PET imaging of dopamine-D2 receptor internalization in schizophrenia.

Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (D2R) trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge DA levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used 'late-phase' imaging after challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late-phase displacement, or a faster return to baseline, in patients compared with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and [11C]raclopride at baseline and two times (3-5 and 6-10 h) following 0.5 mg kg-1 dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BPND) and derived percent reduction from baseline (ΔBPND) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BPND to baseline differed between SZ and HCs, we implemented a linear model with ΔBPND as dependent variable, time after amphetamine as repeated measure and time after amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time after amphetamine significantly affected striatal ΔBPND (F=1.38, P=0.26; F=0.51, P=0.61). These results show similar pattern of return of BPND to baseline as a function of time in patients with SZ and HC, suggesting that striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.

PET imaging of dopamine-D2 receptor internalization in schizophrenia.

This corrects the article DOI: 10.1038/mp.2017.107.

Deficits in striatal dopamine release in cannabis dependence.

Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis dependence is associated with a similar dopaminergic deficit, we examined striatal and extrastriatal dopamine release in severely cannabis-dependent participants (CD), free of any comorbid conditions, including nicotine use. Eleven CD and 12 healthy controls (HC) completed two positron emission tomography scans with [11C]-(+)-PHNO, before and after oral administration of d-amphetamine. CD stayed inpatient for 5-7 days prior to the scans to standardize abstinence. Magnetic resonance spectroscopy (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [11C]-(+)-PHNO-binding potential (ΔBPND) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined. CD had significantly lower ΔBPND in the striatum (P=0.002, effect size (ES)=1.48), including the associative striatum (P=0.003, ES=1.39), sensorimotor striatum (P=0.003, ES=1.41) and the pallidus (P=0.012, ES=1.16). Lower dopamine release in the associative striatum correlated with inattention and negative symptoms in CD, and with poorer working memory and probabilistic category learning performance in both CD and HC. No relationships to MRS glutamate and amphetamine-induced subclinical positive symptoms were detected. In conclusion, this study provides evidence that severe cannabis dependence-without the confounds of any comorbidity-is associated with a deficit in striatal dopamine release. This deficit extends to other extrastriatal areas and predicts subclinical psychopathology.

Imaging glutamate in schizophrenia: review of findings and implications for drug discovery.

Currently, all treatments for schizophrenia (SCZ) function primarily by blocking D(2)-type dopamine receptors. Given the limitations of these medications, substantial efforts have been made to identify alternative neurochemical targets for treatment development in SCZ. One such target is brain glutamate. The objective of this article is to review and synthesize the proton magnetic resonance spectroscopy ((1)H MRS) and positron emission tomography (PET)/single-photon emission computed tomography (SPECT) investigations that have examined glutamatergic indices in SCZ, including those of modulatory compounds such as glutathione (GSH) and glycine, as well as data from ketamine challenge studies. The reviewed (1)H MRS and PET/SPECT studies support the theory of hypofunction of the N-methyl-D-aspartate receptor (NMDAR) in SCZ, as well as the convergence between the dopamine and glutamate models of SCZ. We also review several advances in MRS and PET technologies that have opened the door for new opportunities to investigate the glutamate system in SCZ and discuss some ways in which these imaging tools can be used to facilitate a greater understanding of the glutamate system in SCZ and the successful and efficient development of new glutamate-based treatments for SCZ.

Striatal dopamine release in schizophrenia comorbid with substance dependence.

