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

Abstract

Competition with endogenous dopamine (DA) is usually invoked to explain changes in [11 C]raclopride binding observed after amphetamine administration in animals and humans. This account has recently been questioned because a number of inconsistencies have been reported that contradict it. In the present study, we investigated whether the decrease in [3 H]raclopride binding observed in the rat striatum after an amphetamine challenge reflects true competition with endogenous DA or agonist-mediated internalization of D 2 -receptors. We found that the amphetamine-induced decrease in The addition of Gpp(NH)p had no effect on B max , suggesting that these receptors were not just noncompetitively bound with dopamine at the cell-surface. Subcellular fractionation studies showed that amphetamine treatment led to a decrease in radioligand binding in the cell-surface fraction for both In vivo imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have been applied to assess the endogenous levels of dopamine (DA) in both basic and clinical investigations. These techniques have been used to show that behavioral tasks, such as playing video games or writing, induce an increased release of striatal DA (Koepp et al., 1998;de la Fuente-Fernandez et al., 2001) and that patients with schizophrenia show an abnormally high release of DA when challenged with amphetamine (Laruelle et al., 1996;Breier et al., 1997). Although these techniques are being extensively used, PET and SPECT do not provide a direct measurement of endogenous DA levels. Changes in endogenous DA levels are inferred from changes in the binding of (Innis et al., 1992;Volkow et al., 1994;Laruelle et al., 1995;Smith et al., 1997), whereas the opposite effect is observed with drugs that decrease synaptic DA, such as reserpine and ␣-methyl-paratyrosine (Ginovart et al., 1997;Laruelle et al., 1997a

Nicotine-Induced Dopamine Release in Primates Measured with [11C]Raclopride PET

“…In interpreting this effect, it is also important to note that the competition of DA released through nicotinic activation with [ 11 C]raclopride may not be the only mechanism involved. For example, D2 receptor internalization has been proposed as a possible mechanism for the prolonged displacement of [ 11 C]raclopride after amphetamine administration (Laruelle, 2000) and a recent study has identified this as the primary mechanism in rats (Sun et al, 2003). It is therefore possible that this mechanism contributes to some extent to the reduction of BP observed in this study.…”

SPECT imaging of D2 dopamine receptors and endogenous dopamine release in mice

“…The SPECT measurement is performed 2 h after amphetamine administration at that moment the effect of the amphetamine administration may already be reduced. Competitive inhibition of radioligand binding is the most commonly used postulate to explain reductions in D2R binding after amphetamine administration, but other mechanisms such as dopamine D2R internalization or changes in receptor affinity could attribute as well [12,13]. To assess the ability to detect amphetamine-induced dopamine release in mice, all mice received amphetamine approximately 1 week after the baseline [ 123 I]IBZM SPECT study.…”

Neural Cell Adhesion Molecule Modulates Dopaminergic Signaling and Behavior by Regulating Dopamine D2Receptor Internalization

“…In response to the stimulation of dopamine, D 2 Rs undergo internalization in both cultured cells and brain tissue (Itokawa et al, 1996;Sun et al, 2003). To analyze whether NCAM plays a role in D 2 R internalization, we first determined the surface expression of D 2 Rs in dopamine-stimulated HEK293-D 2 R cells by a cell surface biotinylation approach.…”