Abstract
The dopamine D1, D2, D3 receptors, vesicular monoamine transporter type-2 (VMAT2), and dopamine transporter (DAT) densities were measured in 11 aged human brains (aged 77–107.8, mean: 91 years) by quantitative autoradiography. The density of D1 receptors, VMAT2, and DAT was measured using [3H]SCH23390, [3H]dihydrotetrabenazine, and [3H]WIN35428, respectively. The density of D2 and D3 receptors was calculated using the D3-preferring radioligand, [3H]WC-10 and the D2-preferring radioligand [3H]raclopride using a mathematical model developed previously by our group. Dopamine D1, D2, and D3 receptors are extensively distributed throughout striatum; the highest density of D3 receptors occurred in the nucleus accumbens (NAc). The density of the DAT is 10–20-fold lower than that of VMAT2 in striatal regions. Dopamine D3 receptor density exceeded D2 receptor densities in extrastriatal regions, and thalamus contained a high level of D3 receptors with negligible D2 receptors. The density of dopamine D1 linearly correlated with D3 receptor density in the thalamus. The density of the DAT was negligible in the extrastriatal regions whereas the VMAT2 was expressed in moderate density. D3 receptor and VMAT2 densities were in similar level between the aged human and aged rhesus brain samples, whereas aged human brain samples had lower range of densities of D1 and D2 receptors and DAT compared with the aged rhesus monkey brain. The differential density of D3 and D2 receptors in human brain will be useful in the interpretation of PET imaging studies in human subjects with existing radiotracers, and assist in the validation of newer PET radiotracers having a higher selectivity for dopamine D2 or D3 receptors.
Highlights
The dopaminergic system is involved in neurological disorders such as Parkinson disease, drug addiction and schizophrenia [1,2,3,4]
By using [3H]WC-10 and a D2/D3 ligand [3H]raclopride, we have developed a quantitative autoradiography assay for measuring the absolute densities of dopamine D2 and D3 receptors in the striatal regions of rat and rhesus monkey brain [18]
The binding densities of dopamine D1 receptor, dopamine transporter (DAT) and vesicular monoamine transporter type-2 (VMAT2) were determined by quantitative autoradiography using 1.44 nM [3H]SCH23390, 2.19 nM [3H]WIN355428 and 4.53nM [3H]DTBZ, respectively
Summary
The dopaminergic system is involved in neurological disorders such as Parkinson disease, drug addiction and schizophrenia [1,2,3,4]. Dopamine receptors have been classified into two subtypes: D1like and D2-like receptors. Stimulation of D1-like (D1 and D5) receptors activates adenylate cyclase and increases cAMP (cyclic adenosine monophosphate) production. Stimulation of D2-like (D2, D3 and D4) receptors inhibits adenylate cyclase activity, increases arachadonic acid release and phosphatidylinositol hydrolysis [5,6]. The dopamine transporter (DAT) is a presynaptic membrane protein which is responsible for the reuptake of dopamine into dopaminergic nerve terminals. The vesicular monoamine transporter type-2 (VMAT2) is a vesicular membrane protein that transport monoamines from the cytosol into synaptic vesicles [7]. Both have been used as dopamine presynaptic markers for nigrostriatal neuronal integrity
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