Amphetamine‐sensitized animals show a marked increase in dopamine D₂ high receptors occupied by endogenous dopamine, even in the absence of acute challenges

Abstract

While a range of dopamine D(2)-related behaviors are exaggerated in amphetamine-sensitized animals, studies of the dopamine D(2) receptor have reported either no change or a decrease in dopamine D(2) receptor density--especially when measured using radioraclopride. We hypothesized that a decrease in D(2) receptors may actually be "apparent" and that these receptors may still be present, but are noncompetitively "occupied" by endogenous dopamine. Animals sensitized to amphetamine (and their saline controls) were examined 4 weeks after their last injection. We first measured the [(3)H]raclopride binding in vivo, and observed that sensitized animals showed a 29% lower level of raclopride binding in vivo, suggesting an apparently lower level of dopamine D(2) receptors. To assess the reason for this we examined the density of receptors (using Scatchard analysis in vitro) measured by [(3)H]raclopride in the presence and absence of guanilylimidodiphosphate. This guanine nucleotide converts the dopamine-bound high-affinity state of D(2) receptors into low-affinity states, thereby making measurable the absolute density of the sites. As previously reported, the amphetamine-sensitized animals showed a 31% lower number of D(2) receptors in conventional binding (B(max) 15.6 vs. 22.7 pmol/g). However, with the addition of guanilylimidodiphosphate there was an equalization of both groups (B(max) 25.9 vs. 25.6 pmol/g), revealing an additional 10.3 pmol/g in the sensitized animals, but only 2.9 pmol/g in saline controls. There were no changes in the dissociation constant of [(3)H]raclopride for the receptors. The nearly four-fold increase of dopamine D(2) receptors in the high-affinity state occupied by dopamine may explain why amphetamine-sensitized animals show almost an order of magnitude greater response to dopamine-releasing challenges or dopamine agonists, even though the absolute receptor number is unchanged and the "apparent" receptor number is decreased.

The Dopamine D2 Receptors in High-Affinity State and D3 Receptors in Schizophrenia: A Clinical [11C]-(+)-PHNO PET Study

“…The in vitro studies include competition assays between antagonist radiotracers and agonist ligands in the presence of non-hydrolysable GTP analogs (GppNHp), the latter converting the receptor from its high-affinity state to its low-affinity state (De Lean et al, 1980;Seeman et al, 2002Seeman et al, , 2005b. This differs from the approach in humans which involves a direct study of the high-affinity states with an agonist radioligand.…”

Dopamine D2High receptors measured ex vivo are elevated in amphetamine‐sensitized animals

“…Therefore, considering the successful in vivo detection of high-and low-affinity dopamine D2 receptors by Ross and Jackson (1989) High receptors in vitro (Seeman et al, 2002(Seeman et al, , 2005a, the present coinjection method was used to determine whether such an elevation in D2…”

“…High receptors are consistently between 10 and 20% of the D2 population (Seeman et al, 2005a(Seeman et al, ,b, 2006 High receptors, these receptors should become increased in vivo in the amphetamine-sensitized rat, as occurs in vitro (Seeman et al, 2002). Hence, a series of amphetamine-sensitized rats was prepared, and the data in Figure 4 illustrate that 10 lg/kg NPA displaced 2.36-fold more [ In order to compare the amphetamine-induced 2.36-fold increase in D2…”

Cocaine self-administration produces a persistent increase in dopamine D2High receptors

“…Although it has been reported that experimenter-administered amphetamine increases the number of D2 High receptors (Seeman et al, 2002, no studies have examined the effects of self-administered cocaine on D2 High receptors, which is more directly relevant to human imaging studies. Therefore, in the present study we asked whether cocaine self-administration experience increases the proportion of D2 High receptors in the dorsal striatum, which could account for the well-documented behavioral hypersensitivity to D2 agonists seen in animals with a history of exposure to cocaine.…”