The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D 1 recepto... more Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D 1 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, D 1 receptor availability was measured with positron emission tomography and the selective D 1 receptor antagonist [ 11 C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [ 11 C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of pa-tients with schizophrenia (1.63 Ϯ 0.39 ml/gm) compared with control subjects (1.27 Ϯ 0.44 ml/gm; p ϭ 0.02). In patients with schizophrenia, increased DLPFC [ 11 C]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 D 1 receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D 1 receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.
The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic tra... more The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic transmission at the D2 receptor. We measured in vivo occupancy of striatal D 2 receptors by dopamine in 18 untreated patients with schizophrenia and 18 matched controls, by comparing D2 receptor availability before and during pharmacologically induced acute dopamine depletion. Acute depletion of intrasynaptic dopamine resulted in a larger increase in D 2 receptor availability in patients with schizophrenia (19% ؎ 11%) compared with control subjects (9% ؎ 7%, P ؍ 0.003). The increased occupancy of D2 receptors by dopamine occurred both in first-episode neuroleptic-naive patients and in previously treated chronic patients experiencing an episode of illness exacerbation. In addition, elevated synaptic dopamine was predictive of good treatment response of positive symptoms to antipsychotic drugs. This finding provides direct evidence of increased stimulation of D2 receptors by dopamine in schizophrenia, consistent with increased phasic activity of dopaminergic neurons.
All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3... more All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3 (D3) receptors in vitro. However, there is conflicting evidence from in vivo studies about whether or not antipsychotic medications bind to the D3 receptor (D3R). The purpose of this study was to determine whether acute doses of risperidone bind to the D3R in humans. We performed PET scans on an mCT scanner with [(11)C]-(+)-PHNO injected as a bolus, before and after a 2mg oral dose of risperidone in five medication free subjects with schizophrenia. The subjects were scanned for 120min and underwent an MRI scan for region of interest delineation and coregistration. Cerebellum was used as a reference region. Simplified reference tissue modeling (SRTM) was used to calculate BPND. We observed binding to the D3R receptor by risperidone as evidenced by observable occupancy in regions in which the [(11)C]-(+)-PHNO signal is almost exclusively from the D3R (i.e., substantia nigra/ventral tegmen...
The authors previously observed an increase in striatal dopamine transmission following amphetami... more 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. 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. No differences were observed betwe...
... CH; Erdos J.; D'Souza D.; Rosenblatt W.; McCance-Katz E.; Zea-Ponce Y.; Zoghbi SS; B... more ... CH; Erdos J.; D'Souza D.; Rosenblatt W.; McCance-Katz E.; Zea-Ponce Y.; Zoghbi SS; Baldwin RM; Hoffer PB; Krystal J.; Charney ... An association between schizophrenia and increased dopamine (DA) activity has been postulated since a long time, but direct confirmation of this ...
Progrès en urologie : journal de l'Association française d'urologie et de la Société française d'urologie, 2009
To evaluate secondary effects on cognitive functions as memory and attention impairments in men t... more To evaluate secondary effects on cognitive functions as memory and attention impairments in men treated by androgen suppression for cancer of prostate. A prospective study on men treated with luteinizing hormone-realising hormone analogues (LH-RH analogues) for cancer of prostate was designed. Eighteen men were evaluated with cognitive tests as Mini Mental State (MMS), memory evaluation (Grober-Buschke, Rey Test), attention and executive test (Trail Making Test and Montgomery Asberg Depression Rating Scale [MADRS]) before beginning androgen suppression. Base line pretreatment assessments of every patient were compared with similar tests after six and 12 months of hormone therapy. On 18 patients, 14 were eligible with pretreatment-median PSA of 22ng/ml (13-659), testosterone of 477ng/dl (398-583), which decreased to 1 and 37ng/dl, respectively. Visual-memory test (Rey test) was significantly improved at M6 (p: 0,001) and M12 (p: 0,02) as was the inversed number-memory test (WAIS) aft...
To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the... more To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the D2 occupancy by endogenous dopamine in schizophrenia. 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. 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 ...
Proceedings of the National Academy of Sciences of the United States of America, Jan 20, 1996
The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission... more The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamine-induced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release was estimated by the amphetamine-induced reduction in dopamine D2 receptor availability, measured as the binding potential of the specific D2 receptor radiotracer [123I] (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]benzamide ([123I]IBZM). The amphetamine-induced decrease in [123I]IBZM binding potential was significantly greater in the schizophrenic group (-19.5 +/- 4.1%) compared with the control group (-7.6 +/- 2.1%). In the schizophrenic group, elevated amphetamine effect on [123I]IBZ...
