Faculty Bibliography

BACKGROUND: Postmortem and positron emission tomography (PET) studies have reported several alterations in serotonin 1A receptor (5-HT(1A)) binding parameters in patients with schizophrenia. This study examines 5-HT(1A) availability in vivo in individuals with schizophrenia and schizo-affective disorder. MATERIALS AND METHODS: Twenty-two medication-free individuals with schizophrenia or schizo-affective disorder and 18 healthy subjects underwent PET scans with [(11)C]WAY 100635. Regional distribution volumes (V(T), in milliliters per gram) were derived using a two-tissue compartment kinetic model. Outcome measures for 5-HT(1A) availability included binding potential (BP) and the specific to nonspecific equilibrium partition coefficient (V(3)''). Eleven brain regions with high density of 5-HT(1A) were included in the analysis. RESULTS: No significant differences were observed in regional BP or V(3)'' between patients and controls. No significant relationships were observed between regional 5-HT(1A) availability and symptom severity. CONCLUSION: The postmortem literature reports increased 5-HT(1A) binding in the prefrontal cortex in schizophrenia. This study did not detect differences in 5-HT(1A) 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-HT(1A) receptor play a role in the pathophysiology of schizophrenia.

Frontal cortical efferent fibers are thought to have important regulatory influence on cortico-basal ganglia (BG) circuits. The cortico-midbrain (substantia nigra/ventral tegmental area, SN/VTA) pathway has received particular attention in psychiatric diseases, most notably schizophrenia. Work in rodents demonstrates that the prefrontal cortico (PFC)-midbrain pathway plays a central role in regulating the firing pattern of dopamine (DA) neurons. These findings have led to some important hypotheses concerning PFC/BG interaction in schizophrenia. Descending PFC projections to the SN/VTA have been primarily documented in the rodent. The aim of this study was to determine the degree and organization of PFC afferents to these areas in the Macaque monkey. Anterograde tracer injections were made into discrete orbital, cingulate, and dorsolateral prefrontal areas. Projections were charted to the SN and VTA. Overall, there were very few fibers in the ventral midbrain following injections confined to specific areas of the PFC. To determine the relationship of the descending fibers to the midbrain DA neurons, sections were double stained for the tracer molecules and for tyrosine hydroxylase. In all cases, the prefrontal projections and the TH-positive cells did not appear to be in close juxtaposition. The results show a very limited projection from the PFC to the midbrain DA neurons in primates, terminating both within the SN proper as well as in the VTA. They arise from a broad region of the PFC, including the DLPF, cingulate, and orbital cortices. However, despite the relative lack of cortical input to the midbrain cells, these neurons are rich in glutamate receptors in primates. Thus, while, based on these anatomical studies, direct cortical control of DA neurons remains debatable in primates; the cortex may directly impact other sources of glutamatergic control.

The aim of the present study was to define the optimal analytic method to derive accurate and reliable serotonin transporter (SERT) receptor parameters with (11)C-3-amino-4-(2-[(dimethylamino)methyl]phenylthio)benzonitrile ((11)C-DASB). METHODS: Nine healthy subjects (5 females, 4 males) underwent two (11)C-DASB PET scans on the same day. Five analytic methods were used to estimate binding parameters in 10 brain regions: compartmental modeling with 1- and 2-tissue compartment models (1TC and 2TC), data-driven estimation of parametric images based on compartmental theory (DEPICT) analysis, graphical analysis, and the simplified reference tissue model (SRTM). Two variations in the fitting procedure of the SRTM method were evaluated: nonlinear optimization and basis function approach. The test/retest variability (VAR) and intraclass correlation coefficient (ICC or reliability) were assessed for 3 outcome measures: distribution volume (V(T)), binding potential (BP), and specific to nonspecific equilibrium partition coefficient (V(3)''). RESULTS: All methods gave similar values across all regions. The variability of V(T) was excellent (< or =10%) in all regions, for the 1TC, 2TC, DEPICT, and graphical approaches. The variability of BP and V(3)'' was good in regions of high SERT density and poorer in regions of moderate and lower densities. The ICC of all 3 outcome measures was excellent in all regions. The basis function implementation of SRTM demonstrated improved reliability compared with nonlinear optimization, particularly in moderate and low-binding regions. CONCLUSION: The results of this study indicate that (11)C-DASB can be used to measure SERT parameters with high reliability and low variability in receptor-rich regions of the brain, with somewhat less reliability and increased variability in regions of moderate SERT density and poor reproducibility in low-density regions.

