Low dopamine d(2) receptor binding in subregions of the thalamus in schizophrenia.

OBJECTIVE: Several structural and functional brain imaging studies have pointed to a disturbance of thalamic subnuclei in patients with schizophrenia. The dopamine hypothesis of schizophrenia has, however, not been thoroughly examined in terms of this complex structure, which has connections with most brain regions of central interest in schizophrenia research. The aim of the present study was to examine dopamine D(2) receptor binding in subregions of the thalamus in patients with schizophrenia. METHOD: The authors used positron emission tomography and the radioligand [(11)C]FLB457 to examine dopamine D(2) receptor binding in thalamic subregions of 10 drug-naive patients with schizophrenia. Binding potential was calculated by the reference tissue method and used as an index for dopamine D(2) receptor binding. Comparisons were made with 19 healthy subjects. Subregions of interest were defined on individual magnetic resonance images using a percentage-based operational approach. Clinical symptoms were rated by using the Brief Psychiatric Rating Scale (BPRS). RESULTS: The [(11)C]FLB457 binding potential was lower in the central medial and posterior subregions of the thalamus in patients with schizophrenia. At a functional level, there was a significant negative correlation between binding potential and BPRS positive symptom scores. CONCLUSIONS: The subregions with low D(2) receptor binding comprise primarily the dorsomedial nucleus and pulvinar, two important components in circuitries previously suggested in the pathophysiology of schizophrenia. Aberrant dopaminergic neurotransmission in thalamic subregions might be a mechanism underlying positive symptoms in schizophrenia.

Effect of amphetamine on extrastriatal D2 dopamine receptor binding in the primate brain: a PET study.

[(11)C]raclopride binding to D2 dopamine receptors in the striatum is sensitive to drug-induced changes of endogenous dopamine concentration. We recently developed the new radioligand [(11)C]FLB 457, which is suitable for positron emission tomography (PET) studies of extrastriatal D2 dopamine receptors. The purpose of this PET study was to examine the effect of amphetamine on [(11)C]FLB 457 binding in extrastriatal regions. Each of three cynomolgus monkeys was examined at baseline conditions, 15 min and 3 h after I.V. injection of amphetamine (2 mg/kg). The effect of amphetamine was calculated from the ratio of specific [(11)C]FLB 457 binding to the binding in the cerebellum, a region which was used as reference for free and nonspecific binding in the brain. The changes of the ratio in the striatum, the thalamus, and the neocortex were between -1.2% and -15.5% at 15 min and -2.1% and -16.3% at 3 h, respectively, after amphetamine administration. The reductions of the binding ratios in the extrastriatal regions are similar to those reported for [(11)C]raclopride binding in the striatum. These data in a limited series of monkeys suggest that [(11)C]FLB 457 binding to D2 dopamine receptors in extrastriatal regions is sensitive to changes in the concentration of endogenous dopamine.

Reduction of hydroxamic acids to the corresponding amides catalyzed by rabbit blood.

1. The hydroxamic acids N-hydroxyphenacetin and N-hydroxy-2-acetylaminofluorene were reduced to the corresponding amides, phenacetin and 2-acetylaminofluorene respectively by rabbit blood supplemented with both NAD(P)H and FAD. These reducing activities were found in erythrocytes but not in plasma, and were sensitive to inhibition by carbon monoxide and oxygen. When blood or erythrocytes were boiled, these activities were not abolished. 2. Haemoproteins such as haemoglobin and catalase exhibited the reductase activity in the presence of both NAD(P)H and FAD under anaerobic conditions. The activity was not abolished when the haemoproteins were boiled. 3. Haematin showed a significant reducing activity in the presence of these cofactors. The activity of haematin was also observed with the photochemically reduced form of FAD. 4. The reduction system in blood was composed of NAD(P)H, FAD and haemoglobin. Reduction appears to proceed in two steps, i.e. the reduction of FAD by NADH or NADPH, followed by the non-enzymatic reduction of the hydroxamic acids to the amides by reduced FAD, catalyzed by the haem group of haemoglobin in rabbit erythrocytes.

Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects.

Cocaine blocks the reuptake of dopamine, a neurotransmitter involved in the control of movement, cognition, motivation and reward. This leads to an increase in extracellular dopamine; the reinforcing effect of cocaine is associated with elevated dopamine levels in the nucleus accumbens. But addiction to cocaine involves other effects, such as craving, loss of control and compulsive drug intake; the role of the dopamine system in these effects is less well-understood. We therefore used positron emission tomography (PET) to compare the responses of cocaine addicts and normal controls to intravenous methylphenidate, a drug that, like cocaine, causes an increase in synaptic dopamine. Addicts showed reduced dopamine release in the striatum, the brain region where the nucleus accumbens is located, and also had a reduced 'high' relative to controls. In contrast, addicts showed an increased response to methylphenidate in the thalamus (a region that conveys sensory input to the cortex). This thalamic response was associated with cocaine craving and was not seen in control subjects. Thus, our findings challenge the notion that addiction involves an enhanced striatal dopamine response to cocaine and/or an enhanced induction of euphoria. Moreover, they suggest a participation of thalamic dopamine pathways in cocaine addiction, a possibility that merits further investigation.

Depletion of hepatic 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and sulfate in rats by xenobiotics that are sulfated.

Sulfation is considered a high-affinity but low-capacity conjugation mechanism that is limited by the availability of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), the cosubstrate for sulfation. Salicylamide, phenol and 1-naphthol are all known substrates for the sulfation reaction. This study was conducted to determine whether the xenobiotics that are sulfated when administered to rats will lower hepatic PAPS and its precursor, sulfate. Urinary sulfate excretion was reduced 85% to 95% by these compounds. Hepatic PAPS was reduced 73%, 39%, and 87% by salicylamide, phenol and naphthol, respectively, 2 hr after administration of 2 mmol/kg. These compounds also decreased serum sulfate concentrations by 45% to 86% and lowered hepatic sulfate concentrations. In summary, these studies demonstrate that salicylamide, phenol and 1-naphthol lower hepatic PAPS and sulfate concentrations, as well as serum sulfate concentrations. These findings imply that increased sulfation, as a result of the sulfation of xenobiotics, results in depletion of hepatic PAPS concentrations, possibly because the utilization of PAPS by the sulfotransferases exceeds its generation via sulfate activation. Thus the capacity-limited sulfation of high dosages of xenobiotics appears to be due to the reduced availability of hepatic PAPS, which in turn is limited by the availability of sulfate.

An effect of sulfur nutrition on the metabolism of salicylamide.

The effect of supplementing diets containing 15% casein with inorganic sulfate and/or the sulfur-containing amino acids on the metabolism of salicylamide was determined. The glucuronide-salicylamide:sulfate-salicylamide (GS:SS) ratio in the urine of rats fed the diets containing 15% of casein without inorganic sulfate or sulfur containing amino acid supplementation approached unity. Addition of either 0.02% of inorganic sulfate or 0.625% of methionine reduced this ratio to approximately 0.3%. Addition of 0.325% of methionine or sufficient cysteine to be equimolar with 0.625% methionine did not lower the GS:SS ratio significantly. Therefore, it appears that not only the level but the source of sulfur may be important in the detoxication of drugs.