Serotonin-2 and dopamine-1 binding components of clozapine in frontal cortex and striatum in the human brain visualized by positron emission tomography.

The specific binding of N-methyl-11C-clozapine in the human brain was studied in five healthy volunteers with positron emission tomography (PET). Four of the volunteers were reexamined after treatment with the dopamine D1 and D2 receptor antagonist flupenthixol, and all five volunteers were reexamined after pretreatment with the serotonin2 receptor antagonist ritanserin. The examinations after flupenthixol and ritanserin treatment were performed on different occasions. In the flupenthixol part of the study, two of the subjects were given an oral dose of 1 mg flupenthixol 2-3 h before the posttreatment study with PET. The other two subjects received 0.5 mg orally three times during the 24 h preceding the posttreatment PET study, with the last dose being administered < or = 4 h before the scan. All five ritanserin-treated subjects followed the same dosing regimen. During the 5 days preceding the posttreatment PET study, they were given a 10-mg tablet of ritanserin in the evening. The last dose was administered 2-1/2 hours before the study. Both flupenthixol and ritanserin pretreatment were associated with decreased binding of N-methyl-11C-clozapine in dorsolateral and medial frontal cortical regions. These results support previous findings that clozapine has affinity for both dopamine D1 and serotonin 5-HT2 receptors in the human frontal cortex. No consistent change of binding was observed in striatal regions following flupenthixol or ritanserin pretreatment. The clinical aspects of this feature are discussed, both with respect to efficacy and side effects.

PET studies of presynaptic monoamine metabolism in depressed patients and healthy volunteers.

No deranged presynaptic monoamine metabolism in the brain has been directly demonstrated in mood disorders, in spite of the rich but indirect pharmacological evidence for a decreased efficacy of monoaminergic synaptic transmission in depression, especially as for serotonin. The availability of 11C-labelled 5-hydroxytryptophan (5-HTP) and L-DOPA, the direct precursors in the synthetic pathways to serotonin and dopamine, has allowed positron emission tomographic (PET) studies in 8 healthy volunteers and 6 patients suffering from unipolar depression. Main results indicate (1) decreased uptake of [11C]5-HTP and [11C]L-DOPA over the blood-brain barrier in depression (which is not altered by dietary tryptophan depletion in healthy volunteers), and (2) an increased utilization of [11C]5-HTP (but not [11C]L-DOPA), in the lower region of the medial prefrontal cortex, mainly of the left side. This phenomenon presumably mirrors an increased synthesis of serotonin in this area and might represent a local compensatory increase in a situation of a general serotonergic hypometabolism. Analyses of interactions of both ligands between striatal and prefrontal areas suggest significantly stronger positive correlations in depression than in health, that could be interpreted as a less pronounced autonomy between brain regions in depression.

Uptake and utilization of [beta-11C]5-hydroxytryptophan in human brain studied by positron emission tomography.

The immediate precursor in the serotonin synthetic route, 5-hydroxytryptophan (5-HTP), labeled with 11C in the beta position, has become available for studies using positron emission tomography (PET) to examine serotonin formation in human brain. Normalized uptake and intracerebral utilization of tracer amounts of [beta-11C]5-HTP were studied twice in six healthy male volunteers, three of them before and after pharmacological pretreatments. The kinetic model defines regional utilization as the relative regional radioactivity accumulation rate. Repeat studies showed good reproducibility. Pretreatments with benserazide, p-chlorophenylalanine (PCPA), and unlabeled 5-HTP all significantly increased uptake of [beta-11C]5-HTP. The utilization rates in both striatal and frontal cortex were higher than those in the surrounding brain, indicating that PET studies using [beta-11C]5-HTP as a ligand quantitate selective processes in the utilization of 5-HTP. We tentatively interpret uptake and utilization as a measure of brain serotonin turnover, the selectivity of which was shown by pharmacological interventions in vivo.

Low brain uptake of L-[11C]5-hydroxytryptophan in major depression: a positron emission tomography study on patients and healthy volunteers.

The precursor of serotonin, L-5-hydroxytryptophan (L-5-HTP), was radiolabelled with 11C in the beta-position, yielding [beta-11C]serotonin after decarboxylation, allowing positron emission tomography studies of L-5-HTP uptake across the blood-brain barrier. We studied 8 healthy volunteers and 6 patients with histories of DSM-III major depression, 2 with repeated examinations after clinically successful treatment. We report a significantly lower uptake of [11C]5-HTP across the blood-brain barrier in depressed patients, irrespective of phase of illness. The findings emphasize that serotonin is involved in depressive pathophysiology and support earlier suggestions that the transport of 5-HTP across the blood-brain barrier is compromised in major depression.

Brain kinetics of L-[beta-11C]dopa in humans studied by positron emission tomography.

The in vivo dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) labelled with 11C in the beta position has been used for positron emission tomography studies of L-DOPA utilization in the brain. The brain uptake and kinetics of L-[11C]DOPA-derived radioactivity were studied in healthy male volunteers, and the specific utilization, i.e. decarboxylation rate of L-[11C]DOPA in different brain areas, was quantified using a brain region devoid of specific L-[11C]DOPA utilization as reference. Total uptake of L-[11C]DOPA-derived radioactivity measured in the brain varied two- to three-fold between subjects, with highest radioactivity in the striatal region. Specific utilization of L-[11C]DOPA radioactivity in the striatal region and in the prefrontal cortex varied twofold between subjects. No specific utilization was observed in other regions of the brain. The uptake of radioactivity in the brain increased dose-dependently with the simultaneous administration of unlabelled L-DOPA up to 10 mg. On the other hand, a decrease in brain radioactivity uptake was measured after pretreatment with 1 mg/kg oral L-DOPA, indicating competition for transport across the blood-brain barrier. Benserazide 0.5 mg/kg orally increased somewhat the radioactivity uptake to the brain. None of these pharmacological perturbations demonstrated any clearcut effect on specific utilization of L-[11C]DOPA. Thus, 11C-labelled L-DOPA is introduced as an alternative to the well-established L-6-[18F]fluoro-DOPA methodology in clinical studies on brain L-DOPA uptake and dopamine synthesis.

Failure of successful intrasplenic transplantation of islets from lean mice to cure obese-hyperglycaemic mice, despite islet growth.

Implantation of allogeneic pancreatic islets encapsulated in Millipore diffusion chambers has been reported to normalize the obese-hyperglycaemic syndrome in mice. In the present study, both young and adult ob/ob mice remained hyperglycaemic and gained weight after intrasplenic implantation of 500 isogeneic islets isolated from lean mice. Such islets normalized the elevated blood-glucose of alloxan-diabetic lean mice. Morphometric analysis of the intrasplenically implanted islets showed that the mean islet volume in the ob/ob mice was five times larger than that of the lean, non-diabetic mice. Immunocytochemical staining of the spleens showed an increased proportion of B-cells in the enlarged, intrasplenic islets in the ob/ob mice. Moreover, autoradiographical examination of these islets demonstrated the presence of several labelled cells. These results suggest that the growth of the implanted "lean" islets is due to extrapancreatic factors which stimulate islet cell replication in the obese-hyperglycaemic mouse.