OBJECTIVE: Ketamine is a noncompetitive antagonist at the glutamatergic N-methyl-d-aspartate (NMDA) receptor that is used in human and animal medicine as an injectable anesthetic. The illegal use of ketamine as a recreational drug is rapidly growing. Very little is currently known about the consequences of repeated ketamine exposure in the human brain. Animal studies indicate that the prefrontal dopaminergic system is particularly vulnerable to the toxic effects of repeated administration of NMDA antagonists. In this study, dopamine D(1) receptor availability was assessed by using positron emission tomography and the selective D(1) receptor radioligand [(11)C]NNC 112 in a group of 14 recreational chronic ketamine users and matched healthy subjects. METHOD: History of ketamine abuse was confirmed in subjects by hair analysis. [(11)C]NNC 112 binding potential was measured with kinetic analysis using the arterial input function. RESULTS: Dorsolateral prefrontal cortex D(1) receptor availability was significantly up-regulated in chronic ketamine users ([(11)C]NNC 112 binding potential: mean=1.68 ml/g, SD=0.40) relative to comparison subjects (mean=1.35 ml/g, SD=0.35). No significant differences were noted in other cortical, limbic, or striatal regions. In the chronic ketamine user group, dorsolateral prefrontal cortex [(11)C]NNC 112 binding potential up-regulation was significantly correlated with the number of vials of ketamine (with a vial representing approximately 200-300 mg of ketamine) used per week. CONCLUSIONS: Chronic ketamine users exhibited a regionally selective up-regulation of D(1) receptor availability in the dorsolateral prefrontal cortex, a phenomenon observed following chronic dopamine depletion in animal studies. These data suggest that the repeated use of ketamine for recreational purposes affects prefrontal dopaminergic transmission, a system critically involved in working memory and executive function

BACKGROUND: Postmortem studies have reported several alterations in serotonin transporter (SERT) binding parameters in patients with schizophrenia. The aim of this study was to compare SERT availability in vivo in patients with schizophrenia and matched control subjects. METHODS: Ten medication-free patients with schizophrenia and 10 healthy subjects underwent positron emission tomography (PET) scans for 90 min after 11C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([11C]DASB) injection. Metabolite-corrected arterial input function was measured. Regional distribution volumes (mL/g) were derived with a two tissue compartment kinetic model. Outcome measures for SERT availability included binding potential (BP) and the specific-to-nonspecific equilibrium partition coefficient (V3''). Ten brain regions with high density of SERT and where SERT availability can be reliably quantified with [11C]DASB were included in the analysis. RESULTS: No significant differences were observed in regional BP or V3'' between patients and control subjects. No significant relationships were observed between regional SERT availability and severity of positive, negative, and depressive symptoms. CONCLUSIONS: This study failed to detect alterations of SERT availability in patients with schizophrenia; however, this study does not rule out the possibility that schizophrenia might be associated with alterations of SERT density in the cortical regions, where the [11C]DASB-specific binding signal is too low for reliable quantification of SERT.

OBJECTIVE: The serotonin system is believed to play a role in modulating impulsivity and violence. Previous imaging studies have implicated the anterior cingulate and orbitofrontal cortex in impulsive aggression. This study evaluated regional serotonin transporter distribution in the brain of individuals with impulsive aggression by using positron emission tomography (PET) with the serotonin transporter PET radiotracer [(11)C]McN 5652. METHOD: Ten individuals with impulsive aggression and 10 age- and sex-matched healthy comparison subjects underwent [(11)C]McN 5652 PET. All individuals were medication free at the time of scanning. Regional total distribution volumes were derived by using a one-tissue compartment kinetic model with arterial input function. Outcome measures of serotonin transporter availability included the binding potential and the specific-to-nonspecific partition coefficient (V(3)''). RESULTS: Serotonin transporter availability was significantly reduced in the anterior cingulate cortex of individuals with impulsive aggression compared with healthy subjects, as noted by differences in both binding potential (mean=3.1 ml/g [SD=1.9] versus 5.0 ml/g [SD=2.0], respectively) and V(3)'' (mean=0.15 [SD=0.09] versus 0.26 [SD=0.09]). In other regions examined, serotonin transporter density was nonsignificantly lower in individuals with impulsive aggression compared with healthy subjects. CONCLUSIONS: Pathological impulsive aggressivity might be associated with lower serotonergic innervation in the anterior cingulate cortex, a region that plays an important role in affective regulation.

