W. Gordon Frankle

Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.

CONTEXT A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D(2) receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D(2) receptors is responsible for the antipsychotic action of D(2) receptor antagonists. OBJECTIVE To localize dopaminergic hyperactivity within the striatum in schizophrenia. DESIGN Case-control study. SETTING Inpatient research unit. PARTICIPANTS Eighteen untreated patients with schizophrenia and 18 healthy control subjects matched for age, sex, ethnicity, parental socioeconomic status, cigarette smoking, and weight. MAIN OUTCOME MEASURES Percentage change in dopamine D(2) receptor availability in striatal subregions within each subject measured by positron emission tomography with carbon 11-labeled raclopride before and during pharmacologically induced dopamine depletion. RESULTS In the associative striatum, acute dopamine depletion resulted in a larger increase in D(2) receptor availability in patients with schizophrenia (mean [SD], 15% [7%]) than in control subjects (10% [7%], P = .045), suggesting higher synaptic dopamine concentration. Within the associative striatum, this effect was most pronounced in the precommissural dorsal caudate (15% [8%] in patients vs 9% [8%] in controls, P = .03). No between-group differences were observed in the limbic and sensorimotor striatum. CONCLUSIONS These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.

COMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET.

A common polymorphism (val158met) in the gene encoding catechol-O-methyltransferase (COMT) has been shown to affect dopamine (DA) tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with the positron-emission tomography (PET) radiotracer [11C]NNC112. We compared [11C]NNC 112 binding in healthy volunteers homozygous for the Val allele compared with Met carriers. Subjects were otherwise matched for parameters known to affect [11C]NNC 112 binding. Subjects with Val/Val alleles had significantly higher cortical [11C]NNC 112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [11C]NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia.

The Synaptic Hypothesis of Schizophrenia

12 paginas, 5 figuras.-- The following is a report of the meeting “Synaptic Dysfunction and Schizophrenia” held at the Juan March Center for International Meetings on Biology Workshop in Madrid, Spain, 10–12 February 2003.

Dose-occupancy study of striatal and extrastriatal dopamine D2 receptors by aripiprazole in schizophrenia with PET and [18F]fallypride.

Positron emission tomography (PET) and the high affinity D2/3 radiotracer [18F]fallypride allow the assessment of D2/3 receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D2 agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR+ camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6±5.5% at 2 mg/day to 96.8±5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D2 occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.

Positron emission tomography imaging of amphetamine‐induced dopamine release in the human cortex: A comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride

The use of PET and SPECT endogenous competition binding techniques has contributed to the understanding of the role of dopamine in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of acute changes in synaptic dopamine have been restricted to the striatum. The ligands previously used, such as [11C]raclopride and [123I]IBZM, do not provide sufficient signal to noise ratio to quantify D2 receptors in extrastriatal areas, such as cortex, where the concentration of D2 receptors is much lower than in the striatum. Given the importance of cortical DA function in cognition, a method to measure cortical dopamine function in humans would be highly desirable. The goal of this study was to compare the ability of two high affinity DA D2 radioligands [11C]FLB 457 and [11C]fallypride to measure amphetamine‐induced changes in DA transmission in the human cortex. D2 receptor availability was measured in the cortical regions of interest with PET in 12 healthy volunteers under control and postamphetamine conditions (0.5 mg kg−1, oral), using both [11C]FLB 457 and [11C]fallypride (four scans per subjects). Kinetic modeling with an arterial input function was used to derive the binding potential (BPND) in eight cortical regions. Under controlled conditions, [11C]FLB 457 BPND was 30–70% higher compared with [11C]fallypride BPND in cortical regions. Amphetamine induced DA release led to a significant decrease in [11C]FLB 457 BPND in five out the eight cortical regions evaluated. In contrast, no significant decrease in [11C]fallypride BPND was detected in cortex following amphetamine. The difference between [11C]FLB 457 and [11C]fallypride ability to detect changes in the cortical D2 receptor availability following amphetamine is related to the higher signal to noise ratio provided by [11C]FLB 457. These findings suggest that [11C]FLB 457 is superior to [11C]fallypride for measurement of changes in cortical synaptic dopamine. Synapse 63:447–461, 2009.

