Increased dopamine transmission in schizophrenia: relationship to illness phases.

This study images dopamine release in response to a neurochemically specific challenge with the psychostimulant drug methylphenidate. Changes in synaptic dopamine induced by methylphenidate were evaluated with positron emission tomography and [11C]raclopride, a D2 receptor radioligand that is sensitive to endogenous dopamine. Methylphenidate significantly decreased striatal [11C]raclopride binding. The decrease was variable and was negatively correlated with age. Mood and anxiety at baseline, were also correlated with methylphenidate-induced DA changes. This strategy provides a tool to investigate the responsiveness of the dopamine system in the normal and diseased human brain and to investigate the neurochemical correlates of behavior.

Imaging endogenous dopamine competition with [11C]raclopride in the human brain

Bilatera decreases in striatal 11C-raclopride binding were observed in adult female baboons with high resolution PET following administration of drugs that act centrally on dopaminergic neurons. At baseline and following administration of d-amphetamine (a dopamine-releasing drug), GBR-12909 (a potent dopamine reuptake inhibitor), or tetrabenazine (a biogenic amine depleting drug) PET scans of 11C-raclopride binding were obtained in a CTI 931 positron tomograph. In all studies, the ratio of the distribution volumes for the striatum to the cerebellum for 11C-raclopride binding decreased significantly by an average of 16.2% for d-amphetamine, 22.1% for GBR-12909, and 28.3% for tetrabenazine while there were no significant changes observed in the cerebellum or in the rate of systemic metabolism of the radiotracer. These decreases exceed the test/retest variability of striatal 11C-raclopride binding measured in the same animals under identical experimental conditions (Dewey et al., 1992b). Together these studies demonstrate that PET measurements of striatal 11C-raclopride binding can be used to indirectly and non-invasively monitor changes in synaptic dopamine concentrations that result from a variety of neurophysiologic mechanisms. © 1993 Wiley-Liss, Inc.

Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels.

Neurotransmitter receptors may be involved in a number of neuropsychiatric disease states. The ligand 3-N-[11C]methylspiperone, which preferentially binds to dopamine receptors in vivo, was used to image the receptors by positron emission tomography scanning in baboons and in humans. This technique holds promise for noninvasive clinical studies of dopamine receptors in humans.

Imaging dopamine receptors in the human brain by positron tomography

Isoflurane anesthesia enhances the inhibitory effects of cocaine and GBR12909 on dopamine transporter: PET studies in combination with microdialysis in the monkey brain

The in vivo binding of [3 H]N-methylspiperone (NMSP) and [3 H]raclopride was compared in mice treated with reserpine (5 mg/kg, 24 hr prior to the tracer injection). With both radioligands, selective accumulation of radioactivity in the striatum following intravenous injection was observed, whereas a relatively low accumulation and a rapid decline in radioactivity in the cerebellum was seen. Reserpine significantly decreased [3 H]NMSP binding in vivo, however it increased [3 H]raclopride binding. By compartment model analysis, it was found that the decrease in [3 H]NMSP binding was primarily due to the decrease in the association rate (K3) and the increase in [3 H]raclopride was due to the decrease in the dissociation rate (K4) in vivo. As both Kd and Bmax of dopamine D2 receptors have been reported to be unaltered by reserpine, these results suggested that some unknown factors except Kd and Bmax which influence on in vivo binding of receptors might be changed by reserpine. These results revealed that it is of importance to measure kinetics of ligand-receptor binding in vivo rather than static analysis. These two different types of radioligands can be combined to reveal functional roles of dopamine receptor in vivo, especially in the study of the human brain with positron emission tomography (PET).

Itoh T

Papers

Difference in in vivo receptor binding between [3 H]N-methylspiperone and [3 H]raclopride in reserpine-treated mouse brain

Effect of L-dopa and reserpine on in vivo binding of (3H)-SCH 23390 and (3H)-N-methylspiperone.