RESUMEN
Lorazepam is a widely used anxiolytic drug of the benzodiazepine class. The clinical actions of benzodiazepines are thought to be mediated via specific allosteric benzodiazepine binding sites and enhancement of GABAergic neurotransmission in the brain. However, the indirect effects of benzodiazepines on other neurotransmitter systems have not been extensively studied. Previous experimental evidence suggests that benzodiazepines inhibit striatal dopamine release by enhancing the GABAergic inhibitory effect on dopamine neurons whereas very little is known about cortical or thalamic gamma-amino-butyric (GABA)-dopamine interactions during benzodiazepine administration. We explored the effects of lorazepam (a single 2.5 mg dose) on cortical and thalamic D(2/3) receptor binding using Positron-Emission Tomography (PET) and the high-affinity D(2/3)-receptor ligand [(11)C]FLB 457 in 12 healthy male volunteers. We used a randomized, double-blind and placebo-controlled study design. Dopamine D(2)/D(3) receptor binding potential was measured with the reference tissue method in several extrastriatal D(2)-receptor areas including frontal, parietal, temporal cortices and thalamus. The main subjective effect of lorazepam was sedation. Lorazepam induced a statistically significant decrease of D(2)/D(3) receptor BP(ND) in medial temporal and dorsolateral prefrontal cortex (DLPFC) that was also confirmed by a voxel-level analysis. The sedative effect of lorazepam was associated with a decrease in D(2)/D(3) receptor BP(ND) in the DLPFC. In conclusion, lorazepam decreased [(11)C]FLB 457 binding in frontal and temporal cortex, suggesting that cortical GABA-dopamine interaction may be involved in the central actions of lorazepam in healthy volunteers. The correlation between lorazepam-induced sedation and D(2)/D(3) receptor binding potential (BP) change further supports this hypothesis.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Moduladores del GABA/farmacología , Lorazepam/farmacología , Tomografía de Emisión de Positrones/métodos , Receptores de Dopamina D2/efectos de los fármacos , Tálamo/efectos de los fármacos , Adulto , Análisis de Varianza , Mapeo Encefálico , Isótopos de Carbono/metabolismo , Corteza Cerebral/diagnóstico por imagen , Antagonistas de Dopamina/farmacología , Método Doble Ciego , Moduladores del GABA/sangre , Humanos , Lorazepam/sangre , Masculino , Unión Proteica/efectos de los fármacos , Pirrolidinas/farmacología , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Salicilamidas/farmacología , Tálamo/diagnóstico por imagen , Factores de Tiempo , Adulto JovenRESUMEN
RATIONALE: The noncompetitive glutamate N-methyl-D: -aspartate receptor antagonist ketamine induces transient psychotic symptoms in man. Involvement of dopaminergic mechanisms in these effects has been suggested. OBJECTIVES: The purpose of this article is to study the effects of ketamine on extrastriatal dopamine receptor availability in healthy subjects and extracellular dopamine levels in rat cortex. MATERIALS AND METHODS: The effect of computer-driven subanesthetic ketamine infusion on cortical dopamine release was studied in healthy male subjects using a controlled study design. Dopamine D2/D3 receptor availability was quantified using positron emission tomography (PET) and [11C]FLB 457. A conventional region of interest-based analysis and voxel-based analysis was applied to the PET data. The ketamine-induced cortical dopamine release in rats was studied using in vivo microdialysis. RESULTS: Ketamine infusion reduced significantly the [11C]FLB 457 binding potential (BP) in the posterior cingulate/retrosplenial cortices, suggestive of increased dopamine release. This brain imaging finding was further supported by a microdialysis experiment in rats showing that ketamine increased the extracellular dopamine concentration by up to 200% in the retrosplenial cortex. Ketamine-induced psychotic symptoms were associated with changes in the [11C]FLB 457 BP in the dorsolateral prefrontal and anterior cingulate cortices. CONCLUSIONS: Our results suggest that cortical dopaminergic mechanisms have a role in the emergence of ketamine-induced psychosis-like symptoms in man. The glutamate-dopamine interaction in the posterior cingulate during ketamine infusion is well in line with the recent functional and structural imaging studies suggesting involvement of this cortical area in the development of schizophrenic psychosis.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Dopamina/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/fisiología , Ketamina/farmacología , Psicosis Inducidas por Sustancias/etiología , Adulto , Animales , Radioisótopos de Carbono , Corteza Cerebral/fisiología , Humanos , Masculino , Microdiálisis , Tomografía de Emisión de Positrones , Pirrolidinas/metabolismo , Ratas , Salicilamidas/metabolismoRESUMEN
BACKGROUND: The attempts to evaluate amygdaloid volumes using magnetic resonance imaging (MRI) in patients with schizophrenia have yielded highly divergent results. METHODS: Volumes of the amygdala were measured in 22 healthy participants and 18 neuroleptic-naive patients with first-episode schizophrenia, while controlling for intracranial area, gender, age, and handedness. RESULTS: Persons with schizophrenia presented significantly lower amygdaloid volumes bilaterally. No significant correlations were found between the amygdaloid volumes and either the duration of the disease or the symptom severity. CONCLUSIONS: Amygdaloid volume anomalies are already present in the early phases of schizophrenia.
