Antagonism of the effects of (+)-PD 128907 on midbrain dopamine neurones in rat brain slices by a selective D sub(2) receptor antagonist L-741,626

1 The ability of PD 128907 to activate dopamine receptors in the ventral tegmental area, substantia nigra pars compacta, and striatum was investigated by use of in vitro electrophysiological recording and fast cyclic voltammetry. The affinity of a novel D sub(2) selective antagonist L-741,626 for receptors activated by this agonist was measured to determine if its effects were mediated by D sub(2) or D sub(3) receptors. 2 The active (+) enantiomer of PD 128907 bound with high affinity and selectivity to rat D sub(3) dopamine receptors. The K sub(i) values for (+)-PD 128907 were 620 nM at D sub(2), 1 nM at D sub(3) and 720 nM at D sub(4) receptors. 3 (+)-PD 128907 inhibited cell firing in both the ventral tegmental area and substantia nigra pars compacta with EC sub(50) values of 33 nM (pEC sub(50)=7.48 plus or minus 0.10, n=10) and 38 nM (pEC sub(50)=7.42 plus or minus 0.15, n=5), respectively. No effects of (+)-PD 128907 (100 nM) were observed on glutamate or GABA-mediated synaptic potentials elicited by focal bipolar stimulation. 4 L-741,626 antagonized these effects of (+)-PD 128907 in a concentration-dependent and surmountable manner with an affinity, determined from Schild analysis, of 20 nM (pK sub(B)=7.71 plus or minus 0.14) in the ventral tegmental area and 11 nM (pK sub(B) = 7.95 plus or minus 0.18) in the substantia nigra pars compacta. 5 (+)-PD128907 also inhibited dopamine release in the caudate-putamen with an EC sub(50) of 66 nM (n=5). The affinity of L-741,626 for these nerve terminal autoreceptors (pK sub(B)=7.71 plus or minus 0.06; =20 nM) was identical to that observed on midbrain dopamine neurones. 6 These data demonstrate that the D sub(3) receptor ligand (+)-PD 128907 is a potent agonist on rat midbrain dopamine neurones. However, its lack of regional selectivity, and the high affinity of the selective D sub(2) receptor antagonist L-741,626 for receptors activated by (+)-PD 128907, was more consistent with an action on D sub(2) autoreceptors rather than upon a D sub(3) dopamine receptor subtype.