Native human neocortex release-regulating dopamine D2 type autoreceptors are dopamine D-2 subtype

Dopamine (DA) autoreceptors expressed at DA nerve terminals regulate DA rel ease. Considerable evidence has indicated that, in rodents, these autorecep tors belong to the D2 type of the DA receptor family, which, in turn, compr ises the D-2, D-3 and D-4 subtypes. We investigated here, for the first tim e, the subclassification of native human DA autoreceptors by studying the r elease of [H-3]DA evoked by electrical stimulation in fresh human neocortic al slices. The results have been compared with those obtained in three anim al systems: rat neocortical and striatal slices and rat mesencephalic neuro nal cultures. In human neocortical slices, the D-2/D-3 receptor agonist qui npirole (1 nM-10 mu M) inhibited tritium release with a calculated EC50 of 17 nM and a maximal inhibition of approximate to 75% reached at 1 mu M. In the presence of the D-2/D-3 receptor antagonist (-)-sulpiride (0.1 and 1 mu M), the concentration-response curve of quinpirole was shifted to the righ t, and the apparent pA(2) mean value was 8.5 (8.14-8.77); on the other hand , the inhibitory effects of quinpirole were not affected by the D-3 recepto r-selective antagonist [7-N,N-dipropylamino-5,6,7,8-tetrahydro-naphtho(2,3b ) dihydro,2,3-furane] (S 14297) and the D-4 receptor-selective antagonist 3 -(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo [2,3-b]pyridine (L-74 5,870) (0.01-1 mu M in each case). Superimposable results have been obtaine d when the release was elicited from rat striatal slices or dopamine mesenc ephalic neurons in culture, whereas quantitative differences emerged in the case of rat cortical slices. It is concluded that in human brain, as well as in rat brain, the release of DA in the terminal region of midbrain dopam inergic neurons is regulated through autoreceptors of the D-2 subtype.