Dopamine (DA) has a role in the pathophysiology of schizophrenia and addiction. Imaging studies have indicated that striatal DA release is increased in schizophrenia, predominantly in the precommissural caudate (preDCA), and blunted in addiction, mostly in the ventral striatum (VST). Therefore, we aimed to measure striatal DA release in patients with comorbid schizophrenia and substance dependence. We used [(11)C]raclopride positron emission tomography and an amphetamine challenge to measure baseline DA D2-receptor availability (BPND) and its percent change post-amphetamine (ΔBPND, to index amphetamine-induced DA release) in striatal subregions in 11 unmedicated, drug-free patients with both schizophrenia and substance dependence, and 15 healthy controls. There were no significant group differences in baseline BPND. Linear mixed modeling using ΔBPND as the dependent variable and striatal region of interest as a repeated measure indicated a significant main effect of diagnosis, F(1,24)=8.38, P=0.008, with significantly smaller ΔBPND in patients in all striatal subregions (all P ≤ 0.04) except VST. Among patients, change in positive symptoms after amphetamine was significantly associated with ΔBPND in the preDCA (rs=0.69, P=0.03) and VST (rs=0.64, P=0.05). In conclusion, patients with comorbid schizophrenia and substance dependence showed significant blunting of striatal DA release, in contrast to what has been found in schizophrenia without substance dependence. Despite this blunting, DA release was associated with the transient amphetamine-induced positive-symptom change, as observed in schizophrenia. This is the first description of a group of patients with schizophrenia who display low presynaptic DA release, yet show a psychotic reaction to increases in D2 stimulation, suggesting abnormal postsynaptic D2 function.

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.

Cannabis-associated psychosis: Neural substrate and clinical impact.

Prospective epidemiological studies have consistently demonstrated that cannabis use is associated with an increased subsequent risk of both psychotic symptoms and schizophrenia-like psychoses. Early onset of use, daily use of high-potency cannabis, and synthetic cannabinoids carry the greatest risk. The risk-increasing effects are not explained by shared genetic predisposition between schizophrenia and cannabis use. Experimental studies in healthy humans show that cannabis and its active ingredient, delta-9-tetrahydrocannabinol (THC), can produce transient, dose-dependent, psychotic symptoms, as well as an array of psychosis-relevant behavioral, cognitive and psychophysiological effects; the psychotogenic effects can be ameliorated by cannabidiol (CBD). Findings from structural imaging studies in cannabis users have been inconsistent but functional MRI studies have linked the psychotomimetic and cognitive effects of THC to activation in brain regions implicated in psychosis. Human PET studies have shown that acute administration of THC weakly releases dopamine in the striatum but that chronic users are characterised by low striatal dopamine. We are beginning to understand how cannabis use impacts on the endocannabinoid system but there is much still to learn about the biological mechanisms underlying how cannabis increases risk of psychosis. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".

Shall we really say goodbye to first rank symptoms?

BACKGROUND: First rank symptoms (FRS) of schizophrenia have been used for decades for diagnostic purposes. In the new version of the DSM-5, the American Psychiatric Association (APA) has abolished any further reference to FRS of schizophrenia and treats them like any other "criterion A" symptom (e.g. any kind of hallucination or delusion) with regard to their diagnostic implication. The ICD-10 is currently under revision and may follow suit. In this review, we discuss central points of criticism that are directed against the continuous use of first rank symptoms (FRS) to diagnose schizophrenia. METHODS: We describe the specific circumstances in which Schneider articulated his approach to schizophrenia diagnosis and discuss the relevance of his approach today. Further, we discuss anthropological and phenomenological aspects of FRS and highlight the importance of self-disorder (as part of FRS) for the diagnosis of schizophrenia. Finally, we will conclude by suggesting that the theory and rationale behind the definition of FRS is still important for psychopathological as well as neurobiological approaches today. RESULTS: Results of a pivotal meta-analysis and other studies show relatively poor sensitivity, yet relatively high specificity for FRS as diagnostic marker for schizophrenia. Several methodological issues impede a systematic assessment of the usefulness of FRS in the diagnosis of schizophrenia. However, there is good evidence that FRS may still be useful to differentiate schizophrenia from somatic causes of psychotic states. This may be particularly important in countries or situations with little access to other diagnostic tests. FRS may thus still represent a useful aid for clinicians in the diagnostic process. CONCLUSION: In conclusion, we suggest to continue a tradition of careful clinical observation and fine-grained psychopathological assessment, including a focus on symptoms regarding self-disorders, which reflects a key aspect of psychosis. We suggest that the importance of FRS may indeed be scaled down to a degree that the occurrence of a single FRS alone should not suffice to diagnose schizophrenia, but, on the other hand, absence of FRS should be regarded as a warning sign that the diagnosis of schizophrenia or schizoaffective disorder is not warranted and requires specific care to rule out other causes, particularly neurological and other somatic disorders. With respect to the current stage of the development of ICD-11, we appreciate the fact that self-disorders are explicitly mentioned (and distinguished from delusions) in the list of mandatory symptoms but still feel that delusional perceptions and complex hallucinations as defined by Schneider should be distinguished from delusions or hallucinations of "any kind". Finally, we encourage future research to explore the psychopathological context and the neurobiological correlates of self-disorders as a potential phenotypic trait marker of schizophrenia.

