Effect of reserpine-induced depletion of synaptic dopamine on [11C]Raclopride binding to D2-dopamine receptors in the monkey brain

Abstract

Positron emission tomography was used to examine the in vivo binding of [11C]raclopride to D2-dopamine (DA) receptors in the striatum of two Cynomolgus monkeys after a single dose of reserpine (1 mg/kg, i.v.). A Scatchard procedure was repeated five times to follow D2 receptor density and apparent affinity for 7 weeks after reserpine. Reserpine-induced depletion of DA lead to a marked increase in [11C]raclopride binding, which was still detectable 20 days after treatment. Scatchard analyses indicated that the measured increase in [11C]raclopride binding reflected an increase in receptor affinity but no evident change in receptor density (Bmax). Thus, the increase in [11C]raclopride binding after reserpine should correspond to a reduced competition with endogenous DA for binding to D2 receptors. The results were used to estimate the DA-induced D2 occupancy to be about 40% at physiological conditions.

The Competition Between Endogenous Dopamine and Radioligands for Specific Binding to Dopamine Receptors

“…However, the partial dopamine depletion increased the availability of D 2 antagonist binding sites by less than 20%, even in the schizophrenic subjects. In contrast, the present study and earlier results in experimental animals3,19,24 indicate basal occupancy of antagonist bindings sites of about 40%. Since complete dopamine depletions are not obtained in human PET studies, differences in p B could be attributed to differential lability of the extacellular dopamine in addition to differences in basal occupancy.…”

Positron Emission Tomography Imaging Demonstrates Correlation between Behavioral Recovery and Correction of Dopamine Neurotransmission after Gene Therapy

“…Our results are in agreement with previous reports conducted in reserpine-treated animals repeatedly administered with cocaine, in which alterations of the in vivo binding for both D 1 and D 2 receptors were attributable to apparent modifications of the affinity and not the number of binding sites (Tsukada et al, 1996;Ginovart et al, 1997). An acute challenge with amphetamine, conversely, appears to result in a different type of response that might be mediated by changes in receptors available for ligand binding (Sun et al, 2003;Chefer et al, 2008).…”

In Vivo Evidence for Dopamine-Mediated Internalization of D2-Receptors after Amphetamine: Differential Findings with [3H]Raclopride versus [3H]Spiperone

“…First, not all radioligands show this effect. Although benzamide radioligands (such as raclopride, IBZM, fallypride, clebopride) are always affected by endogenous DA in a manner consistent with the model (Innis et al, 1992;Volkow et al, 1994;Laruelle et al, 1995;Ginovart et al, 1997;Hartvig et al, 1997;Mach et al, 1997;Mukherjee et al, 1997), in vivo and ex vivo binding of butyrophenone compounds (such as spiperone, NMSP, pimozide) to D 2 -receptors show either no change or changes in the direction opposite that expected (Niehoff et al, 1979;Saelens et al, 1980;Bischoff et al, 1991;Onoe et al, 1994;Kobayashi et al, 1995). Second, the amphetamineinduced changes in […”