Abstract
Competition with endogenous dopamine (DA) is usually invoked to explain changes in [11C]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 [3H]raclopride binding observed in the rat striatum after an amphetamine challenge reflects true competition with endogenous DA or agonist-mediated internalization of D2-receptors. We found that the amphetamine-induced decrease in [3H]raclopride binding is caused by a decrease in D2-receptor density (Bmax) with no change in affinity (Kd). In contrast, in the same tissue, neither the Bmax nor theKd were affected when measured with [3H]spiperone. Challenge with amphetamine not only decreased the number of D2-receptors but also eliminated the proportion (22%) of receptors usually in the high-affinity state. The addition of Gpp(NH)p had no effect onBmax, 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 [3H]raclopride and [3H]spiperone; however, in the case of [3H]spiperone, this was accompanied by a compensatory increase in binding in the intracellular compartment, whereas no increase was seen with [3H]raclopride. These data suggest that amphetamine releases dopamine, which binds to the high-affinity state of the D2-receptor, leading to its sequestration in some intracellular compartment; in this compartment, sequestered receptors are inaccessible to [3H]raclopride binding but can still be bound by [3H]spiperone.
Footnotes
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This study was supported by a grant from the Canadian Institutes of Health Research.
- Abbreviations:
- PET
- positron emission tomography
- SPECT
- single photon emission computed tomography
- DA
- dopamine
- IBZM
- iodobenzamide
- NMSP
- N-methyl-spiperone
- GPP(NH)p
- 5′-guanylylimidodiphosphate
- Received July 11, 2002.
- Accepted November 6, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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