Asunto(s)
Amígdala del Cerebelo/patología , Esquizofrenia/patología , Adulto , Estudios de Casos y Controles , Episodio de Atención , Femenino , Humanos , Imagen por Resonancia Magnética , MasculinoAsunto(s)
Ventrículos Cerebrales/patología , Líquido Cefalorraquídeo/fisiología , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Trastornos Psicóticos/patología , Esquizofrenia/patología , Psicología del Esquizofrénico , Adulto , Atrofia , Enfermedad Crónica , Dominancia Cerebral/fisiología , Femenino , Lóbulo Frontal/patología , Humanos , Masculino , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/psicología , Valores de Referencia , Esquizofrenia/diagnóstico , Lóbulo Temporal/patologíaRESUMEN
RATIONALE: A glutamate-dopamine interaction has been implicated in the psychosis-like effects of glutamate N-methyl- D-aspartate (NMDA) receptor antagonists, such as phencyclidine and ketamine. However, recent imaging studies addressing striatal glutamate-dopamine interaction directly in vivo in man have been controversial. OBJECTIVES: To examine whether the NMDA receptor antagonist ketamine in high subanesthetic concentrations decreases striatal [(11)C]raclopride binding potential in man. To further evaluate whether changes in striatal [(11)C]raclopride binding are associated with ketamine-induced behavioral effects. METHODS: The effect of computer-driven subanesthetic ketamine infusion on striatal dopamine release was studied in healthy male subjects using a controlled study design. Dopamine release was studied using positron emission tomography and the [(11)C]raclopride displacement paradigm. A conventional region of interest-based analysis and voxel-based analysis were applied to the positron emission tomography data. RESULTS: The average plasma ketamine concentration was 293+/-29 ng/ml. Ketamine did not alter striatal [(11)C]raclopride binding. Ketamine induced typical behavioral effects, such as hallucinations but there was no correlation between these effects and displacement of [(11)C]raclopride binding. CONCLUSIONS: This controlled study indicates that ketamine does not decrease striatal [(11)C]raclopride binding. Striatal dopamine release is of minor importance in the psychosis-like effects of ketamine.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Ketamina/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Tomografía Computarizada de Emisión , Adulto , Confusión/inducido químicamente , Confusión/diagnóstico por imagen , Cuerpo Estriado/diagnóstico por imagen , Dopamina/metabolismo , Euforia/efectos de los fármacos , Alucinaciones/inducido químicamente , Alucinaciones/diagnóstico por imagen , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Escalas de Valoración Psiquiátrica , Racloprida/farmacocinética , Receptores de Dopamina D2/metabolismoRESUMEN
BACKGROUND: There are sex differences in the clinical features of several neuropsychiatric illnesses associated with dopamine dysfunction. The effects of sex on brain dopaminergic function have been sparsely studied in human subjects using modern imaging techniques. We have previously reported that the apparent affinity of [(11)C]raclopride for striatal D(2) dopamine receptors in vivo is lower in women than in men, whereas D(2) receptor density is not different. This finding indirectly suggests that women have a higher synaptic concentration of dopamine in the striatum. We explored further the basis of this phenomenon in an independent study and hypothesized that striatal presynaptic dopamine synthesis capacity would also be elevated in women. METHODS: A total of 23 healthy men and 12 healthy women (age range 20-60 years) were studied using positron emission tomography and [(18)F]fluorodopa. RESULTS: Women had significantly higher striatal [(18)F]fluorodopa uptake (Ki values) than men. The difference was more marked in the caudate (+26%) than in the putamen (+12%). In addition, there was a negative correlation between striatal [(18)F]fluorodopa Ki values and age in men but not in women. CONCLUSIONS: The results further substantiate sex differences in striatal dopaminergic function in humans. This finding may be associated with sex differences in vulnerability and clinical course of neuropsychiatric disorders with dopaminergic dysregulation, e.g., schizophrenia, alcohol dependence, and Parkinson's disease.
Asunto(s)
Cuerpo Estriado/metabolismo , Dihidroxifenilalanina/análogos & derivados , Dopamina/biosíntesis , Terminales Presinápticos/metabolismo , Adulto , Factores de Edad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Tomografía Computarizada de EmisiónRESUMEN
BACKGROUND: Imaging studies have frequently reported volume loss of limbic structures in schizophrenia, yet there appears to be no quantitative data on entorhinal cortex volumes in patients with neuroleptic naive first-episode schizophrenia. METHODS: The volume of the entorhinal cortices of 22 control subjects and 18 patients with neuroleptic-naïve first-episode schizophrenia were measured from magnetic resonance images (MRI) scans using recently designed anatomic criteria for MRI anatomy of the entorhinal cortex. RESULTS: Smaller entorhinal volumes were found bilaterally in the schizophrenic patients. This volume loss did not correlate with items on the Positive and Negative Syndrome Scale. CONCLUSIONS: These data suggest early involvement of the entorhinal cortex in schizophrenia.