Electroencephalography and clinical neurophysiology
Long latency event-related auditory evoked potentials, particularly the P300 wave, constitute an ... more Long latency event-related auditory evoked potentials, particularly the P300 wave, constitute an objective electrophysiological index of cognitive function. For this reason, these potentials have been studied in a series of 101 patients with multiple sclerosis (MS), classified according to McAlpine's criteria into definite, probable and possible cases. The patients were also classified as depressed or non-depressed according to the DSM-III and Research Diagnostic Criteria. They were also subjected to a battery of psychometric tests. In the patient population the N200 and P300 latencies were increased, as were the P200 latencies, when compared with a control population. This electrophysiological pattern had previously been observed in other conditions characterised by subcortical lesions. Partial correlations (at constant disease duration) between the disability score and the cognitive deficit were found to be significant. Patients with an increased P300 latency had a greater dis...
IMPORTANCE Multiple lines of evidence suggest a deficit in dopamine release in the prefrontal cor... more IMPORTANCE Multiple lines of evidence suggest a deficit in dopamine release in the prefrontal cortex (PFC) in schizophrenia. Despite the prevalence of the concept of prefrontal cortical hypodopaminergia in schizophrenia, in vivo imaging of dopamine release in the PFC has not been possible until now, when the validity of using the positron emission tomographic D2/3 radiotracer carbon 11-labeled FLB457 in combination with the amphetamine paradigm was clearly established.
teers, using a double-blind, randomized placebo-controlled crossover design. D-cycloserine was re... more teers, using a double-blind, randomized placebo-controlled crossover design. D-cycloserine was readily absorbed and did not induce sideeffects. Furthermore, D-cycloserine stimulated LH secretion (MANOYA , p~0.030) and induced a significant rise of the area under the plasma concentration time curve of LH (student t-tests, p=O.038). D-cycloserine did not stimulate cortisol secretion. To our knowledge this is the first study describing the involvement of NMDA receptors in human LH secretion. Furthermore, these neuroendocrine effects indicate that D-cycloscrine can be used to assess NMDA receptor function in schizophrenic patients.
Dopamine (DA) has a role in the pathophysiology of schizophrenia and addiction. Imaging studies h... more 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 D 2 -receptor availability (BP ND ) and its percent change post-amphetamine (DBP ND , 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 BP ND . Linear mixed modeling using DBP ND as the dependent variable and striatal region of interest as a repeated measure indicated a significant main effect of diagnosis, F(1, 24) ¼ 8.38, P ¼ 0.008, with significantly smaller DBP ND in patients in all striatal subregions (all Pp0.04) except VST. Among patients, change in positive symptoms after amphetamine was significantly associated with DBP ND in the preDCA (r s ¼ 0.69, P ¼ 0.03) and VST (r s ¼ 0.64, P ¼ 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 D 2 stimulation, suggesting abnormal postsynaptic D 2 function.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D 1 recepto... more Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D 1 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, D 1 receptor availability was measured with positron emission tomography and the selective D 1 receptor antagonist [ 11 C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [ 11 C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of pa-tients with schizophrenia (1.63 Ϯ 0.39 ml/gm) compared with control subjects (1.27 Ϯ 0.44 ml/gm; p ϭ 0.02). In patients with schizophrenia, increased DLPFC [ 11 C]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 D 1 receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D 1 receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.
The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic tra... more The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic transmission at the D2 receptor. We measured in vivo occupancy of striatal D 2 receptors by dopamine in 18 untreated patients with schizophrenia and 18 matched controls, by comparing D2 receptor availability before and during pharmacologically induced acute dopamine depletion. Acute depletion of intrasynaptic dopamine resulted in a larger increase in D 2 receptor availability in patients with schizophrenia (19% ؎ 11%) compared with control subjects (9% ؎ 7%, P ؍ 0.003). The increased occupancy of D2 receptors by dopamine occurred both in first-episode neuroleptic-naive patients and in previously treated chronic patients experiencing an episode of illness exacerbation. In addition, elevated synaptic dopamine was predictive of good treatment response of positive symptoms to antipsychotic drugs. This finding provides direct evidence of increased stimulation of D2 receptors by dopamine in schizophrenia, consistent with increased phasic activity of dopaminergic neurons.
All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3... more All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3 (D3) receptors in vitro. However, there is conflicting evidence from in vivo studies about whether or not antipsychotic medications bind to the D3 receptor (D3R). The purpose of this study was to determine whether acute doses of risperidone bind to the D3R in humans. We performed PET scans on an mCT scanner with [(11)C]-(+)-PHNO injected as a bolus, before and after a 2mg oral dose of risperidone in five medication free subjects with schizophrenia. The subjects were scanned for 120min and underwent an MRI scan for region of interest delineation and coregistration. Cerebellum was used as a reference region. Simplified reference tissue modeling (SRTM) was used to calculate BPND. We observed binding to the D3R receptor by risperidone as evidenced by observable occupancy in regions in which the [(11)C]-(+)-PHNO signal is almost exclusively from the D3R (i.e., substantia nigra/ventral tegmen...
The authors previously observed an increase in striatal dopamine transmission following amphetami... more 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. 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. No differences were observed betwe...
