Effect of amphetamine-induced dopamine release on radiotracer binding to D1 and D2 receptors in rat brain striatal slices

Abstract

The in vivo binding of positron emission tomography (PET) and single photon emission computer tomography (SPECT) radiotracers to dopamine D2 receptors in the striatum can be influenced by competition with endogenous dopamine. The present study was undertaken to determine if a similar inhibition of radiotracer binding to dopamine receptors could be observed following pharmacologically-evoked dopamine release in rat brain striatal slices. Striatal slices were incubated in a large volume of oxygenated Krebs saline and exposed to amphetamine or methamphetamine to evoke dopamine release within the slice. Amphetamine and methamphetamine, at concentrations up to 30 microM, reduced [3H]raclopride binding in the slices by 77% and 86%, respectively, with 50% inhibition at 1.6 microM amphetamine or 3.0 microM methamphetamine. Neither drug produced a significant effect on binding of [3H]SCH 23390 in the slices. This suggests that dopamine was able to interfere with radiotracer binding to D2 but not D1 receptors. The dopamine uptake blockers, cocaine and methylphenidate, had relatively little effect by themselves on [3H]raclopride binding but, by inhibiting amphetamine-induced dopamine release, significantly reduced inhibition of [3H]raclopride binding by a low (3 microM) amphetamine concentration. At a higher (30 microM) amphetamine concentration the inhibition of [3H]raclopride binding was not antagonized by uptake blockers and data obtained from homogenate binding experiments indicated a direct displacement of [3H]raclopride binding by amphetamine at this concentration. In conclusion the data obtained in the present study demonstrate that the effects of amphetamine on striatal radiotracer accumulation observed in PET and SPECT can also be observed in brain slices in vitro and, at least at low amphetamine concentrations, are mediated by competition with released dopamine.

Do Preclinical Findings of Methamphetamine-Induced Motor Abnormalities Translate to an Observable Clinical Phenotype?

“…As noted above, Gifford et al (2000) found that MA-induced striatal dopamine release interfered with D2 receptor tracer binding. Doudet and Holden (2003) also reported that MA competed for the same D2 receptors as the dopamine antagonist, raclopride.…”

“…For example, Gifford et al (2000) found that MA-induced striatal dopamine release interfered with D2 but not D1 receptor tracer binding. It has been argued that this effect may be due to the dramatic decrease in sensitivity of the D1 receptor to dopamine following MA exposure rather than competition for receptor binding sites Schoffelmeer et al (1994).…”

“…MA has been shown to influence the dopamine regulatory systems in the basal ganglia both presynaptically (Gifford et al, 2000) and postsynaptically (Cadet et al, 1998), and can compromise both excitatory (via a D2 receptor mechanism) and inhibitory (via a D1 receptor mechanism) functions (Toyoshi et al, 1996;Hanson et al, 2002). Contemporary models of basal ganglia function predict that dysfunctions within the nigrostriatal or striatopallidal circuits produce not only a failure to facilitate desired movements, but also failure to inhibit unwanted movements (Mink, 2003).…”

Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

“…These experiments hence suggest that, in contrast to D 2 receptors, the occupancy of D 1 receptors by dopamine under basal conditions may be relatively low. Previous studies examining the sensitivity of D 1 radiotracers to endogenous dopamine have been conducted using either SCH 23390 or NNC 756 and have given results which also indicate an insensitivity of D 1 radiotracer binding to synaptic dopamine (Inoue et al 1991;Thibaut et al 1996;Abi-Dargham et al 1999;Gifford et al 2000). For both the [ 3 H]raclopride experiments and the [ 3 H]A69024 experiments the animals were sacrificed at a 30-min time point after radiotracer administration.…”

“…For non-benzazepine compounds the only D 1 radiotracer which has been evaluated so far is [ 11 C]A69024, which was found to be effective at labeling D 1 receptors in vivo despite a relatively low affinity for the receptor (Kassiou et al 1995). With regard to the effect of endogenous dopamine on the in vivo binding of D 1 radiotracers, the few studies performed to date have been conducted using benzazepine radiotracers such as SCH 23390 and have indicated that the binding of these radiotracers appears to be relatively resistant to pharmacologically induced changes in dopamine levels (Inoue et al 1991;Thibaut et al 1996;Abi-Dargham et al 1999;Gatley et al 2000;Gifford et al 2000). However, by analogy with the high-affinity D 2 radiotracers, it may be expected that the susceptibility of these high-affinity benzazepine derivatives to competition with dopamine will be limited as a result of their non-reversible and flow-dependent binding kinetics.…”