A Comparative Evaluation of the Dopamine D2/3 Agonist Radiotracer [11C](−)-N-Propyl-norapomorphine and Antagonist [11C]Raclopride to Measure Amphetamine-Induced Dopamine Release in the Human Striatum

(−)-N-Propyl-norapomorphine (NPA) is a full dopamine D2/3 receptor agonist, and [11C]NPA is a suitable radiotracer to image D2/3 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study, the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic dopamine was assessed with PET in healthy humans and compared with that of the reference D2/3 receptor antagonist radiotracer [11C]raclopride. Ten subjects (eight females and two males) were studied on two separate days, a minimum of 1 week apart, both with [11C]raclopride and [11C]NPA at baseline and after the administration of 0.5 mg · kg−1 oral d-amphetamine. Kinetic modeling with an arterial input function was used to derive the binding potential relative to nonspecific uptake (BPND) in the ventral striatum (VST), caudate (CAD), and putamen (PUT). [11C]Raclopride BPND was significantly reduced by 9.7 ± 4.4, 8.4 ± 4.2, and 14.7 ± 4.8% after amphetamine administration in the VST, CAD, and PUT. [11C]NPA BPND was also reduced significantly, by 16.0 ± 7.0, 16.1 ± 6.1, and 21.9 ± 4.9% after the same dose of amphetamine in the VST, CAD, and PUT. Although these results suggest that [11C]NPA is more vulnerable to endogenous competition by dopamine compared with [11C]raclopride by a factor of 1.49 to 1.90, the same data for a related outcome measure, binding potential relative to plasma concentration, was not significant. Nevertheless, these data add to the growing literature that suggests D2/3 agonist radiotracers are more vulnerable to endogenous competition by dopamine than existing D2/3 antagonist radiotracers.

Tiagabine increases [11C]flumazenil binding in cortical brain regions in healthy control subjects

Accumulating evidence indicates that synchronization of cortical neuronal activity at γ-band frequencies is important for various types of perceptual and cognitive processes and that GABA-A receptor-mediated transmission is required for the induction of these network oscillations. In turn, the abnormalities in GABA transmission postulated to play a role in psychiatric conditions such as schizophrenia might contribute to the cognitive deficits seen in this illness. We measured the ability to increase GABA in eight healthy subjects by comparing the binding of [11C]flumazenil, a positron emission tomography (PET) radiotracer specific for the benzodiazepine (BDZ) site, at baseline and in the presence of an acute elevation in GABA levels through the blockade of the GABA membrane transporter (GAT1). Preclinical work suggests that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands (termed ‘GABA shift’). Theoretically, such an increase in the affinity of GABA-A receptors should be detected as an increase in the binding of a GABA-A BDZ-receptor site-specific PET radioligand. GAT1 blockade resulted in significant increases in mean (± SD) [11C]flumazenil-binding potential (BPND) over baseline in brain regions representing the major functional domains of the cerebral cortex: association cortex +15.2±20.2% (p=0.05), sensory cortex +13.5±15.5% (p=0.03) and limbic (medial temporal lobe, MTL) +16.4±20.2% (p=0.03). The increase in [11C]flumazenil-BPND was not accounted for by differences in the plasma-free fraction (fP; paired t-test p=0.24) or changes in the nonspecific binding (pons VT, p=0.73). Moreover, the ability to increase GABA strongly predicted (r=0.85, p=0.015) the ability to entrain cortical networks, measured through EEG γ synchrony during a cognitive control task in these same subjects. Although additional studies are necessary to further validate this technique, these data provide preliminary evidence of the ability to measure in vivo, with PET, acute fluctuations in extracellular GABA levels and provide the first in vivo documentation of a relationship between GABA neurotransmission and EEG γ-band power in humans.

