Dopamine receptors in the rat brain

Abstract

Dopamine receptors belong to a large superfamily of G protein-coupled receptors and consist of the D1, D2, D3, D4, and D5 receptors. The D2, D3, and D4 receptors belong to the D2 receptor family which is characterized by having a large third cytoplasmic loop and a short C-terminus projecting into the cytosol, and by inhibiting the enzyme adenylyl cyclase. The facts that the D3 receptor displays high affinity for certain neuroleptics and is preferentially distributed to limbic parts of the basal ganglia have lead to the suggestion that D3 receptors are involved in schizophrenia and other psychiatric disorders.

The aims of the present study were to characterize D3 receptor binding and to investigate the modulating effects of various compounds and treatments on D2 and D3 receptors in the rat brain. D3 receptors were present in the islands of Calleja, islands of Calleja major, accumbens nucleus, caudate-putamen, and cerebellar lobule X. The Bmax values for the D3 receptor agonists [3H]7-OH-DPAT and [3H]PD 128907 were 100-400 fmol/mg protein in the islands of Calleja, and 300-400 fmol/mg protein in the accumbens nucleus (core and shell) and caudate-putamen subregions 1-4. Using membrane preparations, the Bmax values of [3H]7-OH-DPAT were 50-125 and 250-600 fmol/mg in the subcortical limbic area and caudate-putamen, respectively. D3 receptors displayed a high affinity for agonists such as NPA, 7-OH-DPAT, quinpirole, PD 128907, and dopamine and a low affinity for antagonists such as clozapine, raclopride, remoxipride, and GR 218231x.

Dopamine D2 and D3 receptors were modulated by several compounds and treatments. GTP, N- ethylmaleimide, and Na+ decreased and Mg2+ increased [3H]7-oH-DPAT binding, indicating that D3 receptors are G protein-coupled. Neurotensin increased [3H]7-oH-DPAT binding also in the presence of N-ethylmaleimide, suggesting that neurotensin modulates D3 receptor binding through a G protein- independent mechanism. The adenosine A2a agonist CGS 21680 increased [3H]NPA and [3H]PD 128907 binding in certain regions of the basal ganglia, indicating that stimulation of adenosine A receptors in vivo affect the binding characteristics of both D2 and D3 receptors in the basal ganglia. Long-term exposure of 80 ppm toluene lead to persistent increases in the affinity of D2 receptor agonist binding in caudate-putamen, whereas no persistent changes in the affinity of D3 receptor agonist binding were observed. Perinatal asphyxia reduced D2 receptor agonist binding, and increased D3 receptor agonist binding in certain regions. Aging apparently increased the number and decreased the affinity of D3 receptors in the caudate-putamen.

In conclusion, this study shows that the D3 receptor is present in high concentrations in certain regions of the basal ganglia, is G protein-coupled, and that D2 and D3 receptor binding can be modulated by adenosine A2a agonists, neurotensin, toluene exposure, and perinatal asphyxia.