... CH; Erdos J.; D'Souza D.; Rosenblatt W.; McCance-Katz E.; Zea-Ponce Y.; Zoghbi SS; B... more ... CH; Erdos J.; D'Souza D.; Rosenblatt W.; McCance-Katz E.; Zea-Ponce Y.; Zoghbi SS; Baldwin RM; Hoffer PB; Krystal J.; Charney ... An association between schizophrenia and increased dopamine (DA) activity has been postulated since a long time, but direct confirmation of this ...
Progrès en urologie : journal de l'Association française d'urologie et de la Société française d'urologie, 2009
To evaluate secondary effects on cognitive functions as memory and attention impairments in men t... more To evaluate secondary effects on cognitive functions as memory and attention impairments in men treated by androgen suppression for cancer of prostate. A prospective study on men treated with luteinizing hormone-realising hormone analogues (LH-RH analogues) for cancer of prostate was designed. Eighteen men were evaluated with cognitive tests as Mini Mental State (MMS), memory evaluation (Grober-Buschke, Rey Test), attention and executive test (Trail Making Test and Montgomery Asberg Depression Rating Scale [MADRS]) before beginning androgen suppression. Base line pretreatment assessments of every patient were compared with similar tests after six and 12 months of hormone therapy. On 18 patients, 14 were eligible with pretreatment-median PSA of 22ng/ml (13-659), testosterone of 477ng/dl (398-583), which decreased to 1 and 37ng/dl, respectively. Visual-memory test (Rey test) was significantly improved at M6 (p: 0,001) and M12 (p: 0,02) as was the inversed number-memory test (WAIS) aft...
To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the... more To examine the D2 occupancy of two commonly used antipsychotic medications and relate this to the D2 occupancy by endogenous dopamine in schizophrenia. 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. 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 ...
Proceedings of the National Academy of Sciences of the United States of America, Jan 20, 1996
The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission... more The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamine-induced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release was estimated by the amphetamine-induced reduction in dopamine D2 receptor availability, measured as the binding potential of the specific D2 receptor radiotracer [123I] (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]benzamide ([123I]IBZM). The amphetamine-induced decrease in [123I]IBZM binding potential was significantly greater in the schizophrenic group (-19.5 +/- 4.1%) compared with the control group (-7.6 +/- 2.1%). In the schizophrenic group, elevated amphetamine effect on [123I]IBZ...
Electroencephalography and clinical neurophysiology
Long latency event-related auditory evoked potentials, particularly the P300 wave, constitute an ... more Long latency event-related auditory evoked potentials, particularly the P300 wave, constitute an objective electrophysiological index of cognitive function. For this reason, these potentials have been studied in a series of 101 patients with multiple sclerosis (MS), classified according to McAlpine's criteria into definite, probable and possible cases. The patients were also classified as depressed or non-depressed according to the DSM-III and Research Diagnostic Criteria. They were also subjected to a battery of psychometric tests. In the patient population the N200 and P300 latencies were increased, as were the P200 latencies, when compared with a control population. This electrophysiological pattern had previously been observed in other conditions characterised by subcortical lesions. Partial correlations (at constant disease duration) between the disability score and the cognitive deficit were found to be significant. Patients with an increased P300 latency had a greater dis...
IMPORTANCE Multiple lines of evidence suggest a deficit in dopamine release in the prefrontal cor... more IMPORTANCE Multiple lines of evidence suggest a deficit in dopamine release in the prefrontal cortex (PFC) in schizophrenia. Despite the prevalence of the concept of prefrontal cortical hypodopaminergia in schizophrenia, in vivo imaging of dopamine release in the PFC has not been possible until now, when the validity of using the positron emission tomographic D2/3 radiotracer carbon 11-labeled FLB457 in combination with the amphetamine paradigm was clearly established.
teers, using a double-blind, randomized placebo-controlled crossover design. D-cycloserine was re... more teers, using a double-blind, randomized placebo-controlled crossover design. D-cycloserine was readily absorbed and did not induce sideeffects. Furthermore, D-cycloserine stimulated LH secretion (MANOYA , p~0.030) and induced a significant rise of the area under the plasma concentration time curve of LH (student t-tests, p=O.038). D-cycloserine did not stimulate cortisol secretion. To our knowledge this is the first study describing the involvement of NMDA receptors in human LH secretion. Furthermore, these neuroendocrine effects indicate that D-cycloscrine can be used to assess NMDA receptor function in schizophrenic patients.
Dopamine (DA) has a role in the pathophysiology of schizophrenia and addiction. Imaging studies h... more 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 D 2 -receptor availability (BP ND ) and its percent change post-amphetamine (DBP ND , 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 BP ND . Linear mixed modeling using DBP ND as the dependent variable and striatal region of interest as a repeated measure indicated a significant main effect of diagnosis, F(1, 24) ¼ 8.38, P ¼ 0.008, with significantly smaller DBP ND in patients in all striatal subregions (all Pp0.04) except VST. Among patients, change in positive symptoms after amphetamine was significantly associated with DBP ND in the preDCA (r s ¼ 0.69, P ¼ 0.03) and VST (r s ¼ 0.64, P ¼ 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 D 2 stimulation, suggesting abnormal postsynaptic D 2 function.
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