Serotonin 1A receptor availability in patients with schizophrenia and schizo-affective disorder: a positron emission tomography imaging study with [11C]WAY 100635

BackgroundPostmortem and positron emission tomography (PET) studies have reported several alterations in serotonin 1A receptor (5-HT1A) binding parameters in patients with schizophrenia. This study examines 5-HT1A availability in vivo in individuals with schizophrenia and schizo-affective disorder.Materials and methodsTwenty-two medication-free individuals with schizophrenia or schizo-affective disorder and 18 healthy subjects underwent PET scans with [11C]WAY 100635. Regional distribution volumes (VT, in milliliters per gram) were derived using a two-tissue compartment kinetic model. Outcome measures for 5-HT1A availability included binding potential (BP) and the specific to nonspecific equilibrium partition coefficient (V3″). Eleven brain regions with high density of 5-HT1A were included in the analysis.ResultsNo significant differences were observed in regional BP or V3″ between patients and controls. No significant relationships were observed between regional 5-HT1A availability and symptom severity.ConclusionThe postmortem literature reports increased 5-HT1A binding in the prefrontal cortex in schizophrenia. This study did not detect differences in 5-HT1A binding. Whereas in two recently published PET studies, one reports increased binding in the temporal lobe while the other reports decreased binding in the amygdala. These inconsistencies suggest that the alterations demonstrated in postmortem studies cannot be reliably detected at the resolution achieved with PET. This raises the question as to whether major changes in the level of expression of the 5-HT1A receptor play a role in the pathophysiology of schizophrenia.

Increased Serotonin 2A Receptor Availability in the Orbitofrontal Cortex of Physically Aggressive Personality Disordered Patients

BACKGROUND Impulsive physical aggression is a common and problematic feature of many personality disorders. The serotonergic system is known to be involved in the pathophysiology of aggression, and multiple lines of evidence have implicated the serotonin 2A receptor (5-HT(2A)R). We sought to examine the role of the 5-HT(2A)R in impulsive aggression specifically in the orbitofrontal cortex (OFC), given that our own studies and an extensive literature indicate that serotonergic disturbances in the OFC are linked to aggression. We have previously hypothesized that increased 5-HT(2A)R function in the OFC is a state phenomenon that promotes impulsive aggression. METHODS Serotonin 2A receptor availability was measured with positron emission tomography and the selective 5-HT(2A)R antagonist radioligand [(11)C]MDL100907 in two groups of impulsively aggressive personality disordered patients-14 with current physical aggression, and 15 without current physical aggression-and 25 healthy control subjects. Clinical ratings of various symptom dimensions were also obtained. RESULTS Orbitofrontal 5-HT(2A)R availability was greater in patients with current physical aggression compared with patients without current physical aggression and healthy control subjects; no differences in OFC 5-HT(2A)R availability were observed between patients without current physical aggression and healthy control subjects. No significant differences in 5-HT(2A)R availability were observed in other brain regions examined. Among both groups of impulsively aggressive personality disordered patients combined, OFC 5-HT(2A)R availability was correlated, specifically, with a state measure of impulsive aggression. CONCLUSIONS These findings are consistent with our previously described model in which impulsive aggression is related to dynamic changes in 5-HT(2A)R function in the OFC.

Sustained Recreational Use of Ecstasy Is Associated with Altered Pre and Postsynaptic Markers of Serotonin Transmission in Neocortical Areas: A PET Study with [11C]DASB and [11C]MDL 100907

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT2A receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT2A receptors. Positron emission tomography studies using the SERT ligand [11C]DASB and the 5-HT2A receptor ligand [11C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT2A receptor availability (binding potential, BPND) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BPND and higher 5-HT2A receptor BPND in cortical, but not subcortical regions. Decreased SERT BPND was regionally associated with upregulated 5-HT2A receptor BPND. In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.