analysis slightly underestimated BP, and this phenomenon was mostly apparent in small size-high noise regions. Compared with kinetic k3/k4, the reference tissue method underestimated k3/k4 and the underestimation was apparent primarily in regions with high receptor density. Derivation of BP by both kinetic and graphical analysis was highly reliable, with an intraclass correlation coefficient (ICC) of 0.84 ± 0.14 (mean ± SD of 15 regions) and 0.84 ± 0.19, respectively. In contrast, the reliability of k3/k4 was lower, with ICC of 0.53 ± 0.28, 0.47 ± 0.28, and 0.55 ± 0.29 for kinetic, graphical, and reference tissue methods, respectively. In conclusion, derivation of BP by kinetic analysis using the arterial plasma input function appeared as the method of choice because of its higher test—retest reproducibility, lower vulnerability to experimental noise, and absence of bias.