Selective abnormalities of prefrontal serotonergic receptors in schizophrenia. A postmortem study.

BACKGROUND: This study investigates serotonergic receptors in prefrontal cortex of patients with schizophrenia. METHODS: We measured serotonin 2 receptors and serotonin uptake sites in prefrontal and occipital cortex of schizophrenics, patients with chronic schizoaffective disorders, nonpsychotic suicides, and controls. Diagnoses were established according to DSM-III-R criteria from medical chart reviews. RESULTS: In prefrontal cortex, serotonin 2 density was decreased in chronic psychotics dying of natural causes, as opposed to psychotics dying of suicide, controls, and nonpsychotic suicide victims. Serotonin uptake sites were decreased in prefrontal cortex of schizophrenics and nonpsychotic suicides, but not in patients with schizoaffective disorder. None of the observed differences were clearly related to antemortem pharmacological treatments. In the occipital pole, no differences were found among the groups. CONCLUSIONS: Selective prefrontal alterations of both presynaptic and postsynaptic serotonin receptor densities are present in at least some schizophrenic patients.

Increased dopamine transmission in schizophrenia: relationship to illness phases.

BACKGROUND: 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 difficult to demonstrate, given the difficulty to measure dopamine transmission in the living human brain. Such evidence has recently emerged. Three studies reported an increase in dopamine transmission following acute amphetamine challenge in patients with schizophrenia compared to matched healthy control subjects, thus demonstrating a dysregulation of dopamine in schizophrenia. In all studies, a large variance was observed within the schizophrenic group in the magnitude of this finding, and clinical predictors of this effect could not be identified. METHODS: In this paper, we combined previously published and newly acquired data to obtain sufficient power to address this question. RESULTS: The most important findings derived from this extended data set are: 1) dysregulation of dopamine function revealed by the amphetamine challenge is present at onset of illness and in patients never previously exposed to neuroleptic medications; 2) this dysregulation was observed in patients experiencing an episode of illness exacerbation, but not in patients studied during a remission phase. CONCLUSIONS: A hyperdopaminergic state is present in schizophrenia during the initial episode and subsequent relapses, but not in 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.

Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions.

BACKGROUND: The demands of the Wisconsin Card Sorting Test (WCST) change with experience. This report contains two studies designed to examine N-methyl-D-aspartate (NMDA) receptor contributions to the executive components of WCST performance. These aspects of WCST performance figure more prominently in the initial completion of this task than in subsequent task repetitions in healthy populations. METHODS: In the first study, healthy subjects (n = 15) completed the WCST on two occasions separated by 1 week. In the second study, healthy subjects (n = 22) completed two test days spaced by approximately 1 week, during which, they completed the WCST and other assessments after administration of the NMDA antagonist ketamine (intravenous bolus 0.26 mg/kg followed by infusion of 0.65 mg/kg/hour) or matched placebo. RESULTS: In the first study, subjects reduced the number of total and perseverative errors with a single repetition of the WCST. In the second study, ketamine significantly increased the number of total errors and the number and percent of perseverative errors on the first, but not the second test day. Similarly, it reduced the number of category criteria met on the first, but not second test day. Ketamine also increased distractibility, impaired recall, produced psychosis, altered perception, and had effects resembling the negative symptoms of schizophrenia. However, only WCST performance showed order dependency. CONCLUSIONS: This order dependency further implicates NMDA receptors in executive cognitive functions associated with the frontal cortex.

Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [(123)I]beta-CIT.

BACKGROUND: Several lines of evidence derived from imaging and postmortem studies suggest that schizophrenia is associated with hyperactivity of dopamine function and deficiency in serotonin (5-HT) function. The aim of this study was to investigate potential alterations of striatal dopamine transporters (DAT) and brainstem serotonin transporters (SERT) density in schizophrenia. METHODS: Striatal DAT and brainstem SERT were measured in 24 patients with schizophrenia and 22 matched healthy control subjects using single photon emission computed tomography and [(123)I]beta-CIT. In this cohort of subjects, we previously reported an increase in striatal amphetamine-induced dopamine release, measured as the displacement of the D(2) receptor radiotracer [(123)I]IBZM. RESULTS: No differences were observed between patients and control subjects in the equilibrium uptake ratio (V(3)") of [(123)I]beta-CIT in the striatum, indicating that schizophrenia is not generally associated with an alteration of striatal DAT density; however, a trend level association (p =.07) was observed in patients with schizophrenia between low striatal [(123)I]beta-CIT V(3)" and severity of negative symptoms. After controlling for age, striatal [(123)I]beta-CIT V(3)" in patients was not associated with duration of illness, suggesting that this relative deficit was not secondary to a neurodegenerative process. No correlation was observed between DAT density and amphetamine-induced dopamine release, either in the patients or in the controls. Brainstem [(123)I]beta-CIT V(3)" was unaffected in patients with schizophrenia, and was unrelated to symptomatology. CONCLUSIONS: Schizophrenia is generally not associated with alterations of DAT in the striatum or SERT in the brainstem. In some patients, a relative deficit in dopamine nerve terminals might play a role in the pathophysiology of negative symptoms.

Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tisssue input functions.

Serotonin 5-HT(1A) receptors are implicated in the pathophysiology of neuropsychiatric conditions. The goal of this study was to evaluate methods to derive 5-HT(1A) receptor parameters in the human brain with positron emission tomography (PET) and [carbonyl-(11)C]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-HT(1A) receptor parameters that were highly correlated. Results were consistent with the known distribution of 5-HT(1A) 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.

SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates: II. Equilibrium analysis of constant infusion experiments and correlation with in vitro parameters.

In vivo benzodiazepine receptor equilibrium dissociation constant, KD, and maximum number of binding sites, Bmax, were measured by single photon emission computerized tomography (SPECT) in three baboons. Animals were injected with a bolus followed by a constant i.v. infusion of the high affinity benzodiazepine ligand [123I]iomazenil. Plasma steady-state concentration and receptor-ligand equilibrium were reached within 2 and 3 h, respectively, and were sustained for the duration (4-9 h) of the experiments (n = 15). At the end of the experiments, a receptor saturating dose of flumazenil (0.2 mg/kg) was injected to measure nondisplaceable activity. Experiments were carried out at various levels of specific activity, and Scatchard analysis was performed for derivation of the KD (0.59 +/- 0.09 nM) and Bmax (from 126 nM in the occipital region to 68 nM in the striatum). Two animals were killed and [125I]iomazenil Bmax and KD were measured at 22 and 37 degrees C on occipital homogenate membranes. In vitro values of Bmax (114 +/- 33 nM) and 37 degrees C KD (0.66 +/- 0.16 nM) were in good agreement with in vivo values measured by SPECT. This study demonstrates that SPECT can be used to quantify central neuroreceptors density and affinity.

Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility.

To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathology requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomography imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of analysis (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution volume, distribution volume ratio, binding potential (BP), and specific-to-nonspecific equilibrium partition coefficient (k3/k4). Both kinetic and graphic analyses provided BP and k3/k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic analysis was excellent. Time-stability analysis indicated that 90 minutes of data collection generated stable outcome measures. Derivation of BP and k3/k4 by kinetic analysis was highly reliable, with intraclass correlation coefficients (ICCs) of 0.90+/-0.06 (mean +/- SD of 12 regions) and 0.84+/-0.11, respectively. The reliability of these parameters derived by graphical analysis was lower, with ICCs of 0.72+/-0.17 and 0.58+/-0.21, respectively. Noise analysis revealed a noise-dependent bias in the graphical but not the kinetic analysis. In conclusion, kinetic analysis of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor density.

