Visualisation of the cortical dopamine D3 receptors in alcoholics and controls with human whole-hemisphere autoradiography

Abstract

The dopaminergic system is critically involved in reward mechanisms mediating the reinforcing effects of ethanol (di Chiara and Imperato 1988). However, it has remained unclear if the alcohol-abuse-related dopaminergic deficit is specifically associated with a certain dopamine (DA) receptor subtype. One of these DA D1–D5 receptors (Hartman and Lanau 1997), the DA D3 receptor, is expressed primarily in the regions of the brain that are thought to influence cognitive, emotional and behavioural function (Sokoloff and Schwartz 1995). However, the role of the DA D3 receptor in alcoholics has been difficult to study because of its low abundance and the lack of selective ligands, and to our knowledge, there is only one published study on the issue (Tupala et al. 2003a). The aim of this study was to compare DA D3 receptors in the anterior cingulate and frontal and temporal cortices of nine type 1 alcoholics, eight type 2 alcoholics and ten healthy controls by using [H]PD 128907 as a radioligand in postmortem human whole-hemisphere autoradiography. The procedure has been previously described in detail (Tupala et al. 2003a). Type 1 alcoholics are characterised by late onset, social dependency and alternating binges and abstinence, whereas type 2 alcoholics are characterised by early onset with impulsive and antisocial behaviour (Cloninger 1995). [H]PD 128 907 [(+)-(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano-(4,3b)-1, 4-oxazin-9-ol] binds specifically with a high affinity to DA D3 receptors, with 18to 40-fold selectivity for DA D3 over D2 receptors (Pugsley et al. 1995), whereas the more commonly used older ligand [H]7-OH-DPAT has only 7to 24fold selectivity using different assay conditions (Gonzalez and Sibley 1995; Pugsley et al. 1995). In addition, because we have previously shown striatal DA transporter (DAT) binding to correlate between the mesolimbic nucleus accumbens (NAC) and dorsal striatum (caudate and putamen) and a similar phenomenon has been shown in one singlephoton emission tomography (SPET) study in type 1 alcoholics, but not in controls (Repo et al. 1999; Tupala et al. 2001), we also evaluated the correlations of [H]PD 128707 binding between the cortical and subcortical areas by comparing the present results with our earlier studies on the NAC and substantia nigra (SN) to test whether the relative individual levels of these receptors are maintained in different brain areas in these three groups. In addition, we compared the present results with our earlier findings on cortical DA D2 receptors with [ I]epidepride in these same subjects (Tupala et al. 2004). Our results show that, in spite of the very low densities, it is possible to visualise DA D3 receptors in cortical areas of human whole-hemisphere cryosections. The DA D3 receptors were at the same level in all groups (1.75–2.33± 0.42–0.81 fmol/mg, mean±SD) and no statistically significant differences were found. In addition, the calculated effect sizes (Cohen 1988) were also quite low, thus supporting the results. There was some tendency towards posE. Tupala (*) Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Kuopio, 70240 Kuopio, Finland e-mail: erkki.tupala@niuva.fi Tel.: +358-44-5597317 Fax: +358-17-203494