Although abnormal serotonin (5-HT) function is implicated in a range of mental disorders, there is currently no method to directly assess 5-HT synaptic levels in the living human brain. The in vivo binding of some dopamine (DA) radioligands such as (11)C-raclopride is affected by fluctuations in endogenous DA, thus providing an indirect measure of DA presynaptic activity. Attempts to identify a serotonergic radiotracer with similar properties have proved unsuccessful. Here, we investigated in humans the effects of reduced synaptic 5-HT on the in vivo binding of the 5-HT transporter (SERT) radioligand (11)C-DASB, using Positron Emission Tomography (PET) and the rapid tryptophan depletion (RTD) technique. Eight (8) subjects (5M, 3F) were scanned with (11)C-DASB under control and reduced endogenous 5-HT conditions, in a within-subject, double-blind, counterbalanced, crossover design. Regional distribution volumes (V(T)) were calculated using kinetic modeling and metabolite-corrected arterial input function. (11)C-DASB specific binding was estimated as binding potential (BP) and specific to nonspecific equilibrium partition coefficient (V(")(3)), using the cerebellum as reference region. RTD caused small but significant mean reductions in (11)C-DASB V(T) (-6.1%) and BP (-4.5%) across brain regions, probably explained by a concomitant reduction in (11)C-DASB plasma free fraction (f(1)) of similar magnitude. No significant change in (11)C-DASB V(")(3) was observed between control and reduced 5-HT conditions. Nor was there a significant relationship between the magnitude of tryptophan depletion and change in BP and V(")(3) across individual subjects. These results suggest that (11)C-DASB in vivo binding is not affected by reductions in endogenous 5-HT.

BACKGROUND: The fundamental pathologic processes associated with schizophrenia remain uncertain. OBJECTIVE: The goal of this article was to review imaging evidence suggesting that schizophrenia is associated with excessive stimulation of D(2) receptors, as well as imaging experiments supporting the hypothesis that this dysregulation might be secondary to N- methyl-d-aspartate (NMDA) dysfunction. CONCLUSIONS: Recent imaging data support the association of schizophrenia with a dopamine endophenotype involving excessive subcortical dopamine function. Animal and imaging data are consistent with the idea that this abnormality might be secondary to a synaptic disconnectivity involving the prefrontal cortex, which is well modeled by NMDA antagonist administration. In turn, this dopamine dysregulation might worsen synaptic connectivity and NMDA function. Thus, both glutamate/dopamine and dopamine/glutamate interactions may be relevant to schizophrenia pathophysiology and treatment. A deficit in glutamate transmission may lead to the dopamine endophenotype associated with this illness, and dopamine alterations in turn might exacerbate glutamate transmission deficits. The view that NMDA alterations are primary and dopamine alterations are secondary is probably oversimplistic, as both sets of abnormalities reinforce each other. A consequence of this general model is that direct intervention to support NMDA function might be beneficial as an augmentation strategy for the treatment of schizophrenia. Thus, it is proposed that schizophrenia is associated with strongly interconnected abnormalities of glutamate and dopamine transmission: NMDA hypofunction in the prefrontal cortex and its connections might generate a pattern of dysregulation of dopamine systems that, in turn, further weakens NMDA-mediated connectivity and plasticity.

RATIONALE: To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the D2 occupancy by endogenous dopamine in schizophrenia. OBJECTIVES: The aim of this study is to compare the occupancy of striatal D2 receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D2 occupancy by dopamine as a result of these treatments. METHODS: Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [123I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V3") after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]-1. D2 receptor occupancy was calculated by comparing V3" measured in treated patients to an age-corrected V3" value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1-(V3" treated/V3" drug free). RESULTS: V3" was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23+/-0.06 versus 0.34+/-0.08, P=-0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69+/-8% versus 55 +/-11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D2 receptors by antipsychotic medications required to reduce the occupancy of these receptors by endogenous dopamine to control values. In medication-free patients with schizophrenia, the occupancy of striatal D2 receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D2 receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D2 receptors in patients with schizophrenia to control values, 48% receptor occupancy by antipsychotic medications is required. CONCLUSIONS: These data indicate that the dosage of these medications, found to be effective in the treatment of schizophrenia, reduces DA stimulation of D2 receptors to levels slightly lower than those found in unmedicated healthy subjects.