Low dopamine D(2) receptor binding potential in social phobia.

OBJECTIVE: This study compared dopamine D(2) receptor binding potential in patients with social phobia and healthy comparison subjects. METHOD: Dopamine D(2) receptor binding potential was assessed in 10 unmedicated subjects with generalized social phobia and no significant lifetime psychiatric comorbidity and 10 healthy comparison subjects matched for age and sex. Binding potential was measured in the striatum by using single photon emission computerized tomography and constant infusion of the D(2) receptor radiotracer [(123)I]iodobenzamide ([(123)I]IBZM). RESULTS: Mean D(2) receptor binding potential was significantly lower in the subjects with social phobia than in the comparison subjects. Within the social phobia group, there was a nonsignificant correlation of binding potential with the Liebowitz Social Anxiety Scale score. CONCLUSIONS: Generalized social phobia may be associated with low binding of [(123)I]IBZM to D(2) receptors in the striatum.

Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort.

OBJECTIVE: The authors previously observed an increase in striatal dopamine transmission following amphetamine challenge in 15 untreated patients with schizophrenia compared to 15 matched healthy subjects. The purpose of this study was to replicate this finding in a new cohort of schizophrenic patients and healthy subjects. METHOD: Fifteen patients with schizophrenia and 15 healthy subjects matched for age, gender, ethnicity, and parental socioeconomic status were recruited for this study. Patients fulfilled DSM-IV criteria for schizophrenia, had no history of alcohol or substance abuse or dependence, and were neuroleptic free for a minimum of 21 days. Amphetamine-induced dopamine release was assessed by the reduction in dopamine D2 receptor availability induced by an acute amphetamine challenge (0.3 mg/kg, intravenous bolus). Reduction in D2 receptor availability was measured with single photon emission computed tomography and the D2 receptor radiotracer [123I]IBZM. RESULTS: No differences were observed between patients with schizophrenia and the comparison group in D2 receptor availability at baseline. Patients with schizophrenia exhibited a significantly larger reduction in D2 receptor availability following acute amphetamine challenge than the comparison group. In this study, the effect size was smaller than in the first study. Excess dopamine release following amphetamine was associated with transient emergence or worsening of positive symptoms. CONCLUSIONS: In this new cohort of subjects the authors replicated their initial observation of a dysregulation of striatal dopamine release in schizophrenia.

Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil.

OBJECTIVE: Alterations in cortical benzodiazepine receptor density have been described in postmortem and in vivo studies of alcoholic subjects. The authors attempted to replicate these findings using single photon emission computed tomography and the benzodiazepine receptor radiotracer [123I]iomazenil. METHOD: They measured the distribution volume of benzodiazepine receptors in 11 recently detoxified patients with type II alcoholism and 11 healthy comparison subjects. The tracer was given as a bolus followed by a continuous infusion to achieve sustained binding equilibrium at the benzodiazepine receptors. Data were analyzed by using a region of interest method (regions of interest were identified on coregistered magnetic resonance imaging scans) and by a pixel-by-pixel method (distribution volume maps were analyzed with statistical parametric mapping for between-group differences). RESULTS: The region of interest analysis revealed that alcoholic patients had significantly lower benzodiazepine distribution volume than comparison subjects in the frontal, anterior cingulate, and cerebellar cortices. Statistical parametric mapping revealed two large excursions in which the distribution volume in alcoholic patients was significantly lower than in comparison subjects: the anterior cingulate, extending into the right middle frontal gyrus, and the left occipital cortex. CONCLUSIONS: Benzodiazepine receptor distribution volume is significantly lower in several cortical regions and the cerebellum in alcoholic subjects than in healthy comparison subjects. These results are consistent with previous reports and might indicate either a toxic effect of alcoholism on benzodiazepine receptors or a vulnerability factor for developing alcoholism.